bluuebunny/crossref_metadata_2025 huggingface dataset:
Photobiomodulation Does Not Influence Maturation and Leads to Mild Improvements in Functional Healing of Mouse Achilles Tendons
Authors: Locke Ryan C. , Lemmon Elisabeth A. , Dudzinski Ellen , Kopa Sarah C. , Wayne Julianna M. , Soulas Jaclyn M. , De Taboada Luis , Killian Megan L.
Published: August 2019

Tendon rupture can occur at any age and is commonly treated non-operatively, yet can result in persisting symptoms. Thus, a need exists to improve non-operative treatments of injured tendons. Photobiomodulation (PBM) therapy has shown promise in the clinic and is hypothesized to stimulate mitochondrial-related metabolism and improve healing. However, the effect of PBM therapy on mitochondrial function during tendon maturation and healing are unknown, and its effect on tendon structure and function remain unclear. In this study, near-infrared light (980:810nm blend, 2.5J/cm2) was applied at low (30mW/cm2) or high (300mW/cm2) irradiance to unilateral Achilles tendons of CD-1 mice during postnatal growth (maturation) as well as adult mice with bilateral Achilles tenotomy (healing). The chronic effect of PBM therapy on tendon structure and function was determined using histology and mechanics, and the acute effect of PBM therapy on mitochondrial-related gene expression was assessed. During maturation and healing, collagen alignment, cell number, and nuclear shape were unaffected by chronic PBM therapy. We found a sex-dependent effect of PBM therapy during healing on mechanical outcomes (e.g., increased stiffness and Young’s modulus for PBM-treated females, and increased strain at ultimate stress for PBM-treated males). Mitochondria-related gene expression was marginally influenced by PBM therapy for both maturation and healing studies. This study was the first to implement PBM therapy during both growth and healing of the murine tendon. PBM therapy resulted in marginal and sex-dependent effects on murine tendon.
Translational Regulation Promotes Oxidative Stress Resistance in the Human Fungal Pathogen Cryptococcus neoformans
Authors: Leipheimer Jay , Bloom Amanda L. M. , Campomizzi Christopher S. , Salei Yana , Panepinto John C.
Published: August 2019

Cryptococcus neoformans is one of the few environmental fungi that can survive within a mammalian host and cause disease. Although many of the factors responsible for establishing virulence have been recognized, how they are expressed in response to certain host derived cellular stresses is rarely addressed. Here we characterize the temporal translational response of C. neoformans to oxidative stress. We find that translation is largely inhibited through the phosphorylation of the critical initiation factor elF2α by a sole kinase. Preventing elF2α mediated translational suppression resulted in growth sensitivity to hydrogen peroxide (H2O2). Our work suggests that translational repression in response to H2O2 partly facilitates oxidative stress adaptation by accelerating the decay of abundant non-stress related transcripts while facilitating the proper expression of critical oxidative stress response factors. Carbon starvation, which seems to induce translational suppression that is independent elF2α, partly restored transcript decay and the expression of the critical oxidative stress response transcript Thioredoxin Reductase 1 (TRR1). Our results illustrate translational suppression as a key determinant of select mRNA decay, gene expression, and subsequent survival in response to oxidative stress.

Importance

Fungal survival in a mammalian host requires the coordinated expression and downregulation of a large cohort of genes in response to cellular stresses. Initial infection with C. neoformans occurs at the lungs, where it interacts with host macrophages. Surviving macrophage derived cellular stresses, such as the production of reactive oxygen and nitrogen species, is believed to promote dissemination into the central nervous system. Therefore, investigating how an oxidative stress resistant phenotype is brought about in C. neoformans furthers our understanding of not only fungal pathogenesis but also unveils mechanisms of stress induced gene reprogramming. We discovered that H2O2 derived oxidative stress resulted in severe translational suppression and that this suppression was necessary for the accelerated decay and expression of tested transcripts. Surprisingly, compounding oxidative stress with carbon starvation resulted in a decrease in peroxide mediated killing, revealing unexpected synergy between stress responses.
Quantifying free behavior in an open field using k-motif approach
Authors: Könings Marein , Blokpoel Mark , Kapusta Katarzyna , Claassen Tom , Buitelaar Jan K. , Glennon Jeffrey C. , Bielczyk Natalia Z.
Published: August 2019

Quantification and parametrization of movement in animal models is widely used in behavioral paradigms. In particular, free movement of an animal in controlled conditions (e.g., the open field paradigm) is used as a proxy for indices of baseline and drug-induced behavioural changes. However, the analysis of this is often time- and labour-intensive and existing algorithms do not always classify the behaviour correctly.

Here, we propose a new approach to quantify behaviour in an unconstrained environment: searching for frequent patterns (k-motifs) in the time series representing position of the subject over time. Validation of this method was performed using subchronic quinpirole-induced changes in open field experiment behaviors in rodents. Analysis of this data was performed using k-motifs as features to better classify subjects into experimental groups on the basis of behavior in the open field. Our classifier using k-motifs gives as high as 94% accuracy in classifying repetitive behaviour versus controls which is a substantial improvement compared to currently available methods including using standard feature definitions (depending on the choice of feature set and classification strategy, accuracy up to 88%). Furthermore, vizualization of the movement / time patterns is highly predictive of these behaviours. By using machine learning to create features in a data driven fashion, this can be applied to general behavioural analysis across experimental paradigms beyond the open field.
An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types
Authors: Chang Wai Hoong , Lai Alvina G.
Published: August 2019

The AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of cellular energy homeostasis. As a nexus for transducing metabolic signals, AMPK cooperates with other energy-sensing pathways to modulate cellular responses to metabolic stressors. With metabolic reprogramming being a hallmark of cancer, the utility of agents targeting AMPK has received continued scrutiny and results have demonstrated conflicting effects of AMPK activation in tumorigenesis. Harnessing multi-omics datasets from human tumors, we seek to evaluate the seemingly pleiotropic, tissue-specific dependencies of AMPK signaling dysregulation. We interrogated copy number variation and differential transcript expression of 92 AMPK pathway genes across 21 diverse cancers involving over 18,000 patients. Cox proportional hazards regression and receiver operating characteristic analyses were used to evaluate the prognostic significance of AMPK dysregulation on patient outcomes. A total of 24 and seven AMPK pathway genes were identified as having loss- or gain-of-function features. These genes exhibited tissue-type dependencies, where survival outcomes in glioma patients were most influenced by AMPK inactivation. Cox regression and log-rank tests revealed that the 24-AMPK-gene set could successfully stratify patients into high- and low-risk groups in glioma, sarcoma, breast and stomach cancers. The 24-AMPK-gene set could not only discriminate tumor from non-tumor samples, as confirmed by multidimensional scaling analyses, but is also independent of tumor, node and metastasis staging. AMPK inactivation is accompanied by the activation of multiple oncogenic pathways associated with cell adhesion, calcium signaling and extracellular matrix organization. Anomalous AMPK signaling converged on similar groups of transcriptional targets where a common set of transcription factors were identified to regulate these targets. We also demonstrated crosstalk between pro-catabolic AMPK signaling and two pro-anabolic pathways, mammalian target of rapamycin and peroxisome proliferator-activated receptors, where they act synergistically to influence tumor progression significantly. Genetic and transcriptional aberrations in AMPK signaling have tissue-dependent pro- or anti-tumor impacts. Pan-cancer investigations on molecular changes of this pathway could uncover novel therapeutic targets and support risk stratification of patients in prospective trials.
The effects of terminal tagging on homomeric interactions of the sigma 1 receptor
Authors: Yano Hideaki , Liu Leanne , Naing Sett , Shi Lei
Published: August 2019

The sigma 1 receptor (σ1R) has been implicated in cancers, neurological disorders, and substance use disorders. Yet, its molecular and cellular functions have not been well-understood. Recent crystal structures of σ1R reveal a single N-terminal transmembrane segment and C-terminal ligand-binding domain, and a trimeric organization. Nevertheless, outstanding issues surrounding the functional or pharmacological relevance of σ1R oligomerization remain, such as the minimal protomeric unit and the differentially altered oligomerization states by different classes of ligands. Western blot (WB) assays have been widely used to investigate protein oligomerizations. However, the unique topology of σ1R renders several intertwined challenges in WB. Here we describe a WB protocol without temperature denaturization to study the ligand binding effects on the oligomerization state of σ1R. Using this approach, we observed unexpected ladder-like incremental migration pattern of σ1R, demonstrating preserved homomeric interactions in the detergent environment. We compared the migration patterns of intact σ1R construct and the C-terminally tagged σ1R constructs, and found similar trends in response to drug treatments. In contrast, N-terminally tagged σ1R constructs show opposite trends to that of the intact construct, suggesting distorted elicitation of the ligand binding effects on oligomerization. Together, our findings indicate that the N-terminus plays an important role in eliciting the impacts of bound ligands, whereas the C-terminus is amenable for modifications for biochemical studies.
Telomere-to-telomere assembly of a complete human X chromosome
Authors: Miga Karen H. , Koren Sergey , Rhie Arang , Vollger Mitchell R. , Gershman Ariel , Bzikadze Andrey , Brooks Shelise , Howe Edmund , Porubsky David , Logsdon Glennis A. , Schneider Valerie A. , Potapova Tamara , Wood Jonathan , Chow William , Armstrong Joel , Fredrickson Jeanne , Pak Evgenia , Tigyi Kristof , Kremitzki Milinn , Markovic Christopher , Maduro Valerie , Dutra Amalia , Bouffard Gerard G. , Chang Alexander M. , Hansen Nancy F. , Thibaud-Nissen Françoisen , Schmitt Anthony D. , Belton Jon-Matthew , Selvaraj Siddarth , Dennis Megan Y. , Soto Daniela C. , Sahasrabudhe Ruta , Kaya Gulhan , Quick Josh , Loman Nicholas J. , Holmes Nadine , Loose Matthew , Surti Urvashi , Risques Rosa ana , Graves Lindsay Tina A. , Fulton Robert , Hall Ira , Paten Benedict , Howe Kerstin , Timp Winston , Young Alice , Mullikin James C. , Pevzner Pavel A. , Gerton Jennifer L. , Sullivan Beth A. , Eichler Evan E. , Phillippy Adam M.
Published: August 2019

After nearly two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no one chromosome has been finished end to end, and hundreds of unresolved gaps persist 1,2. The remaining gaps include ribosomal rDNA arrays, large near-identical segmental duplications, and satellite DNA arrays. These regions harbor largely unexplored variation of unknown consequence, and their absence from the current reference genome can lead to experimental artifacts and hide true variants when re-sequencing additional human genomes. Here we present a de novo human genome assembly that surpasses the continuity of GRCh38 2, along with the first gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome 3, we reconstructed the ∼2.8 megabase centromeric satellite DNA array and closed all 29 remaining gaps in the current reference, including new sequence from the human pseudoautosomal regions and cancer-testis ampliconic gene families (CT-X and GAGE). This complete chromosome X, combined with the ultra-long nanopore data, also allowed us to map methylation patterns across complex tandem repeats and satellite arrays for the first time. These results demonstrate that finishing the human genome is now within reach and will enable ongoing efforts to complete the remaining human chromosomes.
A Hedgehog-FGF signaling axis patterns anterior mesoderm during gastrulation
Authors: Guzzetta Alexander , Koska Mervenaz , Rowton Megan , Kweon Junghun , Hidalgo Hunter , Eckhart Heather , Back Rebecca , Lozano Stephanie , Moon Anne M. , Basu Anindita , Bressan Michael , Pott Sebastian , Moskowitz Ivan P.
Published: August 2019

The application of single cell technologies to early development holds promise for resolving complex developmental phenotypes. Here we define a novel role for Hedgehog (Hh) signaling for the formation of anterior mesoderm lineages during gastrulation. Single-cell transcriptome analysis of Hh-deficient mesoderm revealed selective deficits in anterior mesoderm populations that later translate to physical defects to anterior embryonic structures including the first pharyngeal arch, heart, and anterior somites. We found that Hh-dependent anterior mesoderm defects were cell non-autonomous to Hh-signal reception. Transcriptional profiling of Hh-deficient mesoderm during gastrulation revealed disruptions to both transcriptional patterning of the mesoderm and a key FGF signaling pathway for mesoderm migration. FGF4 protein application was able to restore cellular migration during gastrulation that was decreased by Hh pathway antagonism. These findings implicate that primitive streak-mediated regulation of anterior mesoderm patterning is controlled by a multicomponent signaling hierarchy activated by Hh signaling and executed by FGF signal transduction.

SIGNIFICANCE STATEMENT

How signaling events during gastrulation pattern the mesoderm is a fascinating developmental process. Although Hedgehog signaling has been implicated in early mesoderm development, its mechanistic role has not been described. We applied single cell sequencing to describe mesodermal defects in Hedgehog pathway mutants—revealing selective defects in anterior mesoderm populations. Transcriptional profiling of gastrulating Hedgehog mutants indicated that several pathways essential for primitive streak function, including FGF, required Hh signaling. Blocking Hedgehog signaling abrogated cell migration during gastrulation, which could be mitigated by addition of FGF4 ligand. This work uncovers a novel Hedgehog to FGF signaling event and describes a unique mechanism by which signals from the node impact to anterior mesoderm formation through the modulation of primitive streak function.
Tandem Requirement for Full Renal D1R and D5R Activity
Authors: Rozyyev Selim , Crusan Annabelle P. , Tiu Andrew C. , Jurgens Julie A. , Quion Justin Michael B. , Asico Laureano D. , Felder Robin A. , Villar Van Anthony M.
Published: August 2019

The peripheral dopaminergic system promotes the maintenance of blood pressure homeostasis by engendering natriuresis, mainly through the renal D1R and D5R receptors. This effect is most apparent under conditions of moderate body sodium excess. Human and rodent renal proximal tubules express both receptors, which share common structural features and pharmacological profiles. Genetic ablation of either receptor in the kidney results in hypertension in mice. In this study, we demonstrated that in renal proximal tubules, these two receptors colocalized, co-immunoprecipitated, co-segregated in lipid rafts, and heterodimerized with one another, which was enhanced by treatment with the D1R/D5R agonist fenoldopam (1 μM, 30 min). Gene silencing via antisense oligonucleotides in renal proximal tubule cells abrogated cAMP production and sodium transport in response to fenoldopam. Our results highlight the cooperation and co-dependence of these two receptors through heterodimerization in renal proximal tubule cells.
Evidence for influenza B virus hemagglutinin adaptation to the human host: high cleavability, acid-stability and preference for cool temperature
Authors: Laporte Manon , Stevaert Annelies , Raeymaekers Valerie , Boogaerts Talitha , Nehlmeier Inga , Chiu Winston , Benkheil Mohammed , Vanaudenaerde Bart , Pöhlmann Stefan , Naesens Lieve
Published: August 2019

Influenza A virus (IAV) and influenza B virus (IBV) cause yearly epidemics with significant morbidity and mortality. When zoonotic IAVs enter the human population, the viral hemagglutinin (HA) requires adaptation to achieve sustained virus transmission. In contrast, IBV has been circulating in humans, its only host, for a long period of time. Whether this entailed adaptation of IBV HA to the human airways is unknown. To address this question, we compared seasonal IAV (A/H1N1 and A/H3N2) and IBV viruses (B/Victoria and B/Yamagata lineage) with regard to host-dependent activity of HA as the mediator of membrane fusion during viral entry. We first investigated proteolytic activation of HA, by covering all type II transmembrane serine protease (TTSP) and kallikrein enzymes, many of which proved present in human respiratory epithelium. Compared to IAV, the IBV HA0 precursor is cleaved by a broader panel of TTSPs and activated with much higher efficiency. Accordingly, knockdown of a single protease, TMPRSS2, was sufficient to abrogate spread of IAV but not IBV in human respiratory epithelial cells. Second, the HA fusion pH proved similar for IBV and human-adapted IAVs (one exception being HA of 1918 IAV). Third, IBV HA exhibited higher expression at 33°C, a temperature required for membrane fusion by B/Victoria HA. This indicates pronounced adaptation of IBV HA to the mildly acidic pH and cooler temperature of human upper airways. These distinct and intrinsic features of IBV HA are compatible with extensive host-adaptation during prolonged circulation of this respiratory virus in the human population.

Importance

Influenza epidemics are caused by influenza A (IAV) and influenza B (IBV) viruses. IBV causes substantial disease, however it is far less studied than IAV. While IAV originates from animal reservoirs, IBV circulates in humans only. Virus spread requires that the viral hemagglutinin (HA) is active and sufficiently stable in human airways. We here resolve how these mechanisms differ between IBV and IAV. Whereas human IAVs rely on one particular protease for HA activation, this is not the case for IBV. Superior activation of IBV by several proteases should enhance shedding of infectious particles. IBV HA exhibits acid-stability and a preference for 33°C, indicating pronounced adaptation to the human upper airways, where the pH is mildly acidic and a cooler temperature exists. These adaptive features are rationalized by the long existence of IBV in humans, and may have broader relevance for understanding the biology and evolution of respiratory viruses.
Cerebellar plasticity and associative memories are controlled by perineuronal nets
Authors: Carulli Daniela , Broersen Robin , de Winter Fred , Muir Elizabeth M. , Mešković Maja , de Waal Matthijs , de Vries Sharon , Boele Henk-Jan , Canto Cathrin B. , De Zeeuw Chris I. , Verhaagen Joost
Published: August 2019

Perineuronal nets (PNNs) are assemblies of extracellular matrix molecules, which surround the cell body and dendrites of many types of neuron and regulate neural plasticity. PNNs are prominently expressed around neurons of the deep cerebellar nuclei (DCN) but their role in adult cerebellar plasticity and behavior is far from clear. Here we show that PNNs in the DCN are diminished during eyeblink conditioning (EBC), a form of associative motor learning that depends on DCN plasticity. When memories are fully acquired, PNNs are restored. Enzymatic digestion of PNNs in the DCN improves EBC learning, but intact PNNs are necessary for memory retention. At the structural level, PNN removal induces significant synaptic rearrangementsin vivo, resulting in increased inhibition of DCN baseline activity in awake behaving mice. Together, these results demonstrate that PNNs are critical players in the regulation of cerebellar circuitry and function.
Plasmodium vivaxMalaria viewed through the lens of an eradicated European strain
Authors: Dorp Lucy van , Gelabert Pere , Rieux Adrien , Manuel Marc de , de-Dios Toni , Gopalakrishnan Shyam , Carøe Christian , Sandoval-Velasco Marcela , Fregel Rosa , Olalde Iñigo , Escosa Raül , Aranda Carles , Huijben Silvie , Mueller Ivo , Marquès-Bonet Tomàs , Balloux François , Gilbert M. Thomas P , Lalueza-Fox Carles
Published: August 2019

The protozoanPlasmodium vivaxis responsible for 42% of all cases of malaria outside Africa. The parasite is currently largely restricted to tropical and subtropical latitudes in Asia, Oceania and the Americas. Though, it was historically present in most of Europe before being finally eradicated during the second half of the 20th century. The lack of genomic information on the extinct European lineage has prevented a clear understanding of historical population structuring and past migrations ofP. vivax. We used medical microscope slides prepared in 1944 from malaria-affected patients from the Ebro Delta in Spain, one of the last footholds of malaria in Europe, to generate a genome of a EuropeanP. vivaxstrain. Population genetics and phylogenetic analyses placed this strain basal to a cluster including samples from the Americas. This genome allowed us to calibrate a genomic mutation rate forP. vivax, and to estimate the mean age of the last common ancestor between European and American strains to the 15th century. This date points to an introduction of the parasite during the European colonisation of the Americas. In addition, we found that some known variants for resistance to anti-malarial drugs, including Chloroquine and Sulfadoxine, were already present in this European strain, predating their use. Our results shed light on the evolution of an important human pathogen and illustrate the value of antique medical collections as a resource for retrieving genomic information on pathogens from the past.
Convolutional Neural Network Analysis of Social Novelty Preference using DeepLabCut
Authors: Worley Nicholas B. , Djerdjaj Anthony , Christianson John P.
Published: August 2019

The description and quantification of social behavior in laboratory rodents is central to basic and translational research. Conventional ethological approaches to social behavior are fraught with challenges including bias, significant human effort and temporal accuracy. Here we show proof of principle that machine learning can be applied to laboratory tests of social decision making. Rats underwent social novelty preference tests which were scored both by hand and again by a convolutional neural network generated in the DeepLabCut computer vision package of Mathis and colleagues. The CNN generated temporally (30Hz) and locally (<5pixels) accurate identification of rat nose, eye and ear positions which were then used to compute social interaction and topography heat maps. In sum, hand- and computer-scoring were strongly correlated, and each identified significant preferences to interact with novel conspecifics which sets the stage for applying DeepLabCut analysis to other types of social interaction in the future.
RASInternal Tandem Duplication Disrupts GAP-binding to Activate Oncogenic Signaling
Authors: Nelson Andrew C. , Turbyville Thomas , Dharmaiah Srisathiyanarayanan , Rigby Megan , Yang Rendong , Columbus John , Stephens Robert , Sciacca Drew , Onsongo Getiria , Sarver Anne , Subramanian Subbaya , Nissley Dwight V. , Simanshu Dhirendra K. , Lou Emil
Published: August 2019

Molecular testing of oncogenicRASmutations in colorectal cancer (CRC) have led to increased identification of mutations in patients with CRC.NRAS-mutated CRC has not been well characterized because it is less common (<6%) thanKRASmutations. Here, we report a novel 10 amino acid internal tandem duplication (ITD) inNRAS, which disrupts the switch II domain, in a patient with widely disseminated CRC. Hotspot next generation sequencing of a brain metastasis identified theNRASITD and aTP53missense mutation (p.P275F). Whole exome sequencing of the primary tumor and two metastatic lesions (lung and brain) confirmed that theNRASITD andTP53mutation were conserved between the primary tumor and both metastatic tumors, and identified an additional pathogenic mutation inCSMD1(a tumor suppressor gene). Structural biology and biochemical analyses demonstrated that theNRASITD prevented binding to GAP protein, leading to sustained RAS activation, increased interaction with RAF, and downstream MAPK activation. Additionally, we provide the first crystal structure of theRASITD. In conclusion, these studies indicate that theNRASITD was the probable primary driver mutation of this aggressive CRC. Identical or biologically similar ITDs inNRASandKRASmay be rare drivers of CRC and other aggressive malignancies.
The McdAB Carboxysome Positioning System is Widespread Among β-cyanobacteria
Authors: MacCready Joshua S. , Basalla Joseph L. , Vecchiarelli Anthony G.
Published: August 2019

Carboxysomes are protein-based organelles that are essential for allowing cyanobacteria to fix CO2. Previously we identified a two-component system, McdAB, responsible for equidistantly positioning carboxysomes in the model cyanobacterium Synechococcus elongatus PCC 7942. McdA, a ParA-type ATPase, non-specifically binds the nucleoid in the presence of ATP. McdB, a novel factor that directly binds carboxysomes, displaces McdA from the nucleoid. Removal of McdA from the nucleoid in the vicinity of carboxysomes by McdB causes a global break in McdA symmetry, and carboxysome motion occurs via a Brownian-ratchet based mechanism towards the highest concentration of McdA. Despite the importance for cyanobacteria to properly position their carboxysomes, whether the McdAB system is widespread among cyanobacteria remains an open question. Here, we used neighborhood analysis to show that the McdAB system is widespread among β-cyanobacteria and often clusters near carboxysome-related components. Moreover, we show that two distinct McdAB systems exist in β-cyanobacteria, with Type 2 systems being the most abundant (>98% of β-cyanobacteria) and Type 1 systems, like that of S. elongatus, possibly being acquired more recently. Surprisingly, our analysis suggests that the McdAB system is completely absent in α-cyanobacteria. Lastly, all McdB proteins we identified share the sequence signatures of a protein capable of undergoing Liquid-Liquid Phase Separation (LLPS). Indeed, we find that S. elongatus McdB undergoes LLPS in vitro, the first example of a ParA-type ATPase partner protein exhibiting this behavior. This is an intriguing finding given the recent demonstration of LLPS activity by β-carboxysome core components. Our results have broader implications for understanding carboxysome biogenesis and positioning across all β-cyanobacteria.

In Brief

We found that the McdAB carboxysome positioning system is widespread among β-cyanobacteria, absent in α-cyanobacteria, exists in two distinct forms, and that S. elongatus McdB undergoes liquid-liquid phase separation.
Query Combinators: Domain Specific Query Languages for Medical Research
Authors: Evans Clark C. , Simonov Kyrylo
Published: August 2019

A new way to conceptualize computations, Query Combinators, can be used to create a data processing environment shared among the entire medical research team. For a given research context, a domain specific query language can be created that represents data sources, analysis methods, and integrative domain knowlege. Research questions can then have an intuitive, high-level form that can be reasoned about and discussed.
Chromosomal Mcm2-7 distribution is the primary driver of the genome replication program in species from yeast to humans
Authors: Foss Eric J. , Sripathy Smitha , Gatbonton-Schwager Tonibelle , Kwak Hyunchang , Thiesen Adam H. , Lao Uyen , Bedalov Antonio
Published: August 2019

The spatio-temporal program of genome replication across eukaryotes is thought to be driven both by the uneven loading of pre-replication complexes (pre-RCs) across the genome at the onset of S-phase, and by differences in the timing of activation of these complexes during S-phase. To determine the degree to which distribution of pre-RC loading alone could account for chromosomal replication patterns, we mapped the binding sites of the Mcm2-7 helicase complex (MCM) in budding yeast, fission yeast, mouse and humans. We observed identical MCM double-hexamer footprints across the species, but notable differences in their distribution: In budding yeast, complexes were present in sharp peaks comprised largely of single double-hexamers; in fission yeast, corresponding peaks typically contained 4 to 8 double-hexamers, were more disperse, and showed a striking correlation with AT content. In mouse and humans, complexes were even more disperse, with a preference for regions of high GC content. Nonetheless, most fluctuations in replication timing in all four organisms could be accounted for by differences in chromosomal MCM distribution. This analysis also identified genomic regions whose replication timing was clearly not attributable to MCM density. The most notable was the inactive X-chromosome, which replicates late in S phase despite the fact that both MCM abundance and chromosomal distribution were comparable to those on the early replicating active X-chromosome. We conclude that, although certain genomic regions, most notably the inactive X-chromosome, are subject to post-licensing regulation, most differences in replication timing along the chromosome reflect uneven chromosomal distribution of stochastically firing pre-replication complexes.
mTOR dependent transformed human cells have a distinct set of essential genes from bcr-abl transformed cells
Authors: Benjamin Don , Colombi Marco , Moroni Christoph , Hall Michael N.
Published: August 2019

Constitutively active intracellular signaling drives and sustains cancer growth. The mTOR kinase integrates multiple inputs sensing nutrient, energy and growth factor levels to promote protein synthesis and anabolic metabolism, and is hyperactivated in a broad range of cancers. The bcr-abl kinase is a fusion protein generated by chromosomal translocation and gives rise to chronic myeloid leukemia and a small sub-set of leukemias. Using an in vitro transformed murine cell model, we performed shRNA knockdown of 25 genes previously shown to be essential for mTOR dependent oncogenic growth and survival. None of the genes were essential in the bcr-abl transformed line. Interrogation of this gene set in human cancer cell lines revealed that many of these genes were essential in cells dependent on mTOR signaling (defined by sensitivity to pharmacological mTOR inhibition). However, none of the genes were essential in bcr-abl transformed K562 cells that are insensitive to mTOR inhibition. Thus there is a clear divide between cells transformed via bcr-abl directed oncogenesis and other modes of transformation where mTOR, due to its central role in regulating cell growth and metabolism, is recruited as part of an oncogenic program. These validated hits represent a set of genes essential for executing critical functions downstream of mTOR and may be novel therapeutic targets for cancer.
Reducing sample consumption for serial crystallography using acoustic drop ejection
Authors: Davy Bradley , Axford Danny , Beale John H. , Butryn Agata , Docker Peter , Ebrahim Ali , Leen Gabriel , Orville Allen M. , Owen Robin L. , Aller Pierre
Published: August 2019

Efficient sample delivery is an essential aspect of serial crystallography at both synchrotrons and X-ray free-electron lasers. Rastering fixed target chips through the X-ray beam is an efficient method for serial delivery from the perspectives of both sample consumption and beam time usage. Here, an approach for loading fixed targets using acoustic drop ejection is presented that does not compromise crystal quality, can reduce sample consumption by more than an order of magnitude and allows serial diffraction to be collected from a larger proportion of the crystals in the slurry.
Differences of food intakes with gender, the year in college and body mass index among university students in Beijing, China
Authors: Cheng Li , Liu Zuchen
Published: August 2019

Purpose

The transition from high school to university poses many challenges for university students including dietary behaviors’ change and subsequent obesity risk. More tailored interventions and promotions to establish a healthier eating habit are needed to reduce obesity risks. The purpose of this paper is to investigate food intake differences on obesity risk among university students in China through exploring the differences of food intakes with gender, the year in college and body mass index (BMI).

Design/methodology/approach

Cross-sectional study was carried in five universities which were randomly selected in all the universities located in different geographical areas of Beijing, China. The sample consisted of 631 university students whom aged from 18 to 25 years. t-tests and one-way ANOVA tests were used to find differences of food intakes with gender, the year in college and BMI.

Findings

Having more consumption of food with high protein, high fat and high sugar, but less consumption of fruits and vegetables, may give university students a greater chance to be obese, and food intakes were significantly varied in different genders among Chinese university students.

Originality/value

There is a lack of evidence for investigating the differences of food intakes with gender on obesity among young adults in China. Findings of this study indicated that the food intakes of male students might make them more prone to obesity than female students, and suggested more tailored interventions, food marketing strategies and promotions on controlling students’ food intakes for a healthier life are needed.
The economic value of using CAW-type models to forecast covariance matrix
Authors: Zhao Shuran , Li Jinchen , Jiang Yaping , Ren Peimin
Published: August 2019

Purpose

The purpose of this paper is twofold: to improve the traditional conditional autoregressive Wishart (CAW) and heterogeneous autoregressive (HAR)-CAW model to account for heterogeneous leverage effect and to adjust the high-frequency volatility. The other is to confirm whether CAW-type models that have statistical advantages have economic advantages.

Design/methodology/approach

Based on the high-frequency data, this study proposed a new model to describe the volatility process according to the heterogeneous market hypothesis. Thus, the authors acquire needed and credible high-frequency data.

Findings

By designing two mean-variance frameworks and considering several economic performance measures, the authors find that compared with five other models based on daily data, CAW-type models, especially LHAR-CAW and HAR-CAW, indeed generate the substantial economic values, and matrix adjustment method significantly improves the three CAW-type performances.

Research limitations/implications

The findings in this study suggest that from the aspect of economics, LHAR-CAW model can more accurately built the dynamic process of return rates and covariance matrix, respectively, and the matrix adjustment can reduce bias of realized volatility as covariance matrix estimator of return rates, and greatly improves the performance of unadjusted CAW-type models.

Practical implications

Compared with traditional low-frequency models, investors should allocate assets according to the LHAR-CAW model so as to get more economic values.

Originality/value

This study proposes LHAR-CAW model with the matrix adjustment, to account for heterogeneous leverage effect and empirically show their economic advantage. The new model and the new bias adjustment approach are pioneering and promote the evolution of financial econometrics based on high-frequency data.
General equity vs DVR share of Tata Motors: investors’ dilemma
Authors: Rajhans Rajni Kant
Published: August 2019

Subject area

Finance.

Study level/applicability

Graduate/Under Graduate Progammes

Case overview/synopsis

The case presents the valuation gap between general equity and DVRs shares of TML. The case presents DVRs as an alternate asset class for investment for retail investors and shows its various characteristics taking the case of TML. The case presents global evidences of the valuation gaps and hence helps in making informed decisions. The case makes the reader perplex with a varied global evidence and then presents other data (increasing interest by institutional investors in DVRs of TML) which may help to take final decision “BUY or NOT”.

Expected learning outcomes

The readers will be able to recall “how do finance managers use a diverse type of equity for providing new sources of finance?” The readers will be able to describe the characteristics of differential voting right (DVR) shares. The participants will be able to present various reasons for the price difference between DVR shares and general equity shares. The readers will be in a position to analyze the price pattern of Tata Motors Limited (TML’s) DVR together with global experience. The participants will be able to justify the trade-off between extra dividend and loss of voting rights in the case of DVR shares.

Supplementary materials

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

Subject code

CSS 1: Accounting and Finance.
A Big Data and FMEA-based construction quality risk evaluation model considering project schedule for Shanghai apartment projects
Authors: Ma Guofeng , Wu Ming
Published: August 2019

Purpose

The purpose of this paper is to mine information on the construction process of previous projects to develop a construction plan that meets both quality requirements and schedule constraints.

Design/methodology/approach

This paper uses a failure mode and effect analysis to evaluate the construction quality of 311 apartments in Shanghai. The authors also evaluate construction-scheduling control using the earned value management technique and implement an artificial neural network to correlate the results. The authors then develop a quality risk and schedule correlation model based on Big Data. The model can predict the relationship between the planned schedule and the project quality risk using multiple variables such as the number of layers, the schedule performance index and budget costs.

Findings

The methodology offers an innovative approach for assessment on the relationship between quality risk and project schedule. The authors have also built a multiple regression analysis model for comparative purposes with the model. The results show that the proposed model can better describe the relationship. The model can provide a quantitative quality risk value that changes with the planned schedule, as well as help project managers to understand the relationship between quality risk and project scheduling more accurately.

Research limitations/implications

The research approach only focuses on quality risk under the impact of scheduling. Future efforts might focus on developing a model that connects failure models with project schedules and costs in order to improve the effort of quality management.

Practical implications

The model based on Big Data in this paper is developed using real projects and reflects the relationship between project quality risk and scheduling in real environments. The created application provides support for project managers to develop and adjust quality plans and schedules, thereby reducing deviations in quality and scheduling objectives.

Originality/value

The authors make full use of historical project data from the perspective of both quality and schedule management, and provide a novel method to intelligently and objectively analyze the relationship between quality risk and scheduling.
Condition monitoring of structures using limited noisy data modal slope and curvature of mode shapes
Authors: Ali Jafar , Bandyopadhyay Debasish
Published: August 2019

Purpose

Condition monitoring (CM) has become significantly important, particularly in the context of ensuring safety, reliability and future usefulness of civil infrastructural systems. Most of the age old structures require immediate attention. Nondestructive tests and/or load tests along with routine maintenance inspections are common practice. However, most of the NDT techniques are location-dependent and are conducted in a piecewise manner. The paper aims to discuss these issues.

Design/methodology/approach

Numerical methods incorporating inverse techniques are a global approach to identify structural parameters using dynamic responses. However, measurement at all degrees of freedom does not seem to be feasible, due to practical constraints. Parameter identification of structures based on limited dynamic responses like modal slope and curvature mode shapes at the element level in a finite element platform is proposed in the present paper. The structural property for each element is derived adopting a two-phase analysis process, consisting modal extraction and structural parameter identification. It is important to study the accuracy of the predicted parameters with the number of measured modes. The structural property is identified using measured responses at those selected MDOF.

Findings

The proposed method is demonstrated in detail with a numerical example. The method seems to be an attractive proposition as the results obtained are very accurate even with noise-contaminated data.

Research limitations/implications

However, for practical problems, the experimental validation is significantly important prior to its application in real-life problems.

Practical implications

The developed model seems to be feasible for practical applications after experimental validation, as it is able to identify the structural parameters from limited noisy dynamic responses in frequency domains measured for few modes.

Social implications

Structural CM is the need of the hour, particularly for infrastructural systems including buildings and bridges, etc. System identification with a global dynamic response at few measurement locations may address the issue of health assessment of structures, which will have great social implications with respect to safety.

Originality/value

The proposed numerical model is originally developed by the authors with judicial modifications and combination of earlier research contributions to achieve greater accuracy. Limited measurement and the effect of random noise with numerical example are considered for the successful validation.
Weaving together media, technologies and people
Authors: Dodson Samuel , Roll Ido , Harandi Negar M. , Fels Sidney , Yoon Dongwook
Published: August 2019

Purpose

Students in flipped classrooms are challenged to orchestrate an increasingly heterogeneous collection of learning objects, including audiovisual materials as well as traditional learning objects, such as textbooks and syllabi. This study aims to examine students' information practices interacting with and synthesizing across learning objects, technologies and people in flipped classrooms.

Design/methodology/approach

This grounded theory study explores the information practices of 12 undergraduate engineering students as they learned in two flipped classrooms. An artifact walkthrough was used to elicit descriptions of how students conceptualize and work around interoperability problems between the diverse and distributed learning objects by weaving them together into information tapestries.

Findings

Students maintained a notebook as an information tapestry, weaving fragmented information snippets from the available learning objects, including, but not limited to, instructional videos and textbooks. Students also connected with peers on Facebook, a back-channel that allowed them to sidestep the academic honesty policy of the course discussion forum, when collaborating on homework assignments.

Originality/value

The importance of the interoperability of tools with elements of students' information space and the significance of designing for existing information practices are two outcomes of the grounded theory approach. Design implications for educational technology including the weaving of mixed media and the establishment of spaces for student-to-student interaction are also discussed.
The building blocks of coding: a comparison of early childhood coding toys
Authors: Clarke-Midura Jody , Lee Victor R. , Shumway Jessica F. , Hamilton Megan M.
Published: August 2019

Purpose

This paper aims to be a think piece that promotes discussion around the design of coding toys for children. In particular, the authors examine three different toys that have some sort of block-based coding interface. The authors juxtapose three different design features and the demands they place on young children learning to code. To examine the toys, the authors apply a framework developed based on Gibson’s theory of affordances and Palmer’s external representations. The authors look specifically at the toys: interface design, intended play scenario and representational conventions for computational ideas.

Design/methodology/approach

As a research team, the authors have been playing with toys, observing their own children play with the toys and using them in kindergarten classrooms. In this paper, the authors reflect specifically on the design of the toys and the demands they place on children.

Findings

The authors make no claims about whether one toy/design approach is superior to another. However, the differences that the authors articulate should serve as a provocation for researchers and designers to be mindful about what demands and expectations they place on young children as they learn to code and use code to learn in any given system.

Research limitations/implications

As mentioned above, the authors want to start a discussion about design of these toys and how they shape children's experience with coding.

Originality/value

There is a push to get coding and computational thinking into K-12, but there is not enough research on what this looks like in early childhood. Further, while research is starting to emerge on block-based programming vs text-based for older children and adults, little research has been done on the representational form of code for young children. The authors hope to start a discussion on design of coding toys for children.