bluuebunny/crossref_metadata_2025 huggingface dataset:
A truncated form of HpARI stabilises IL-33, amplifying responses to the cytokine
Authors: Chauché Caroline , Vacca Francesco , Chia Shin Li , Richards Josh , Gregory William F , Ogunkanbi Adefunke , Wear Martin , McSorley Henry J
Published: April 2020

1

The murine intestinal nematodeHeligmosomoides polygyrusreleases theH. polygyrusAlarmin Release Inhibitor (HpARI) - a protein which binds to IL-33 and to DNA, effectively tethering the cytokine in the nucleus of necrotic cells. Previous work showed that a non-natural truncation consisting of the first 2 domains of HpARI (HpARI_CCP1/2) retains binding to both DNA and IL-33, and inhibited IL-33 releasein vivo. Here, we show that the affinity of HpARI_CCP1/2 for IL-33 is significantly lower than that of the full-length protein, and that HpARI_CCP1/2 lacks the ability to prevent interaction of IL-33 with its receptor. When HpARI_CCP1/2 was appliedin vivoit potently amplified IL-33-dependent immune responses toAlternaria alternataallergen,Nippostrongylus brasiliensisinfection and recombinant IL-33 injection. Mechanistically, we found that HpARI_CCP1/2 is able to bind to and stabilise IL-33, preventing its degradation and maintaining the cytokine in its active form. This study highlights the importance of IL-33 inactivation, the potential for IL-33 stabilisationin vivo, and describes a new tool for IL-33 research.
Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis
Authors: Kwon Ok-Seon , Kwon Eun-Ji , Kong Hyeon-Joon , Choi Jeong-Yoon , Kim Yun-Jeong , Lee Eun-Woo , Kim Wankyu , Lee Haeseung , Cha Hyuk-Jin
Published: April 2020

Erastin, which has been initially identified as a synthetic lethal compound against cancer expressing an RAS oncogene, inhibits cystine/glutamate antiporters and causes ferroptic cell death in various cell types, including therapy-resistant mesenchymal cancer cells. However, despite recent emerging evidence for the mechanisms underlying ferroptosis, molecular biomarkers associated with erastin-dependent ferroptosis have not yet been identified. In the present study, we employed isogenic lung cancer cell models with therapy-resistant mesenchymal properties to show that a redox imbalance leads to glutathione depletion and ferroptotic cell death. Subsequent gene expression analysis of pan-cancer cell lines revealed that the activity of transcription factors, including nuclear factor erythroid 2-related factor 2 (NRF2) and aryl hydrocarbon receptor (AhR), serve as important markers of erastin resistance. Based on the integrated expression of genes in the nuclear receptor meta-pathway (NRM), we constructed an NRM model and validated its robustness using an independent pharmacogenomics dataset. The NRM model was further evaluated by employing it in the sensitivity testing of nine cancer cell lines for which erastin sensitivities had not yet been undetermined. Our pharmacogenomics approach has the potential to pave the way for the efficient classification of patients for therapeutic intervention using erastin or erastin analogs.
CBL mutations promote activation of PI3K/AKT signaling via LYN kinase
Authors: Belizaire Roger , Koochaki Sebastian H.J. , Udeshi Namrata D. , Vedder Alexis , Sun Lei , Svinkina Tanya , Hartigan Christina , Stanclift Caroline , Schenone Monica , Carr Steven A. , Padron Eric , Ebert Benjamin L.
Published: April 2020

CBLencodes an E3 ubiquitin ligase and signaling adaptor that acts downstream of cytokine receptors. RecurrentCBLmutations occur in myeloid malignancies, but the mechanism by which these mutations drive oncogenesis remains incompletely understood. Here we performed a series of studies to define the phosphoproteome, CBL interactome and molecular mechanisms of signaling activation in cells expressing an allelic series ofCBLmutants. Our analyses revealed that increased LYN activation and interaction with mutant CBL are key drivers of enhanced PIK3R1 recruitment and downstream PI3K/AKT signaling inCBL-mutant cells. Furthermore, we demonstratedin vitroandin vivoefficacy of LYN inhibition by dasatinib inCBL-mutant cell lines and primary chronic myelomonocytic leukemia cells. Overall, our data provide rationale for exploring the therapeutic potential of LYN inhibition in patients withCBL-mutated myeloid malignancies.

Statement of Significance

We investigated the oncogenic mechanisms of myeloid malignancy-associatedCBLmutations by mass spectrometry-based proteomics and interactomics. Our findings indicate that increased LYN kinase activity inCBL-mutant cells stimulates PI3K/AKT signaling, revealing opportunities for the use of targeted inhibitors inCBL-mutated myeloid malignancies.
Bioinformatic characterization of angiotensin-converting enzyme 2, the entry receptor for SARS-CoV-2
Authors: Barker Harlan , Parkkila Seppo
Published: April 2020

The World Health Organization declared the COVID-19 epidemic a public health emergency of international concern on March 11th, 2020, and the pandemic is rapidly spreading worldwide. COVID-19 is caused by a novel coronavirus SARS-CoV-2, which enters human target cells via angiotensin converting enzyme 2 (ACE2). We used a number of bioinformatics tools to computationally characterize ACE2 by determining its cell-specific expression in trachea, lung, and small intestine, derive its putative functions, and predict transcriptional regulation. The small intestine expressed higher levels of ACE2 than any other organ. The large intestine, kidney and testis showed moderate signals, whereas the signal was weak in the lung. Single cell RNA-Seq data from trachea indicated positive signals along the respiratory tract in key protective cell types including club, goblet, proliferating, and ciliary epithelial cells; while in lung the ratio of ACE2-expressing cells was low in all cell types (<2.6%), but was highest in vascular endothelial and goblet cells. Gene ontology analysis suggested that, besides its classical role in renin-angiotensin system, ACE2 may be functionally associated with angiogenesis/blood vessel morphogenesis. Using a novel tool for the prediction of transcription factor binding sites we identified several putative binding sites within two tissue-specific promoters of theACE2gene. Our results also confirmed that age and gender play no significant role in the regulation of ACE2 mRNA expression in the lung.

IMPORTANCE

Vaccines and new medicines are urgently needed to prevent spread of COVID-19 pandemic, reduce the symptoms, shorten the duration of disease, prevent virus spread in the body, and most importantly to save lives. One of the key drug targets could be angiotensin-converting enzyme 2 (ACE2), which is a crucial receptor for the corona virus (SARS-CoV-2). It is known that SARS coronavirus infections lead to worse outcome in the elderly and in males. Therefore, one aim of the present study was to investigate whether age or sex could contribute to the regulation of ACE2 expression. We also decided to explore the transcriptional regulation ofACE2gene expression. Since data on ACE2 distribution is still conflicting, we aimed to get a more comprehensive view of the cell types expressing the receptor of SARS-CoV-2. Finally, we studied the coexpression of ACE2 with other genes and explored its putative functions using gene ontology enrichment analysis.
A high-throughput genomic screen identifies a role for the plasmid-borne Type II secretion system ofEscherichiacoli O157:H7 (Sakai) in plant-microbe interactions
Authors: Holmes Ashleigh , Pritchard Leighton , Hedley Peter , Morris Jenny , McAteer Sean P. , Gally David L. , Holden Nicola J.
Published: April 2020

Food-borne illness arising from Shiga-toxigenicEscherichia coli(STEC) is often linked to consumption of fruit and vegetables as the bacteria have the ability to interact with plants and use them as alternative or secondary hosts. The initial stages of the interaction involve chemotaxis, attachment and potentially, responding to the early stages of microbe perception by the plant host. We used a high-throughput positive-selection approach to identify early interaction factors ofE. coliO157:H7 isolate Sakai to spinach. A bacterial artificial chromosome (BAC) clone library was quantified by microarray hybridisation, and gene loci enrichment measured using a Bayesian hierarchical model. The screen of four successive rounds of short-term (2 hour) interaction with spinach roots produced in 115 CDS credible candidates, comprising seven contiguous genomic regions. Two candidate regions were selected for functional assessment: a chaperone-usher fimbrial gene cluster (loc6) and the pO157 plasmid-encoded type two secretion system (T2SS). Interaction of bacteria with spinach tissue was reduced in the absence of the pO157 plasmid, which was appeared to involve the T2SS EtpD secretin protein, whereas loss ofloc6did not impact interactions. The T2SS genes,etpDandetpC, were expressed at a plant-relevant temperature of 18 °C, andetpDexpressedin plantabyE. coliSakai on spinach plants. Thus, a whole genome screening approach using a combination of computational modelling and functional assays has identified a novel function for STEC T2SS in interactions with plant tissue.
CNV-PG: a machine-learning framework for accurate copy number variation predicting and genotyping
Authors: Wang Taifu , Sun Jinghua , Zhang Xiuqing , Wang Wen-Jing , Zhou Qing
Published: April 2020

Motivation

Copy-number variants (CNVs) are one of the major causes of genetic disorders. However, current methods for CNV calling have high false-positive rates and low concordance, and a few of them can accurately genotype CNVs.

Results

Here we propose CNV-PG (CNV Predicting and Genotyping), a machine-learning framework for accurately predicting and genotyping CNVs from paired-end sequencing data. CNV-PG can efficiently remove false positive CNVs from existing CNV discovery algorithms, and integrate CNVs from multiple CNV callers into a unified call set with high genotyping accuracy.

Availability

CNV-PG is available athttps://github.com/wonderful1/CNV-PG
Proteome analysis of human visceral and subcutaneous adipocytes identifies depot-specific heterogeneity at metabolic control points
Authors: Raajendiran Arthe , Krisp Christoph , Souza David P. De , Ooi Geraldine , Burton Paul R. , Taylor Renea A. , Molloy Mark P. , Watt Matthew J.
Published: April 2020

Adipose tissue is a primary regulator of energy balance and metabolism. The distribution of adipose tissue depots is of clinical interest because the accumulation of upper-body subcutaneous (ASAT) and visceral adipose tissue (VAT) is associated with cardiometabolic diseases, whereas lower-body gluteal-femoral adipose tissue (GFAT) appears to be protective. There is heterogeneity in morphology and metabolism of adipocytes obtained from different regions of the body, but detailed knowledge of the constituent proteins in each depot is lacking. Here, we determined the human adipocyte proteome from ASAT, VAT and GFAT using high-resolution SWATH mass spectrometry proteomics. We quantified 4220 proteins in adipocytes, and 2329 proteins were expressed in all three adipose depots. Comparative analysis revealed significant differences between adipocytes from different regions (6 and 8% when comparing VATvs.ASAT and GFAT, 3% when comparing ASATvs.GFAT), with marked differences in proteins that regulate metabolic functions. The VAT adipocyte proteome was overrepresented with proteins of glycolysis, lipogenesis, oxidative stress and mitochondrial dysfunction. The GFAT adipocyte proteome predicted activation of PPARα, fatty acid and BCAA oxidation, enhanced TCA cycle flux and oxidative phosphorylation, which was supported by metabolomic data obtained from adipocytes from the same patient donors. Together, this proteomic analysis provides an important resource and novel insights that enhance the understanding of metabolic heterogeneity in the regional adipocytes of humans.
Whole genome comparisons of ergot fungi reveals the divergence and evolution of species within the genus Claviceps are the result of varying mechanisms driving genome evolution and host range expansion
Authors: Wyka Stephen A. , Mondo Stephen J. , Liu Miao , Dettman Jeremy , Nalam Vamsi , Broders Kirk D.
Published: April 2020

The genus Claviceps has been known for centuries as an economically important fungal genera for pharmacology and agricultural research. Only recently have researchers begun to unravel the evolutionary history of the genus, with origins in South America and classification of four distinct sections through ecological, morphological, and metabolic features (Claviceps sects. Citrinae, Paspalorum, Pusillae, and Claviceps). The first three sections are additionally characterized by narrow host range, while sect. Claviceps is considered evolutionarily more successful and adaptable as it has the largest host range and biogeographical distribution. However, the reasons for this success and adaptability remain unclear. Our study elucidates factors influencing adaptability by sequencing and annotating 50 Claviceps genomes, representing 21 species, for a comprehensive comparison of genome architecture and plasticity in relation to host range potential. Our results show the trajectory from specialized one-speed genomes (sects. Citrinae and Paspalorum) towards adaptive two-speed genomes (sects. Pusillae and Claviceps) through co-localization of transposable elements around predicted effectors and a putative loss of repeat-induced point mutation resulting in unconstrained tandem gene duplication coinciding with increased host range potential and speciation. Alterations of genomic architecture and plasticity can substantially influence and shape the evolutionary trajectory of fungal pathogens and their adaptability. Furthermore, our study provides a large increase in available genomic resources to propel future studies of Claviceps in pharmacology and agricultural research, as well as, research into deeper understanding of the evolution of adaptable plant pathogens.
ISG15 drives immune pathology and respiratory failure during viral infection
Authors: Shaabani Namir , Zak Jaroslav , Johnson Jennifer L. , Huang Zhe , Nguyen Nhan , Lazar Daniel C. , Vartabedian Vincent F. , Honke Nadine , Prinz Marco , Knobeloch Klaus-Peter , Arimoto Kei-ichiro , Zhang Dong-Er , Catz Sergio D. , Teijaro John R.
Published: April 2020

Cytokine storm during respiratory viral infection is an indicator of disease severity and poor prognosis. Type 1 interferon (IFN-I) production and signaling has been reported to be causal in cytokine storm-associated pathology in several respiratory viral infections, however, the mechanisms by which IFN-I promotes disease pathogenesis remain poorly understood. Here, usingUsp18-deficient, USP18 enzymatic-inactive andIsg15-deficient mouse models, we report that lack of deISGylation during persistent viral infection leads to severe immune pathology characterized by hematological disruptions, cytokine amplification, lung vascular leakage and death. This pathology requires T cells but not T cell-intrinsic deletion ofUsp18. However, lack ofUsp18in myeloid cells mimicked the pathological manifestations observed inUsp18-/-orUsp18C61Amice which were dependent onIsg15. We further mechanistically demonstrate that interrupting the ISGylation/deISGylation circuit increases extracellular levels of ISG15 which is accompanied by inflammatory neutrophil accumulation to the lung. Importantly, neutrophil depletion reversed morbidity and mortality inUsp18C61Amice. In summary, we reveal that the enzymatic function ofUsp18is crucial for regulating extracellular release of ISG15. This is accompanied by altered neutrophil differentiation, cytokine amplification and mortality following persistent viral infection. Moreover, our results suggest that extracellular ISG15 may drive the inflammatory pathology observed and could be both a prospective predictor of disease outcome and a therapeutic target during severe respiratory viral infections.
Investigate the relevance of major signaling pathways in cancer survival using a biologically meaningful deep learning model
Authors: Feng Jiarui , Zhang Heming , Li Fuhai
Published: April 2020

Survival analysis and prediction are important in cancer studies. In addition to the Cox proportional hazards model, recently deep learning models have been proposed to integrate the multi-omics data for survival prediction. Cancer signaling pathways are important and interpretable concepts that define the signaling cascades regulating cancer development and drug resistance. Thus, it is interesting and important to investigate the relevance to patients’ survival of individual signaling pathways. In this exploratory study, we propose to investigate the relevance and difference of a small set of core cancer signaling pathways in the survival analysis of cancer patients. Specifically, we built a biologically meaningful and simplified deep neural network, DeepSigSurvNet, for survival prediction. In the model, the gene expression and copy number data of 1648 genes from 46 major signaling pathways are used. We applied the model on 4 types of cancer and investigated the relevance and difference of the 46 signaling pathways among the 4 types of cancer. Interestingly, the interpretable analysis identified the distinct patterns of these signaling pathways, which are helpful to understand the relevance of the signaling pathways in terms of their association with cancer survival time. These highly relevant signaling pathways can be novel targets, combined with other essential signaling pathways inhibitors, for drug and drug combination prediction to improve cancer patients’ survival time.
Existing actin filaments orient new filament growth to provide structural memory of filament alignment during cytokinesis
Authors: Li Younan , Munro Edwin
Published: April 2020

During cytokinesis, animal cells rapidly remodel the equatorial cortex to build an aligned array of actin filaments called the contractile ring. Local reorientation of filaments by equatorial contraction is thought to underlie the emergence of filament alignment during ring assembly. Here, combining single molecule analysis and modeling in one-cellC. elegansembryos, we show that filaments turnover is far too fast for reorientation of single filaments by equatorial contraction/cortex compression to explain the observed alignment, even if favorably oriented filaments are selectively stabilized. Instead, by tracking single Formin/CYK-1::GFP speckles to monitor local filament assembly, we identify a mechanism that we call filament-guided filament assembly (FGFA), in which existing filaments serve as templates to guide/orient the growth of new filaments. We show that FGFA sharply increases the effective lifetime of filament orientation, providing structural memory that allows slow equatorial contraction to build and maintain highly aligned filament arrays, despite rapid turnover of individual filaments.
Origin, Conservation, and Loss of Alternative Splicing Events that Diversify the Proteome in Saccharomycotina Budding Yeasts
Authors: Hurtig Jennifer E. , Kim Minseon , Orlando-Coronel Luisa J. , Ewan Jellisa , Foreman Michelle , Notice Lee-Ann , Steiger Michelle A. , van Hoof Ambro
Published: April 2020

Many eukaryotes use alternative splicing to express multiple proteins from the same gene. However, while the majority of mammalian genes are alternatively spliced, other eukaryotes use this process less frequently. The budding yeastSaccharomyces cerevisiaehas been successfully used to study the mechanism of splicing and the splicing machinery, but alternative splicing in yeast is relatively rare and has not been extensively studied. We have recently shown that the alternative splicing ofSKI7/HBS1is widely conserved, but that yeast and a few other eukaryotes have replaced this one alternatively spliced gene with a pair of duplicated unspliced genes as part of a whole genome doubling (WGD). Here we show that other examples of alternative splicing that were previously found to have functional consequences are widely conserved within the Saccharomycotina. We also show that the most common mechanism by which alternative splicing has disappeared is by the replacement of an alternatively spliced gene with duplicate genes. Saccharomycetaceae that diverged before WGD use alternative splicing more frequently thanS. cerevisiae. This suggests that the WGD is a major reason for the low frequency of alternative splicing in yeast. We anticipate that whole genome doublings in other lineages may have had the same effect.
Caspases from Scleractinian Coral Show Unique Regulatory Features
Authors: Shrestha Suman , Tung Jessica , Grinshpon Robert D. , Swartz Paul , Hamilton Paul T. , Dimos Bradford , Mydlarz Laura , Clark A. Clay
Published: April 2020

Diseases affecting coral have led to massive decline and altered the community structure of reefs. In response to immune challenges, cnidaria activate apoptotic or autophagic pathways, and the particular pathway correlates with disease sensitivity (apoptosis) or resistance (autophagy). Although cnidaria contain complex apoptotic signaling pathways, similar to those in vertebrates, the mechanisms leading to cell death are largely unexplored. We identified and characterized two caspases each fromOrbicella faveolata, a disease-sensitive stony coral, andPorites astreoides, a disease-resistant stony coral. The four caspases are predicted homologs of human caspases-3 and −7, but OfCasp3a and PaCasp7a contain an amino-terminal caspase activation and recruitment domain (CARD) similar to human initiator/inflammatory caspases. In contrast, OfCasp3b and PaCasp3 have short pro-domains, like human effector caspases. We show that OfCasp3a and PaCasp7a are DxxDases, like human caspases-3 and −7, while OfCasp3b and PaCasp3 are more similar to human caspase-6, with VxxDase activity. Our biochemical analyses suggest a mechanism in coral in which the CARD-containing DxxDase is activated on death platforms, but the protease does not directly activate the VxxDase. We also report the first X-ray crystal structure of a coral caspase, that of PaCasp7a determined at 1.57Å resolution. The structure reveals overall conservation of the caspase-hemoglobinase fold in coral as well as an N-terminal peptide bound near the active site that may serve as a regulatory exosite. The binding pocket has been observed in initiator caspases of other species, suggesting mechanisms for the evolution of substrate selection while maintaining common activation mechanisms of CARD-mediated dimerization.
Flow over seal whiskers: importance of geometric features for force and frequency response
Authors: Lyons Kathleen , Murphy Christin T. , Franck Jennifer A.
Published: April 2020

The complex undulated geometry of seal whiskers has been shown to substantially modify the turbulent structures directly downstream, resulting in a reduction of hydrodynamic forces as well as modified vortex-induced-vibration response when compared with smooth whiskers. Although the unique hydrodynamic response has been well documented, an understanding of the fluid flow effects from each geometric feature remains incomplete. In this computational investigation, nondimensional geometric parameters of the seal whisker morphology are defined in terms of their hydrodynamic relevance, such that wavelength, aspect ratio, undulation amplitudes, symmetry and undulation off-set can be varied independently of one another. A two-factor fractional factorial design of experiments procedure is used to create 16 unique geometries, each of which dramatically amplifies or attenuates the geometric parameters compared with the baseline model. The flow over each unique topography is computed with a large-eddy simulation at a Reynolds number of 500 with respect to the mean whisker thickness and the effects on force and frequency are recorded. The results determine the specific fluid flow impact of each geometric feature which will inform both biologists and engineers who seek to understand the impact of whisker morphology or lay out a framework for biomimetic design of undulated structures.
A new pathway for forming acetate and synthesizing ATP during fermentation in bacteria
Authors: Zhang Bo , Bowman Courtney , Hackmann Timothy J.
Published: April 2020

Many bacteria and other organisms form acetate during fermentation. Forming acetate from high energy-precursors (acetyl-CoA or acetyl phosphate) is one of the few ways that fermentative bacteria generate ATP. Here we found a biochemical pathway for forming acetate and synthesizing ATP that was unknown in bacteria. We found the bacteriumCutibacterium granulosumformed acetate during fermentation of glucose. With enzymatic assays, we showed it formed acetate using a pathway involving two enzymes. The first enzyme, succinyl-CoA:acetate CoA-transferase (SCACT), forms acetate from acetyl-CoA. The second enzyme, succinyl-CoA synthetase (SCS), synthesizes ATP. This pathway is common in eukaryotes, but it has not been found in bacteria or other organisms. We found two related bacteria (C.acnesandAcidipropionibacterium acidipropionici) also used this pathway. None used the most common pathway for forming acetate in bacteria (involving acetate kinase and phosphotransacetylase). The SCACT/SCS pathway may be used by many bacteria, not justC.granulosumand relatives. When we searched genomes for bacteria known to form acetate, we found over 1/6 encoded this pathway. These bacteria belong to 104 different species and subspecies in 12 different phyla. With this discovery, all five pathways known to form acetate and ATP during fermentation can be found in bacteria. This discovery is important to manipulating fermentation and to the evolution of biochemical pathways.
Divergence in photoperiod responses of a classical biological control agentNeogalerucella calmariensis(Coleoptera: Chrysomelidae) across a climatic and latitudinal gradient
Authors: Wepprich Tyson , Grevstad Fritzi S.
Published: April 2020

A key knowledge gap in classical biological control is to what extent insect agents evolve to novel environments. The introduction of biological control agents to new photoperiod regimes and climates may disrupt the coordination of diapause timing that evolved to the growing season length in the native range. We tested whether populations ofNeogalerucella calmariensis(L.) have evolved in response to the potential mismatch of their diapause timing since their intentional introduction to the United States from Germany in the 1990s. Populations collected from 39.4° to 48.8° latitude in the western USA were reared in growth chambers to isolate the effects of photoperiod on diapause induction and development time. For all populations, shorter day lengths increased the proportion of beetles that entered diapause instead of reproducing. The critical photoperiods, or the day length at which half of a population diapauses, differed significantly among the sampled populations, generally decreasing at lower latitudes. The latitudinal trend reflects changes in growing season length, which determines the number of generations possible, and in local day lengths at the time beetles are sensitive to this cue. Development times were similar across populations, with one exception, and did not vary with photoperiod. These results show that there was sufficient genetic variation from the two German source populations to evolve different photoperiod responses across a range of environmental conditions. This study adds to the examples of rapid evolution of seasonal adaptations in introduced insects.
Tocotrienol decreases β-amyloid mediated toxicity inCaenorhabditis elegansmodel of Alzheimer’s disease
Authors: Yuen Chee Wah , Halim Mardani Abdul , Murugaiyah Vikneswaran , Najimudin Nazalan , Azzam Ghows
Published: April 2020

Alzheimer’s disease (AD) is a neurological disease caused by the accumulation of extracellular senile plaques consisting of β-amyloid peptide (Aβ) in the brain. A transgenicCaenorhabditis eleganswhich demonstrated paralysis due to the expression of human beta amyloid Aβ42gene was used to study the anti-paralysis effect of mixed tocotrienols. The content of the mixed tocotrienols were 12.1% α-, 2.7% β-, 18.6% γ-, and 8.1% δ-tocotrienols. Mixed tocotrienols significantly delayed the Aβ-induced paralysis in the transgenic nematode and exhibited anti-oxidant properties towards Aβ-generated oxidative stress. The mixture also presented potent inhibitory activities against Aβ aggregation with an IC50value of 600 ng/ml. It is concluded that mixed tocotrienols could potentially serve as a new therapeutic candidate for AD.
Selective Peptidomimetic Inhibitors of NTMT1/2: Rational design, synthesis, characterization, and crystallographic studies
Authors: Mackie Brianna D. , Chen Dongxing , Dong Guangping , Dong Cheng , Parker Haley , Tooley Christine E. Schaner , Noinaj Nicholas , Min Jinrong , Huang Rong
Published: April 2020

Protein N-terminal methyltransferases (NTMTs) methylate the α-N-terminal amines of proteins starting with the canonical X-P-K/R motif. Genetic studies imply that NTMT1 regulates cell mitosis and DNA damage repair. Herein, we report the rational design and development of the first potent peptidomimetic inhibitors for NTMT1. Biochemical and co-crystallization studies manifest thatBM30(IC50of 0.89 ± 0.10 µM) is a competitive inhibitor to the peptide substrate and noncompetitive to the cofactor S-adenosylmethionine.BM30exhibits over 100-fold selectivity to NTMT1/2 among a panel of 41 methyltransferases, indicating the potential to achieve high selectivity when targeting the peptide substrate binding site of NTMT1/2. Its cell-permeable analog DC432 (IC50of 54 ± 4 nM) decreases the N-terminal methylation level of SET protein in HCT116 cells. This proof-of principle study provides valuable probes for NTMT1/2 and highlights the opportunity to develop more cell-potent inhibitors to elucidate the function of NTMTs in future.
Sequential Vaccination for Containing Epidemics
Authors: Tennenholtz Guy , Caramanis Constantine , Mannor Shie
Published: April 2020

The dynamics of infectious diseases spread is crucial in determining their risk and offering ways to contain them. We study sequential vaccination of individuals in networks, where there is a limit on the number of individuals that can be vaccinated every day. Effective allocation of vaccine will play a critical role in preventing the spread and reducing the effects of a future pandemic. We derive methods for calculating upper and lower bounds of the expected number of infected individuals, as well as provide estimates on the number of vaccinations that is needed for containment. We calculate these explicitly on trees, d-dimensional grids, and Erdős Rényi graphs. Finally, we construct a time-dependent budget allocation strategy and demonstrate its superiority over constant budget allocation on real networks following first acquaintance vaccination. Our results provide a principled approach to assess the needed vaccination rate given the social graph topology.
The IDR-containing protein PID-2 affects Z granules and is required for piRNA-induced silencing in the embryo
Authors: Placentino Maria , de Jesus Domingues António Miguel , Schreier Jan , Dietz Sabrina , Hellmann Svenja , de Albuquerque Bruno F. M. , Butter Falk , Ketting René F.
Published: April 2020

InCaenorhabditis elegans, the piRNA (21U RNA) pathway is required to establish proper gene regulation and an immortal germline. To achieve this, PRG-1-bound 21U RNAs trigger silencing mechanisms mediated by RNA-dependent RNA polymerase (RdRP)-synthetized 22G RNAs. This silencing can become PRG-1-independent, and heritable over many generations. This state is named RNAe. It is unknown how and when RNAe is established, and how it is maintained. We show that maternally provided 21U RNAs can be sufficient to trigger RNAe in embryos. Additionally, we identify the IDR-containing protein PID-2, as a factor required to establish and maintain RNAe. PID-2 interacts with two novel, partially redundant, eTudor domain proteins, PID-4 and PID-5. Additionally, PID-5 has a domain related to the X-prolyl aminopeptidase protein APP-1, and binds APP-1, implicating N-terminal proteolysis in RNAe. All three proteins are required for germline immortality, localize to perinuclear foci, affect Z granules, and are required for balancing of 22G RNA populations. Overall, our study identifies three new proteins with crucial functions in theC. eleganssmall RNA silencing network.
Analysis of ISCB honorees and keynotes reveals disparities
Authors: Le Trang T. , Himmelstein Daniel S. , Hippen Anderson Ariel A. , Gazzara Matthew R. , Greene Casey S.
Published: April 2020

Delivering a keynote talk at a conference organized by a scientific society, or being named as a fellow by such a society, indicates that a scientist is held in high regard by their colleagues. To explore if the distribution of such indicators of esteem in the field of bioinformatics reflects the composition of this field, we compared the gender, name-origin, country of affiliation and race/ethnicity of 412 researchers who had been recognized by theInternational Society for Computational Biology(75 fellows and 337 keynote speakers) with over 170,000 researchers who had been the last authors on computational biology papers between 1993 and 2019. The proportion of female fellows and keynote speakers was similar to that of the field overall. However, names of East Asian origin have been persistently underrepresented among fellows and keynote speakers. Moreover, fellows and keynote speakers with an affiliation in the United States were overrepresented by a factor of 2.1; almost two thirds of this excess was accounted for by a deficit of 101 fellows and keynote authors from China, India, France and Italy. Within the US, we found an excess of white fellows and keynote speakers and a depletion of Asian fellows and keynote speakers.
X-ray diffraction using focused-ion-beam-prepared single crystals
Authors: Weigel Tina , Funke Claudia , Zschornak Matthias , Behm Thomas , Stöcker Hartmut , Leisegang Tilmann , Meyer Dirk C.
Published: April 2020

High-quality single-crystal X-ray diffraction measurements are a prerequisite for obtaining precise and reliable structure data and electron densities. The single crystal should therefore fulfill several conditions, of which a regular defined shape is of particularly high importance for compounds consisting of heavy elements with high X-ray absorption coefficients. The absorption of X-rays passing through a 50 µm-thick LiNbO3crystal can reduce the transmission of Mo Kα radiation by several tens of percent, which makes an absorption correction of the reflection intensities necessary. In order to reduce ambiguities concerning the shape of a crystal, used for the necessary absorption correction, a method for preparation of regularly shaped single crystals out of large samples is presented and evaluated. This method utilizes a focused ion beam to cut crystals with defined size and shape reproducibly and carefully without splintering. For evaluation, a single-crystal X-ray diffraction study using a laboratory diffractometer is presented, comparing differently prepared LiNbO3crystals originating from the same macroscopic crystal plate. Results of the data reduction, structure refinement and electron density reconstruction indicate qualitatively similar values for all prepared crystals. Thus, the different preparation techniques have a smaller impact than expected. However, the atomic coordinates, electron densities and atomic charges are supposed to be more reliable since the focused-ion-beam-prepared crystal exhibits the smallest extinction influences. This preparation technique is especially recommended for susceptible samples, for cases where a minimal invasive preparation procedure is needed, and for the preparation of crystals from specific areas, complex material architectures and materials that cannot be prepared with common methods (breaking or grinding).
A phase-retrieval toolbox for X-ray holography and tomography
Authors: Lohse Leon M. , Robisch Anna-Lena , Töpperwien Mareike , Maretzke Simon , Krenkel Martin , Hagemann Johannes , Salditt Tim
Published: April 2020

Propagation-based phase-contrast X-ray imaging is by now a well established imaging technique, which – as a full-field technique – is particularly useful for tomography applications. Since it can be implemented with synchrotron radiation and at laboratory micro-focus sources, it covers a wide range of applications. A limiting factor in its development has been the phase-retrieval step, which was often performed using methods with a limited regime of applicability, typically based on linearization. In this work, a much larger set of algorithms, which covers a wide range of cases (experimental parameters, objects and constraints), is compiled into a single toolbox – the HoloTomoToolbox – which is made publicly available. Importantly, the unified structure of the implemented phase-retrieval functions facilitates their use and performance test on different experimental data.
Methods to improve UAV performance using hybrid-electric architectures
Authors: Yezeguelian Axel , Isikveren Askin T.
Published: April 2020

Purpose

When comparing and contrasting different types of fixed-wing military aircraft on the basis of an energetic efficiency figure-of-merit, unmanned aerial vehicles (UAVs) dedicated to tactical medium-altitude long-endurance (MALE) operations appear to have significant potential when hybrid-electric propulsion and power systems (HEPPS) are implemented. Beginning with a baseline Eulair drone, this paper aims to examine the feasibility of retro-fitting with an Autarkic-Parallel-HEPPS architecture to enhance performance of the original single diesel engine.

Design/methodology/approach

In view of the low gravimetric specific energy performance attributes of batteries in the foreseeable future, the best approach was found to be one in which the Parallel-HEPPS architecture has the thermal engine augmented by an organic rankine cycle (ORC). For this study, with the outer mould lines fixed, the goal was to increase endurance without increasing the Eulair drone maximum take-off weight beyond an upper limit of +10%. The intent was to also retain take-off distance and climb performance or, where possible, improve upon these aspects. Therefore, as the focus of the work was on power scheduling, two primary control variables were identified as degree-of-hybridisation for useful power and cut-off altitude during the en route climb phase. Quasi-static methods were used for technical sub-space modelling, and these modules were linked into a constrained optimisation algorithm.

Findings

Results showed that an Autarkic-Parallel-HEPPS architecture comprising an ORC thermal energy recovery apparatus and high-end year-2020 battery, the endurance of the considered aircraft could be increased by 11%, i.e. a total of around 28 h, including de-icing system, in-flight recharge and emergency aircraft recovery capabilities. The same aircraft with the de-icing functionality removed resulted in a 20% increase in maximum endurance to 30 h.

Practical implications

Although the adoption of Series/Parallel-HEPPS only solutions do tend to generate questionable improvements in UAV operational performance, combinations of HEPPS with energy recovery machines that use, for example, an ORC, were found to have merit. Furthermore, such architectural solutions could also offer opportunity to facilitate additional functions like de-icing and emergency aircraft recovery during engine failure, which is either not available for UAVs today or prove to be prohibitive in terms of operational performance attributes when implemented using a conventional PPS approach.

Originality/value

This technical paper highlights a new degree of freedom in terms of power scheduling during climbing transversal flight operations. A control parameter of cut-off altitude for all types of HEPPS-based aircraft should be introduced into the technical decision-making/optimisation/analysis scheme and is seen to be a fundamental aspect when conducting trade-studies with respect to degree-of-hybridisation for useful power.
Pilot-aircraft haptic feedback tests
Authors: Zikmund Pavel , Horpatzká Michaela , Dubnický Lukáš , Macík Miroslav , Jebáček Ivo
Published: April 2020

Purpose

The purpose of this study is to lead to an improvement in pilot-aircraft interaction. The goal of the performed tests is an assessment of haptic feedback, which mediates flight parameters to the pilot. Pedals indicate side-slip angle by vibrations, whereas a sliding element inside the control stick is able to continuously indicate both angles of attack and side-slip.

Design/methodology/approach

Haptic feedback applied on rudder pedals and control stick were tested on a flight simulator and flight tests in a couple of tasks. Pilot workload, readability of feedback and side-slip were then evaluated when the flight was turning.

Findings

As a useful instrument for aircraft control, haptic feedback was assessed. The feedback settings were then individually perceived, and haptic feedback slightly improved side-slip while turning in a flight test; however, the results are not statistically significant.

Practical implications

The tests provided promising results for human pilot performance. The training phase and personal settings of haptic feedback is an approach for improving the performance of human pilots.

Originality/value

The designed and tested device is a unique tool for improving pilot-aircraft interaction. This study brings valuable experiences from its flight simulator and in-flight tests.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/AEAT-12-2019-0265/
Are jacks-of-all-trades successful entrepreneurs? Revisiting Lazear's theory of entrepreneurship
Authors: Kurczewska Agnieszka , Mackiewicz Michał
Published: April 2020

Purpose

The purpose of this paper is to identify human capital factors that pertain both to setting up and successfully running a business. To achieve this objective, the authors apply and extend the theory of career choice offered by Lazear (2005) that explains individual selection into entrepreneurship.

Design/methodology/approach

The authors hypothesise that individuals with broader educational and professional backgrounds are more likely to start a business and are more likely to run a business in the long term. The authors tested the hypotheses using unique data from 800 current entrepreneurs, 800 employees who were previously entrepreneurs and 842 employees with no entrepreneurial experience, by means of a logit regression with robust standard errors and extensive robustness checks.

Findings

The authors empirically show that individuals with more diverse educational and professional backgrounds tend to have both greater chances of starting a company, as well as a higher probability of entrepreneurial success. Surprisingly, having managerial experience proved to exert a negative influence on the likelihood of starting a business while having an insignificant impact on the odds of entrepreneurial success.

Research limitations/implications

The findings are informative for those planning or pursuing an entrepreneurial career, but they are also relevant for the purpose of entrepreneurship education.

Originality/value

The author's extend the body of research supporting Lazear's (2005) theory by showing that broad education and professional experience not only contribute to a higher propensity to start a company but they are also success factors in business per se.
Predicting abandonment of brand social media accounts
Authors: Sanders W. Scott , Freberg Karen
Published: April 2020

Purpose

The purpose of this study is to describe online factors that predict abandonment of social media accounts.

Design/methodology/approach

This study conducts an analysis of 3,380 Twitter corporate brand accounts belonging to Interbrand's top 100 global brands to determine if brand posting behavior and network position predicts the length of time accounts survive.

Findings

Results found that both posting volume and consistency as well as network position were significant predictors of account survival time yet surprisingly, the number of account followers was not. Brand social media accounts were often not formally closed or protected but allowed to fall inactive.

Originality/value

Despite the existence of a healthy body of research on why individuals quit social media, there is little research on how brands' abandon their social media accounts or the factors that predict abandonment. This study identifies indicators for at-risk accounts and provides guidance regarding best practices when abandoning accounts.
New branch establishment – Keerthar Food Restaurant
Authors: Shaikh Abdul Rehman , Qazi Asad Ali
Published: April 2020

Learning outcomes

The learning outcomes are as follows: to understand and develop the framework for the selection of location; to understand the resource-based theory (RBT) of entrepreneurship and develop the framework for RBT; to project a firm’s growth path in terms of achieving size; to analyze the important obstacles for same; and to calculate and forecast accurate market demand and customer footfall.

Case overview/synopsis

Abdul Jabbar Soomro recently quit his corporate job to achieve one of his dreams. He had always wanted to establish his own business venture and to be a successful entrepreneur. After completing his MBA in 2005, he started his career with one of the multinational companies at a very handsome salary. However, after 10 years of a corporate job, he left the job and started his own food venture. He faced a lot of challenges from his family, but he pursued his dream and started searching for the best location. By October 2015, he was all set and ready for the inauguration of his branch. He received a very positive response from market, and the number of customers kept on increasing on a daily basis. The major reasons behind his success were the environment, ambiance and product quality as promised. After two years of successful operations, Abdul Jabbar Soomro was wondering either to start a new branch or to proceed for expansion and better space management at the existing branch. He was unable to accommodate all the customers at his existing space.

Complexity academic level

BBA

Supplementary materials

Teaching Notes are available for educators only.

Subject code

CSS: 3 Entrepreneurship
HMSolution and the search for product-market fit
Authors: Leiva Fernando , Kuschel Katherina
Published: April 2020

Learning outcomes

The learning outcomes are as follows: business model pivot, minimum viable product, strategic alliances, return on equity and burn-rate.

Case overview/synopsis

HMSolution’s (HM’s) mission is removing arsenic from drinking water. The case tells how HMS pivoted its business model between 2014 and 2015 and its challenge when faced with several growth opportunities. The first possible partner company proposed adopting HMS’s technology through either an alliance or outsourcing. The second company wanted to acquire HMS. However, Margaret – the founder and CEO – managed to find a third option in the form of an important sanitation sewage treatment company in Chile with international presence, with which she could reach a wider territory in her country of origin, as well as in other countries where that company had a presence. This case study presents Margaret’s dilemma of deciding the best course to follow and finding the best fit for her product and the needs of the market.

Complexity academic level

The instructor can adapt the requirements and depth of the topics addressed, ranging from an undergraduate audience to an executive training audience. Undergraduate courses, namely, entrepreneurship, business creation, administration and strategy. For students of business careers, administration, commercial engineering, industrial civil engineering and industrial engineering. Continuous training, namely, entrepreneurship, business creation, administration and strategy.

Supplementary materials

Teaching Notes are available for educators only.

Subject code

CSS 3: Entrepreneurship.