bluuebunny/crossref_metadata_2025 huggingface dataset:
Visual processing speed is linked to functional connectivity between right frontoparietal and visual networks
Authors: Küchenhoff Svenja , Sorg Christian , Schneider Sebastian , Kohl Oliver , Müller Hermann J. , Finke Kathrin , Ruiz-Rizzo Adriana L.
Published: November 2020

Visual information processing requires an efficient visual attention system. The neural theory of visual attention (TVA) proposes that visual processing speed depends on the coordinated activity between frontoparietal and occipital brain areas. Previous research has shown that the coordinated activity between (i.e., functional connectivity, ‘inter-FC’) cingulo-opercular (COn) and right-frontoparietal (RFPn) networks is linked to visual processing speed. However, evidence for how inter-FC of COn and RFPn withvisualnetworks links to visual processing speed is still missing. Forty-eight healthy human adult participants (27 females) underwent resting-state (rs-)fMRI and performed a whole-report psychophysical task. To obtain inter-FC, we analyzed the entire frequency range available in our rs-fMRI data (i.e., 0.01-0.4 Hz) to avoid discarding neural information. Following previous approaches, we analyzed the data across frequency bins (Hz): Slow-5 (0.01-0.027), Slow-4 (0.027-0.073), Slow-3 (0.073-0.198), and Slow-2 (0.198-0.4). We used the mathematical TVA framework to estimate an individual, latent-level visual processing speed parameter. We found that visual processing speed was negatively associated with inter-FC between RFPn and visual networks in Slow-5 and Slow-2, with no corresponding significant association for inter-FC between COn and visual networks. These results provide first empirical evidence that links inter-FC between RFPn and visual networks with the visual processing speed parameter. These findings suggest a direct connectivity between occipital and right frontoparietal, but not frontoinsular, regions, to support visual processing speed.

Significance statement

An efficient visual processing is at the core of visual cognition. Here, we provide evidence for a brain correlate of how fast individuals process visual stimuli. We used mathematical modeling of performance in a visual report task to estimate visual processing speed. A frequency-based analysis of resting-state fMRI signals revealed that functional connectivity between the right frontoparietal network and primary and dorsal occipital networks is linked to visual processing speed. This link was present in the slowest, typical frequency of the fMRI signal but also in the higher frequencies that are routinely discarded. These findings imply that the coordinated spontaneous activity between right frontoparietal and occipital regions supports the individual potential of the visual system for efficient processing.
Biophysical characterization of two commercially available preparations of the drug containingEscherichia coliL-Asparaginase 2
Authors: de Araújo Talita Stelling , Scapin Sandra M. N. , de Andrade William , Fasciotti Maira , de Magalhães Mariana T. Q. , Almeida Marcius S. , Lima Luís Maurício T. R.
Published: November 2020

The hydrolysis of asparagine and glutamine by L-asparaginase has been used to treat acute lymphoblastic leukemia for over four decades. Each L-asparaginase monomer has a long loop that closes over the active site upon substrate binding, acting as a lid. Here we present a comparative study two commercially available preparations of the drug containing Escherichia coli L-Asparaginase 2, performed by a comprehensive array of biophysical and biochemical approaches. We report the oligomeric landscape and conformational and dynamic plasticity ofE. colitype 2 L-asparaginase (EcA2) present in two different formulations, and its relationship with L-aspartic acid, which is present in Aginasa, but not in Leuginase. EcA2 shows a composition of monomers and oligomers up to tetramers, which is mostly not altered in the presence of L-Asp. The N-terminal loop of Leuginase, which is part of the active site is flexibly disordered, but gets ordered as in Aginasa in the presence os L-Asp, while L-Glu only does so to a limited extent. Ion-mobility spectrometry–mass spectrometry reveals two conformers for the monomeric EcA2, one of which can selectively bind to L-Asp and L-Glu. Aginasa has higher resistance toin vitroproteolysis than Leuginase, and this is directly related to the presence of L-Asp.
Rothmund-Thomson Syndrome-like RECQL4 truncating mutations cause a haploinsufficient low bone mass phenotype in mice
Authors: Castillo-Tandazo Wilson , Frazier Ann E , Sims Natalie A , Smeets Monique F , Walkley Carl R
Published: November 2020

Rothmund-Thomson Syndrome (RTS) is an autosomal recessive disorder characterized by poikiloderma, sparse or absent hair, and defects in the skeletal system such as bone hypoplasia, short stature, low bone mass, and an increased incidence of osteosarcoma. RTS type 2 patients typically present with germline compound bi-allelic protein-truncating mutations ofRECQL4. As existing murine models predominantly employRecql4null alleles, we have here attempted to more accurately model the mutational spectrum of RTS by generating mice with patient-mimicking truncatingRecql4mutations. We found that truncating mutations impaired stability and subcellular localization of RECQL4, which translated to a homozygous embryonic lethality and haploinsufficient low bone mass and reduced cortical bone thickness phenotypes. Combination of a truncating mutation with a conditionalRecql4null allele demonstrated that these defects were intrinsic to the osteoblast lineage. However, the truncating mutations did not promote tumorigenesis, even after exposure to irradiation. We also utilized murineRecql4null cells to assess the impact of a wider range of humanRECQL4mutations using anin vitrocomplementation assay. We found differential effects of distinct RECQL4 mutations. While some created unstable protein products, others altered subcellular localization of the protein. Interestingly, the severity of the phenotypes correlated with the extent of protein truncation. Collectively, our results reveal that truncating RECQL4 mutations lead to the development of an osteoporosis-like phenotype through defects in early osteoblast progenitors in mice and identify RECQL4 gene dosage as a novel regulator of bone mass.
Biased re-orientation in the chemotaxis of peritrichous bacteria
Authors: Nakai T. , Ando T. , Goto T
Published: November 2020

Many kinds of peritrichous bacteria that repeat runs and tumbles by using multiple flagella exhibit chemotaxis by sensing a difference in the concentration of the attractant or repellent between two adjacent time points. If a cell senses that the concentration of an attractant has increased, their flagellar motors decrease the switching frequency from counterclockwise to clockwise direction of rotation, which causes a longer run in swimming up the concentration gradient than swimming down. We investigated the turn angle in tumbles of peritrichous bacteria swimming across the concentration gradient of a chemoattractant because the change in the switching frequency in the rotational direction may affect the way tumbles. We tracked several hundreds of runs and tumbles of singleSalmonella typhimuriumcells in the concentration gradient of L-serine, and found that the turn angle depends on the concentration gradient that the cell senses just before the tumble. The turn angle is biased toward a smaller value when the cells swim up the concentration gradient, whereas the distribution of the angle is almost uniform (random direction) when the cells swim down the gradient. The effect of the observed bias in the turn angle on the degree of chemotaxis was investigated by random walk simulation. In the concentration field where attractants diffuse concentrically from the point source, we found that this angular distribution clearly affects the reduction of the mean square displacement of the cell that has started at the attractant source, that is, the bias in the turn angle distribution contributes to chemotaxis in peritrichous bacteria.

Statement of Significance

We found another aspect in the chemotactic behavior of peritrichous bacteria. Chemotactic behaviors in peritrichous bacteria were predicted to be observed at the turn angles during tumbles motion as well as at the duration of runs; smaller changes in the swimming direction of cells swimming up the attractant’s gradient can be observed. This behavior is appropriate because the nature of bacterial chemotaxis changes the switching rate of the rotational direction of the flagellar motors according to the environment. Cells swimming upward reduce the turn angle by switching fewer flagellar motors to loosen flagellar filaments from the bundle during tumbles. We have shown that this prediction is correct.
The chemotherapeutic drug methotrexate selects for antibiotic resistance
Authors: Gudmundsdóttir Jónína S. , Fredheim Elizabeth G. A. , Koumans Catharina I. M. , Hegstad Joachim , Tang Po-Cheng , Andersson Dan I. , Samuelsen Ørjan , Johnsen Pål J.
Published: November 2020

Understanding drivers of antibiotic resistance evolution is fundamental for designing optimal treatment strategies and interventions to reduce the spread of antibiotic resistance. Various cytotoxic drugs used in cancer chemotherapy have antibacterial properties, but how bacterial populations are affected by these selective pressures is unknown. Here we test the hypothesis that the widely used cytotoxic drug methotrexate affects the evolution and selection of antibiotic resistance through the same mechanisms as the antibiotic trimethoprim. We show that methotrexate can select for trimethoprim resistance determinants located on the chromosome or a plasmid in clinical strains ofEscherichia coli. Additionally, methotrexate can co-select for virtually any antibiotic resistance determinant when present together with trimethoprim resistance on a multidrug-resistance clinical plasmid. These selective effects occur at concentrations 40- to >320-fold below the methotrexate minimal inhibitory concentration forE. coli, suggesting a selective role of methotrexate chemotherapy for antibiotic resistance in patients that strongly depend on effective antibiotic treatment.

Significance statement

The presented data show that methotrexate has the potential to select for virtually any given antibiotic resistance gene when genetically linked to trimethoprim resistance. This study highlights the need for increased awareness of the presence of acquired antibiotic resistance determinants in the gut of patients with impaired immunity undergoing methotrexate treatment to preserve the effects of downstream antibiotic treatments.
Structure of HIV-1 gp41 with its membrane anchors targeted by neutralizing antibodies
Authors: Caillat Christophe , Guilligay Delphine , Torralba Johana , Friedrich Nikolas , Nieva Jose L. , Trkola Alexandra , Chipot Christophe , Dehez François , Weissenhorn Winfried
Published: November 2020

The HIV-1 gp120/gp41 trimer undergoes a series of conformational changes in order to catalyze gp41-induced fusion of viral and cellular membranes. Here, we present the crystal structure of gp41 locked in a fusion intermediate state by an MPER-specific neutralizing antibody. The structure illustrates the conformational plasticity of the six membrane anchors arranged asymmetrically with the fusion peptides and the transmembrane regions pointing into different directions. Hinge regions located adjacent to the fusion peptide and the transmembrane region facilitate the conformational flexibility that allows high affinity binding of broadly neutralizing anti-MPER antibodies. Molecular dynamics simulation of the MPER Ab-induced gp41 conformation reveals the transition into the final post-fusion conformation with the central fusion peptides forming a hydrophobic core with flanking transmembrane regions. This, thus, suggests that MPER-specific broadly neutralizing antibodies can block final steps of refolding of the fusion peptide and the transmembrane region, which is required for completing membrane fusion.
Comprehensive dataset of shotgun metagenomes from stratified freshwater lakes and ponds
Authors: Buck Moritz , Garcia Sarahi L. , Vidal Leyden Fernandez , Martin Gaëtan , Rodriguez Gustavo A. Martinez , Saarenheimo Jatta , Zopfi Jakob , Bertilsson Stefan , Peura Sari
Published: November 2020

Stratified lakes and ponds featuring steep oxygen gradients are significant net sources of greenhouse gases and hotspots in the carbon cycle. Despite their significant biogeochemical roles, the microbial communities, especially in the oxygen depleted compartments, are poorly known. Here, we present a comprehensive dataset including 267 shotgun metagenomes from 41 stratified lakes and ponds mainly located in the boreal and subarctic regions, but also including one tropical reservoir and one temperate lake. For most lakes and ponds, the data includes a vertical sample set spanning from the oxic surface to the anoxic bottom layer. The majority of the samples were collected during the open water period, but also a total of 29 samples were collected from under the ice. In addition to the metagenomic sequences, the dataset includes environmental variables for the samples, such as oxygen, nutrient and organic carbon concentrations. The dataset is ideal for further exploring the microbial taxonomic and functional diversity in freshwater environments and potential climate change impacts on the functioning of these ecosystems.
A retrospective cluster analysis of COVID-19 cases by county
Authors: Megahed Fadel M. , Jones-Farmer L. Allison , Rigdon Steven E.
Published: November 2020

The COVID-19 pandemic in the U.S. has exhibited distinct waves, the first beginning in March 2020, the second beginning in early June, and additional waves currently emerging. Paradoxically, almost no county has exhibited this multi-wave pattern. We aim to answer three research questions: (1) How many distinct clusters of counties exhibit similar COVID-19 patterns in the time-series of daily confirmed cases?; (2) What is the geographic distribution of the counties within each cluster? and (3) Are county-level demographic, socioeconomic and political variables associated with the COVID-19 case patterns? We analyzed data from counties in the U.S. from March 1 to October 24, 2020. Time series clustering identified clusters in the daily confirmed cases of COVID-19. An explanatory model was used to identify demographic, socioeconomic and political variables associated the cluster patterns. Four patterns were identified from the timing of the outbreaks including counties experiencing a spring, an early summer, a late summer, and a fall outbreak. Several county-level demographic, socioeconomic, and political variables showed significant associations with the identified clusters. The timing of the outbreak is related both to the geographic location within the U.S. and several variables including age, poverty distribution, and political association. These results show that the reported pattern of cases in the U.S. is observed through aggregation of the COVID-19 cases, suggesting that local trends may be more informative. The timing of the outbreak varies by county, and is associated with important demographic, socioeconomic and geographic factors.
The transcription factor Rreb1 regulates epithelial architecture and invasiveness in gastrulating mouse embryos
Authors: Morgani Sophie M. , Su Jie , Nichols Jennifer , Massagué Joan , Hadjantonakis Anna-Katerina
Published: November 2020

Ras-responsive element-binding protein 1 (Rreb1) is a zinc-finger transcription factor downstream of RAS signaling.Rreb1has been implicated in cancer but little is known about its role in mammalian non-disease states. Here, we found that Rreb1 is essential for mouse embryonic development. Loss ofRreb1led to a reduction in the expression of vasculogenesis factors, cardiovascular defects and embryonic lethality. During gastrulation, the absence ofRreb1also resulted in the upregulation of cytoskeleton-associated genes, a change in the organization of F-ACTIN and adherens junctions within the pluripotent epiblast, and perturbed epithelial architecture characterized by irregular tissue folding and abnormal accumulations of cells. Moreover,Rreb1mutant cells ectopically exited the epiblast epithelium through the underlying basement membrane, paralleling cell behaviors observed during metastasis. Thus, disentangling the function of Rreb1 in development could shed light on its role in cancer and other diseases involving loss of epithelial integrity.
Functional characterization of the cnidarian antiviral immune response reveals ancestral complexity
Authors: Lewandowska Magda , Sharoni Ton , Admoni Yael , Aharoni Reuven , Moran Yehu
Published: November 2020

Animals developed a broad repertoire of innate immune sensors and downstream effector cascades for defense against RNA viruses. Yet, this system highly varies between different bilaterian animals, masking its ancestral state. In this study we aimed to characterize the antiviral immune response of the cnidarianNematostella vectensisand decipher the function of the retinoic acid-inducible gene I-like receptors (RLRs) known to detect viral double-stranded RNA (dsRNA) in bilaterians, but activate different antiviral pathways in vertebrates and nematodes. We show that a mimic of long viral dsRNA triggers a complex antiviral immune response bearing features distinctive for both vertebrate and invertebrate systems. Furthermore, the results of affinity assays and knockdown experiments provide functional evidence for the conserved role of RLRs in initiating immune response to dsRNA that originated before the cnidarian-bilaterian split and lay a strong foundation for future research on the evolution of the immune responses to RNA viruses.
Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs
Authors: Brighi Carlo , Salaris Federico , Soloperto Alessandro , Cordella Federica , Ghirga Silvia , de Turris Valeria , Rosito Maria , Porceddu Pier Francesca , Reggiani Angelo , Rosa Alessandro , Di Angelantonio Silvia
Published: November 2020

Fragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of theFMR1gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models, however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenicFMR1knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show increased proliferation of GFAP positive cells, likely astrocytes, increased spontaneous network activity and depolarizing GABAergic transmission. Cortical brain organoid models show increased proliferation of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.
Functional correlates of immediate early gene expression in mouse visual cortex
Authors: Mahringer David , Zmarz Pawel , Okuno Hiroyuki , Bito Haruhiko , Keller Georg B.
Published: November 2020

Abstract

During visual development, response properties of layer 2/3 neurons in visual cortex are shaped by experience. Both visual and visuomotor experience are necessary to coordinate the integration of bottom-up visual input and top-down motor-related input. Whether visual and visuomotor experience engage different plasticity mechanisms, possibly associated with the two separate input pathways, is still unclear. To begin addressing this, we measured the expression level of three different immediate early genes (IEG) (c-fos, egr1 or Arc) and neuronal activity in layer 2/3 neurons of visual cortex before and after a mouse’s first visual exposure in life, and subsequent visuomotor learning. We found that expression levels of all three IEGs correlated positively with neuronal activity, but that first visual and first visuomotor exposure resulted in differential changes in IEG expression patterns. In addition, IEG expression levels differed depending on whether neurons exhibited primarily visually driven or motor-related activity. Neurons with strong motor-related activity preferentially expressed EGR1, while neurons that developed strong visually driven activity preferentially expressed Arc. Our findings are consistent with the interpretation that bottom-up visual input and top-down motor-related input are associated with different IEG expression patterns and hence possibly also with different plasticity pathways.
Morc3 silences endogenous retroviruses by enabling Daxx-mediated H3.3 incorporation
Authors: Groh Sophia , Milton Anna Viktoria , Marinelli Lisa , Sickinger Cara V. , Bollig Heike , de Almeida Gustavo Pereira , Forné Ignasi , Schmidt Andreas , Imhof Axel , Schotta Gunnar
Published: November 2020

Endogenous retroviruses (ERVs) comprise a significant portion of mammalian genomes. Although, specific ERV loci feature regulatory roles for host gene expression, most ERV integrations are transcriptionally repressed by Setdb1 mediated H3K9me3 and DNA methylation. However, the protein network which regulates deposition of these chromatin modifications is still incompletely understood. Here, we performed a genome-wide sgRNA screen for genes involved in ERV silencing and identified the GHKL ATPase protein Morc3 as top scoring hit. Morc3 knock-out cells display de-repression, reduced H3K9me3 and increased chromatin accessibility of distinct ERV classes. We found that the GHKL ATPase domain of Morc3 is critical for ERV silencing, since mutants which cannot bind ATP, or which are defective in ATP hydrolysis cannot rescue the Morc3 ko phenotype. Proteomic analysis revealed that Morc3 mutant protein which cannot bind ATP fails to interact with the H3.3 chaperone Daxx. This interaction depends on Morc3 SUMOylation, as Daxx lacking the SUMO interaction domain shows reduced association with Morc3. Notably, in Morc3 ko cells, we observed strongly reduced H3.3 on Morc3 binding sites. Thus, our data demonstrate Morc3 as critical regulator of Daxx-mediated H3.3 incorporation to ERV regions.
Nucleosome structural variations in interphase and metaphase chromosomes
Authors: Arimura Yasuhiro , Shih Rochelle M. , Froom Ruby , Funabiki Hironori
Published: November 2020

Structural heterogeneity of nucleosomes in functional chromosomes is unknown. Here we report cryo-EM structures of nucleosomes isolated from interphase and metaphase chromosomes at up to 3.4 Å resolution. Averaged chromosomal nucleosome structures are highly similar to canonical left-handed recombinant nucleosome crystal structures, with DNA being selectively stabilized at two defined locations. Compared to free mono-nucleosomes, which exhibit diverse linker DNA angles and large structural variations in H3 and H4, chromosomal nucleosome structures are much more uniform, characterized by a closed linker DNA angle with interactions between the H2A C-terminal tail and DNA. Exclusively for metaphase nucleosomes, structures of the linker histone H1.8 at the on-dyad position of nucleosomes can be reconstituted at 4.4 Å resolution. We also report diverse minor nucleosome structural variants with rearranged core histone configurations, which are more prevalent in metaphase than in interphase chromosomes. This study presents structural characteristics of nucleosomes in interphase and mitotic chromosomes.

Highlights

3.4~ Å resolution nucleosome structures from interphase and metaphase chromosomes

Nucleosome structures in chromosomes are more uniform than in free mono-nucleosomes

Histone H1.8 binds to the nucleosome dyad axis in metaphase chromosomes

Nucleosome structural variants are more prevalent in metaphase than in interphase

NOTES TO READERS

We would like to emphasize the importance of supplemental movies S1-S3, which should greatly help readers to understand characteristics of the nucleosome structural variants that we report in this study.
Stenoparib, an inhibitor of cellular poly (ADP-ribose) polymerase (PARP), blocks replication of the SARS-CoV-2 human coronavirusin vitro
Authors: Stone Nathan E. , Jaramillo Sierra A. , Jones Ashley N. , Vazquez Adam J. , Martz Madison , Versluis Lora M. , Raniere Marlee O. , Nunnally Haley E. , Zarn Katherine E. , Nottingham Roxanne , Sahl Jason W. , Wagner David M. , Knudsen Steen , Settles Erik W. , Keim Paul S. , French Christopher T.
Published: November 2020

By late 2020, the coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2 has caused tens of millions of infections and over 1 million deaths worldwide. A protective vaccine and more effective therapeutics are urgently needed. We evaluated a new PARP inhibitor, stenoparib, which was recently advanced to Stage II clinical trials for treatment of ovarian cancer, for activity against human respiratory coronaviruses, including SARS-CoV-2,in vitro. Stenoparib exhibits dose-dependent suppression of SARS-CoV-2 multiplication and spread in Vero E6 monkey kidney and Calu-3 human lung adenocarcinoma cells. Stenoparib was also strongly inhibitory to the HCoV-NL63 human seasonal respiratory coronavirus. Compared to remdesivir, which inhibits viral replication downstream of cell entry, stenoparib impedes entry and post-entry processes as determined by time-of-addition (TOA) experiments. Moreover, a 10 μM dosage of stenoparib – below the approximated 25.5 μM half-maximally effective concentration (EC50), combined with 0.5 μM remdesivir suppressed coronavirus growth by more than 90%, indicating a potentially synergistic effect for this drug combination. Stenoparib as a standalone or as part of combinatorial therapy with remdesivir should be a valuable addition to the arsenal against COVID-19.

Importance

New therapeutics are urgently needed in the fight against COVID-19. Repurposing drugs that are either already approved for human use or are in advanced stages of the approval process can facilitate more rapid advances toward this goal. The PARP inhibitor stenoparib may be such a drug, as it is currently in Stage II clinical trials for the treatment of ovarian cancer and its safety and dosage in humans has already been established. Our results indicate that stenoparib possesses strong antiviral activity against SARS-CoV-2 and other coronavirusesin vitro.This activity appears to be based on multiple modes of action, where both pre-entry and post-entry viral replication processes are impeded. This may provide a therapeutic advantage over many current options that have a narrower target range. Moreover, our results suggest that stenoparib and remdesivir in combination may be especially potent against coronavirus infection.
A cell-to-patient machine learning transfer approach uncovers novel basal-like breast cancer prognostic markers amongst alternative splice variants
Authors: Villemin Jean-Philippe , Lorenzi Claudio , Oldfield Andrew , Cabrillac Marie-Sarah , Ritchie William , Luco Reini F.
Published: November 2020

Background

Breast cancer is amongst the 10 first causes of death in women worldwide. Around 20% of patients are misdiagnosed leading to early metastasis, resistance to treatment and relapse. Many clinical and gene expression profiles have been successfully used to classify breast tumours into 5 major types with different prognosis and sensitivity to specific treatments. Unfortunately, these profiles have failed to subclassify breast tumours into more subtypes to improve diagnostics and survival rate. Alternative splicing is emerging as a new source of highly specific biomarkers to classify tumours in different grades. Taking advantage of extensive public transcriptomics datasets in breast cancer cell lines (CCLE) and breast cancer tumours (TCGA), we have addressed the capacity of alternative splice variants to subclassify highly aggressive breast cancers.

Results

Transcriptomics analysis of alternative splicing events between luminal, basal A and basal B breast cancer cell lines identified a unique splicing signature for a subtype of tumours, the basal B, whose classification is not in use in the clinic yet. Basal B cell lines, in contrast with luminal and basal A, are highly metastatic and express epithelial-to-mesenchymal (EMT) markers, which are hallmarks of cell invasion and resistance to drugs. By developing a semi-supervised machine learning approach, we transferred the molecular knowledge gained from these cell lines into patients to subclassify basal-like triple negative tumours into basal A- and basal B-like categories. Changes in splicing of 25 alternative exons, intimately related to EMT and cell invasion such as ENAH, CD44 and CTNND1, were sufficient to identify the basal-like patients with the worst prognosis. Moreover, patients expressing this basal B-specific splicing signature also expressed newly identified biomarkers of metastasis-initiating cells, like CD36, supporting a more invasive phenotype for this basal B-like breast cancer subtype.

Conclusions

Using a novel machine learning approach, we have identified an EMT-related splicing signature capable of subclassifying the most aggressive type of breast cancer, which are basal-like triple negative tumours. This proof-of-concept demonstrates that the biological knowledge acquired from cell lines can be transferred to patients data for further clinical investigation. More studies, particularly in 3D culture and organoids, will increase the accuracy of this transfer of knowledge, which will open new perspectives into the development of novel therapeutic strategies and the further identification of specific biomarkers for drug resistance and cancer relapse.
Homemade Bread: Repurposing an Ancient Technology forin vitroTissue Engineering
Authors: Holmes Jessica T. , Jaberansari Ziba , Collins William , Latour Maxime Leblanc , Modulevsky Daniel J. , Pelling Andrew E.
Published: November 2020

Numerous synthetic and naturally-occurring biomaterials have been developed to provide such architectures to support the proliferation of mammalian cells in vitro and in vivo. Our group, and others, have shown that scaffolds derived from plants can be utilized for tissue engineering applications in biomedicine and in the burgeoning cultured meat industry. Such scaffolds are ideally straightforward and inexpensive to prepare, allowing researchers to take advantage of their intrinsic 3D microarchitectures. These efforts inspired us to continue to pursue the development of novel and unconventional biomaterials that are easily produced and high performingin vitro. With this in mind, few plant-derived materials are more ubiquitous than bread. Having observed the porosity of the crumb (i.e. the internal bulk) we sought to investigate whether it might support the proliferation of mammalian cellsin vitro. Here, we develop and validate a yeast-free “soda bread” that maintains its mechanical stability over several weeks in culture conditions. Importantly, we also demonstrate that control over the mechanical stability of the scaffold can also be achieved with both chemical and enzymatic means. The scaffolding is a heterogeneous and complex structure of isolated and interconnected pores which allow for the proliferation of multiple cell types. We demonstrate here that mouse fibroblasts, myoblasts and pre-osteoblasts are able to proliferate up to four weeks in culture. Immunohistochemistry demonstrates that the fibroblasts are able to deposit their own fibronectin extracellular matrix and that mouse myoblasts are able to differentiate and fuse into myotubes. Although the pre-osteoblasts proliferated over the course of four weeks their ability to differentiate was inconclusive. Metabolic analyses of proliferation, cytotoxicity and oxidative stress reveal that cells remain highly viable and functional on these novel bread scaffolds. While the results presented in this proof-of-concept study create many new questions and opportunities, the results open up novel possibilities in the development of edible scaffolds that may be utilized in future food applications. Bread derived scaffolds represent a surprising alternative to synthetic or animal-derived scaffolds for addressing a diverse variety of tissue engineering challenges in food science. Future studies will delve deeper into investigating these how possibilities might take advantage of the immense breadth of knowledge about bread making and examine their applicability in the development of lab grown foods and broader applications in cellular agriculture.
Drivers of digital adoption: a multiple case analysis among low and high-tech industries in Malaysia
Authors: Lee Yan Yin , Falahat Mohammad , Sia Bik Kai
Published: November 2020

Purpose

This paper identifies the forces that drive digital adoption among SMEs from low and high-tech industries in Malaysia.

Design/methodology/approach

This research uses multiple case analyses based on data gathered by in-depth interviews with key representatives of 20 firms from low and high-tech industries in Malaysia.

Findings

The findings suggest that digital adoption among SMEs derives by four fundamental forces, which are sales, marketing, process improvement and product development.

Research limitations/implications

This study employed qualitative research, but lack of geographic diversity limits the generalisability of the case findings. This study provides several suggestions to policymakers and technology suppliers on how to encourage adoption of digitalisation among SMEs.

Originality/value

This study proposes a model that presents the critical forces that drive digital adoption for export-oriented firms, thus enriching the knowledge in SME digitalisation literature.
Should hospitals invest in customised on-demand 3D printing for surgeries?
Authors: Chaudhuri Atanu , Naseraldin Hussein , Søberg Peder Veng , Kroll Ehud , Librus Michael
Published: November 2020

Purpose

The purpose of this research is to (1) analyse the effect of customised on-demand 3DP on surgical flow time, its variability and clinical outcomes (2) provide a framework for hospitals to decide whether to invest in 3DP or to outsource.

Design/methodology/approach

The research design included interviews, workshops and field visits. Design science approach was used to analyse the impact of the 3D printing (3DP) interventions on specific outcomes and to develop frameworks for hospitals to invest in 3DP, which were validated through further interviews with stakeholders.

Findings

Evidence from this research shows that deploying customised on-demand 3DP can reduce surgical flow time and its variability while improving clinical outcomes. Such outcomes are obtained due to rapid development of the anatomical model and surgical guides along with precise cutting during surgery.

Research limitations/implications

We outline multiple opportunities for research on supply chain design and performance assessment for surgical 3DP. Further empirical research is needed to validate the results.

Practical implications

The decision to implement 3DP in hospitals or to engage service providers will require careful analysis of complexity, demand, lead-time criticality and a hospital's own objectives. Hospitals can follow different paths in adopting 3DP for surgeries depending on their context.

Originality/value

The operations and supply chain management community has researched on-demand distributed manufacturing for multiple industries. To the best of our knowledge, this is the first paper on customised on-demand 3DP for surgeries.
UK charities and the pandemic: navigating the perfect storm
Authors: Hyndman Noel
Published: November 2020

Purpose

The purpose of this study is to discuss the impact of COVID-19 on the UK charity sector, outline possible opportunities for researchers in accounting/management as a consequence and discuss possible strategies to respond to the pandemic.

Design/methodology/approach

Literature-based personal critical reflection.

Findings

COVID-19 has created a perfect storm for charities, as major swathes of income have been lost, demands on services have increased and some are unable to operate at all because of imposed constraints.

Originality/value

Possible avenues for research, arising from the context of the crisis in the sector, are highlighted. Moreover, several useful strategies are emphasised to enable charities to navigate the crisis.
Food fraud: an international snapshot and lessons for Australia
Authors: Lindley Jade
Published: November 2020

Purpose

Economically motivated food crimes are widespread, and it appears countries and consumers across the globe are affected. Foods targeted and ways of dealing with food crimes vary according to several factors, including the source and destination of the food; demand; availability (e.g. short growing season); price; environmental impacts, such as sustainability (e.g. seafood); likely consumers (e.g. babies); and regulatory controls. Internationally, several foods are well known to be commonly targeted by unscrupulous criminal groups, ultimately leaving unsuspecting consumers exposed economically and physiologically. The purpose of this paper is to understand the nature of food fraud and the criminals committing it.

Design/methodology/approach

Building on a systematic search of international scholarly literature from a wide cross-section of disciplines, parliamentary documents and media articles relating to food crime, this paper cautions the vulnerabilities to food crimes in Australia from a criminological perspective. It draws on crime opportunity theory to explain the modus operandi of criminals engaging in food fraud.

Findings

Inadequate testing regimes, unclear definitions and inadequate laws expose consumers and vulnerable industries to food crimes. With reference to uniquely Australian examples, this paper highlights exposure opportunities and concludes with lessons drawn internationally. Further research is underway to explore how these vulnerabilities can be resolved through closing regulatory gaps and the introduction of innovative technology.

Originality/value

This paper usefully draws on trends in the literature and applies crime opportunity theory to understand how food fraud may present in Australia for everyday foods, as well as emerging and highly prized markets.
Effect of location on access to finance: international evidence on the moderating role of employee training
Authors: Bakhadirov Mukhammadfoik , Pashayev Zakir , Farooq Omar
Published: November 2020

Purpose

The paper answers the following questions: (1) Do firms located in rural areas experience greater problems in accessing financial services? (2) If this is the case, what can these firms do to improve their access to finance?

Design/methodology/approach

This paper uses the pooled logistic regression and the data collected by the World Bank's Enterprise Surveys during the period between 2008 and 2018 to answer the aforementioned questions.

Findings

The results of this paper show that firms headquartered in rural (urban) areas experience greater (lower) problems in accessing finance than other firms. This paper attributes these findings to higher (lower) levels of information asymmetry and lower (higher) levels of density of banking operations in rural (urban) areas. The results of this paper also show that firms headquartered in rural areas can improve their access to finance by increasing the skill levels of their employees.

Originality/value

This paper highlights the actions that rural firms can undertake to overcome the adverse impact of their geographic location.
Do leverage decisions mediate the relationship between board structure and insolvency risk? A comparative mediating role of capital structure and debt maturity
Authors: Hussain Rana Yassir , Wen Xuezhou , Hussain Haroon , Saad Muhammad , Zafar Zuhaib
Published: November 2020

Purpose

Corporate boards monitor managerial decisions as concluded by the monitoring hypothesis. In this scenario, the present study stresses that leverage decisions can be used as a tool to control insolvency risk.

Design/methodology/approach

This study aims at investigating the intervention of capital structure and debt maturity on the relationship between corporate board composition and insolvency risk by employing Preacher and Hayes’s (2008) approach. The study sample comprises 284 firms from 2013 to 2017. Structural equation modeling is used to study the direct and indirect relationships among study variables.

Findings

Results show that debt maturity is a significant mediator between CEO duality and insolvency risk and between board size and insolvency risk relationships. However, the capital structure did not mediate any of the proposed links.

Research limitations/implications

This study suggests using more long-term debt to tackle insolvency risk in listed non-financial firms of Pakistan. It is also inferred that decisions regarding debt maturity are more crucial than capital structure decisions because insolvency risk is concerned.

Originality/value

This study evaluates the comparative mediating role of the debt maturity and the capital structure. Such role is uncommon in the literature addressing the relationship between governance variables and insolvency risk.
A review of learning theories and models underpinning technology-enhanced learning artefacts
Authors: Hammad Rawad , Khan Zaheer , Safieddine Fadi , Ahmed Allam
Published: November 2020

Purpose

Various technology-enhanced learning software and tools exist where technology becomes the main driver for these developments at the expense of pedagogy. The literature reveals the missing balance between technology and pedagogy in the continuously evolving technology-enhanced learning domain. Consequently, e-learners struggle to realise the pedagogical value of such e-learning artefacts. This paper aims to understand the different pedagogical theories, models and frameworks underpinning current technology-enhanced learning artefacts to pave the way for designing more effective e-learning artefacts.

Design/methodology/approach

To achieve this goal, a review is conducted to survey the most influential pedagogical theories, models and frameworks. To carry out this review, five major bibliographic databases have been searched, which has led to identifying a large number of articles. The authors selected 34 of them for further analysis based on their relevance to our research scope. The authors critically analysed the selected sources qualitatively to identify the most dominant learning theories, classify them and map them onto the key characteristics, criticism, approaches, models and e-learning artefacts.

Findings

The authors highlighted the significance of pedagogies underpinning e-learning artefacts. Furthermore, the authors presented the common and special aspects of each theory to support our claim, which is developing a hybrid pedagogical approach. Such a hybrid approach remains a necessity to effectively guide learners and allow them to achieve their learning outcomes using e-learning artefacts.

Originality/value

The authors found that different pedagogical approaches complement rather than compete with each other. This affirms our recommended approach to adopt a hybrid approach for learning to meet learners' requirements. The authors also found that a substantive consideration for context is inevitable to test our evolving understanding of pedagogy.
Environment dependent microbial co‐occurrences across a cyanobacterial bloom in a freshwater lake
Authors: Wu Gang , Ge Leixin , Zhao Na , Liu Fei , Shi Zunji , Zheng Ningning , Zhou Dan , Jiang Xingpeng , Halverson Larry , Xie Bo
Published: November 2020

Microbial taxon–taxon co‐occurrences may directly or indirectly reflect the potential relationships between the members within a microbial community. However, to what extent and the specificity by which these co‐occurrences are influenced by environmental factors remains unclear. In this report, we evaluated how the dynamics of microbial taxon–taxon co‐occurrence is associated with the changes of environmental factors in Nan Lake at Wuhan city, China with a Modified Liquid Association method. We were able to detect more than 1000 taxon–taxon co‐occurrences highly correlated with one or more environmental factors across a phytoplankton bloom using 16S rRNA gene amplicon community profiles. These co‐occurrences, referred to as environment dependent co‐occurrences (ED_co‐occurrences), delineate a unique network in which a taxon–taxon pair exhibits specific, and potentially dynamic correlations with an environmental parameter, while the individual relative abundance of each may not. Microcystis involved ED_co‐occurrences are in important topological positions in the network, suggesting relationships between the bloom dominant species and other taxa could play a role in the interplay of microbial community and environment across various bloom stages. Our results may broaden our understanding of the response of a microbial community to the environment, particularly at the level of microbe–microbe associations.
The microbial safety of fish and fish products: Recent advances in understanding its significance, contamination sources, and control strategies
Authors: Sheng Lina , Wang Luxin
Published: November 2020

Microorganisms play a crucial and unique role in fish and fish product safety. The presence of human pathogens and the formation of histamine caused by spoilage bacteria make the control of both pathogenic and spoilage microorganisms critical for fish product safety. To provide a comprehensive and updated overview of the involvement of microorganisms in fish and fish product safety, this paper reviewed outbreak and recall surveillance data obtained from government agencies from 1998 to 2018 and identified major safety concerns associated with both domestic and imported fish products. The review also summarized all available literature about the prevalence of major and emerging microbial safety concerns, includingSalmonellaspp.,Listeria monocytogenes, andAeromonas hydrophila, in different fish and fish products and the survival of these pathogens under different storage conditions. The prevalence of antibiotic‐resistant bacteria (ARB) and antibiotic‐resistant genes (ARGs), two emerging food safety concerns, is also reviewed. Pathogenic and spoilage microorganisms as well as ARB and ARGs can be introduced into fish and fish products in both preharvest and postharvest stages. Many novel intervention strategies have been proposed and tested for the control of different microorganisms on fish and fish products. One key question that needs to be considered when developing and implementing novel control measures is how to ensure that the measures are cost and environment friendly as well as sustainable. Over the years, regulations have been established to provide guidance documents for good farming and processing practices. To be more prepared for the globalization of the food chain, harmonization of regulations is still needed.