bluuebunny/crossref_metadata_2025 huggingface dataset:
SAMGEP: A Novel Method for Prediction of Phenotype Event Times Using the Electronic Health Record
Authors: Ahuja Yuri , Hong Chuan , Xia Zongqi , Cai Tianxi
Published: March 2021

Objective

While there exist numerous methods to predict binary phenotypes using electronic health record (EHR) data, few exist for prediction of phenotype event times, or equivalently phenotype state progression. Estimating such quantities could enable more powerful use of EHR data for temporal analyses such as survival and disease progression. We propose Semi-supervised Adaptive Markov Gaussian Embedding Process (SAMGEP), a semi-supervised machine learning algorithm to predict phenotype event times using EHR data.

Methods

SAMGEP broadly consists of four steps: (i) assemble time-evolving EHR features predictive of the target phenotype event, (ii) optimize weights for combining raw features and feature embeddings into dense patient-timepoint embeddings, (iii) fit supervised and semi-supervised Markov Gaussian Process models to this embedding progression to predict marginal phenotype probabilities at each timepoint, and (iv) take a weighted average of these supervised and semi-supervised predictions. SAMGEP models latent phenotype states as a binary Markov process, conditional on which patient-timepoint embeddings are assumed to follow a Gaussian Process.

Results

SAMGEP achieves significantly improved AUCs and F1 scores relative to common machine learning approaches in both simulations and a real-world task using EHR data to predict multiple sclerosis relapse. It is particularly adept at predicting a patient’s longitudinal phenotype course, which can be used to estimate population-level cumulative probability and count process estimators. Reassuringly, it is robust to a variety of generative model parameters.

Discussion

SAMGEP’s event time predictions can be used to estimate accurate phenotype progression curves for use in downstream temporal analyses, such as a survival study for comparative effectiveness research.
Motor neuron boutons remodel through membrane blebbing
Authors: Fernandes Andreia R. , Mendes César S. , Gomes Edgar R. , Teodoro Rita O.
Published: March 2021

Wired neurons form new presynaptic boutons in response to increased synaptic activity, but the mechanism by which this occurs remains uncertain. The neuromuscular junction (NMJ) is a synapse formed between motor neurons (MNs) and skeletal muscle fibers and is critical for control of muscle contraction. BecauseDrosophilaMNs have clearly discernible boutons that display robust structural plasticity, it is the ideal system in which to study bouton genesis. Here we show usingex-vivoand by live imaging that in response to depolarization, MNs form new boutons by membrane blebbing, a pressure-driven mechanism used in 3-D migration, but never described as a neuronal remodeling strategy. In accordance, F-actin is decreased during bouton growth (a hallmark of blebs) and we show that non-muscle myosin-II (a master regulator of blebbing) is recruited to newly formed boutons. Furthermore, we discovered that muscle contraction plays a mechanical role in activity-dependent plasticity, promoting bouton addition by increasing MNs confinement. Overall, we provide a novel mechanism by which established circuits create new boutons allowing their structural expansion and plasticity, using trans-synaptic physical forces as the main driving force. Understanding MN-muscle interplay during activity-dependent plasticity can help clarify the mechanisms leading to MN degeneracy observed in neuromuscular diseases.
A Fundamental Distinction in Early Neural Processing of Implicit Social Interpretation in Schizophrenia and Bipolar Disorder
Authors: Madeira Nuno Gonçalo Gomes Fernandes , Martins Ricardo Filipe Alves , Duarte João Valente , Costa Gabriel Nascimento Ferreira , Santos António João Ferreira Macedo , Castelo-Branco Miguel Sá Sousa
Published: March 2021

Background

Social cognition impairment is a key phenomenon in serious mental disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). Although genetic and neurobiological studies have suggested common neural correlates, here we hypothesized that a fundamental dissociation of social processing occurs at an early level in these conditions.

Methods

Based on the hypothesis that key structures in the social brain, namely the temporoparietal junction, should present distinctive features in SCZ and BPD during low-level social judgment, we conducted a case-control study in SCZ (n=20) and BPD (n=20) patients and controls (n=20), using task-based fMRI during a Theory-of-Mind (ToM) visual paradigm leading to interpretation of social meaning based on simple geometric figures.

Results

We found opposite neural responses in two core ToM regions : SCZ patients showed social content-related deactivation (relative to controls and BPD) of the right supramarginal gyrus, a region which activity is required to overcome egocentric “overmentalizing”, while the opposite pattern was found in BPD; reverse patterns, relative to controls and SCZ, were found in the left posterior superior temporal gyrus, a region involved in inferring other’s intentions. Receiver-operating-characteristic curve analysis showed 88% accuracy in discriminating the two clinical groups based on these neural responses.

Conclusions

These contrasting activation patterns of the temporoparietal junction in SCZ and BPD represent mechanistic differences of social cognitive dysfunction that may be explored as biomarkers or therapeutic targets.
A general computational framework for COVID-19 modelling with applications to testing varied interventions in education environments
Authors: Moore Joshua W. , Lau Zechariah , Kaouri Katerina , Dale Trevor C. , Woolley Thomas E.
Published: March 2021

We construct a spatially-compartmental individual-based model of the spread of Covid-19 in indoor spaces. The model can be used to predict the infection rates in a variety of locations when various non-pharmaceutical interventions (NPIs) are introduced. Tasked by the Welsh Government, we apply the model to secondary schools and Further and Higher Education environments. Specifically, we consider student populations mixing in a classroom and in halls of residence. We focus on assessing the potential efficacy of Lateral Flow Devices (LFDs) when used in broad-based screens for asymptomatic infection or in ‘test-to-release’ scenarios in which individuals who have been exposed to infection are released from isolation given a negative result. LFDs are also compared to other NPIs; we find that, although LFD testing can be used to mitigate the spread of Covid-19, it is more effective to invest in personal protective equipment, e.g. masks, and in increasing ventilation quality. In addition, we provide an open-access and user-friendly online applet that simulates the individual-based model, complete with user tutorials to encourage the use of the model to aid educational policy decisions as input infection data evolves (https://bit.ly/CV19_INTER_IBM).
Underwater photo-identification of marine megafauna: an identity card catalogue of sperm whales (Physeter macrocephalus) off Mauritius Island
Authors: Véronique Sarano , François Sarano , Justine Girardet , Axel Preud’homme , Hugues Vitry , René Heuzey , Marion Sarano , Fabienne Delfour , Hervé Glotin , Olivier Adam , Bénédicte Madon , Jean-Luc Jung
Published: March 2021

The long-term monitoring of long-lived animal populations often requires individual identification. For cetacean populations, this identification is mostly based on morphological characters observable from a boat such as shape, spots and cuts of the back, caudal and dorsal fins. This is well suited for species easily displaying their caudal fins, such as the humpback whalesMegaptera novaeangliae, or those whose skin pigmentation patterns enable individual identification.

However, for elusive or shier species such as the sperm whalesPhyseter macrocephalus, this approach may be more challenging as individuals display a rather uniform skin pigmentation. They also do not show very often their caudal fin that must be photographed perpendicularly to the water surface, vertically and fully emerged, uneasing the individual identification from a boat. Immature sperm whales that usually have a caudal fin without any distinctive marks may sometimes be excluded from photo-identification catalogues.

Within the framework of the Maubydick project, focusing on the long-term monitoring of sperm whales in Mauritius, passive underwater observation and video recording were used to identify long-lasting body markers (e.g., sex, ventral white markings, cut outs of fins) to improve individual identification. A catalogue of individual identity cards was developed and 38 individuals were recorded (six adult males, 18 adult females and 14 immatures). This catalogue was used in the field and enabled observers to record some nearly-daily and yearly recaptures. Advantages and disadvantages of this method are presented here.

Such catalogues represent a robust baseline for conducting behavioural, genetic and acoustic studies in marine megafauna social species. Benefits of such newly acquired knowledge are of first importance to implement relevant conservation plans in the marine realm.
Allicin From Garlic Disrupts the Cytoskeleton in Plants
Authors: Noll Ulrike , Schreiber Miriam , Hermanns Monika , Mertes Christopher A. , Slusarenko Alan J. , Gruhlke Martin C.H.
Published: March 2021

Allicin is a defence substance produced by garlic cells upon injury. It is a thiosulfinate showing redox-activity and a broad range of antimicrobial and biocidal activity. It is known that allicin efficiently oxidizes thiol-groups and it has been described as a redox toxin. In order to learn more about the effect of allicin on plants we used pure synthetized allicin, and investigated cytoplasmic streaming in sterile filaments ofTradescantia fluminensis, organelle movement using transgenicArabidopsiswith organelle-specifics GFP-tags, and effects on actin and tubulin in the cytoskeleton using GFP-tagged lines. Auxin distribution in roots was investigated using PIN1:GFP, PIN3:GFP, DR5:GFP and DII-VENUS Arabidopsis reporter lines.

Allicin inhibited cytoplasmic streaming inT. fluminensisand organelle movement of peroxisomes and the Golgi apparatus in a concentration-dependent manner, inhibited root growth and destroyed the correct root tip distribution of auxin.

We speculate that the cytoskeleton can be a primary “receptor” for allicin’s oxidizing properties and as a consequence cytoskeleton-dependent cellular processes are disrupted.
Allopregnanolone mediates affective switching through modulation of oscillatory states in the basolateral amygdala
Authors: Antonoudiou Pantelis , Colmers Phillip LW , Walton Najah L , Weiss Grant L , Smith Anne C , Nguyen David P , Lewis Mike , Quirk Michael C , Melon Laverne C , Maguire Jamie L
Published: March 2021

Brexanolone (allopregnanolone), was recently approved by the FDA for the treatment of post-partum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators (PAMs) of GABAareceptors, we still do not fully understand how allopregnanolone exerts these persistent antidepressant effects. Here, we demonstrate that allopregnanolone and similar synthetic neuroactive steroid analogs, SGE-516 (tool-compound) and zuranolone (SAGE-217, investigational-compound), are capable of modulating oscillatory states across species, which we propose may contribute to long-lasting changes in behavioral states. We identified a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for delta-containing GABAaRs in mediating the ability of neurosteroids to modulate network and behavioral states. Actions of allopregnanolone in the BLA is sufficient to alter behavioral states and enhance BLA high-theta oscillations (6-12Hz) through delta-containing GABAareceptors, a mechanism distinct from other GABAaPAMs, such as benzodiazepines. Moreover, treatment with the allopregnanolone analog SGE-516 induces long-lasting protection from chronic stress-induced disruption of network states, which correlates with improved behavioral outcomes. Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.
Characterizing neural phase-space trajectories via Principal Louvain Clustering
Authors: Dekker Mark M. , França Arthur S. C. , Panja Debabrata , Cohen Michael X
Published: March 2021

Background

With the growing size and richness of neuroscience datasets in terms of dimension, volume, and resolution, identifying spatiotemporal patterns in those datasets is increasingly important. Multivariate dimension-reduction methods are particularly adept at addressing these challenges.

New Method

In this paper, we propose a novel method, which we refer to as Principal Louvain Clustering (PLC), to identify clusters in a low-dimensional data subspace, based on time-varying trajectories of spectral dynamics across multisite local field potential (LFP) recordings in awake behaving mice. Data were recorded from prefrontal cortex, hippocampus, and parietal cortex in eleven mice while they explored novel and familiar environments.

Results

PLC-identified subspaces and clusters showed high consistency across animals, and were modulated by the animals’ ongoing behavior.

Conclusions

PLC adds to an important growing literature on methods for characterizing dynamics in high-dimensional datasets, using a smaller number of parameters. The method is also applicable to other kinds of datasets, such as EEG or MEG.
Synergism between potassium and nitrate enhances the alleviation of ammonium toxicity in rice seedling root
Authors: Fang Gen , Yang Jing , Sun Tong , Wang Xiaoxin , Li Yangsheng
Published: March 2021

Ammonium toxicity in plants is considered a global phenomenon, but the primary mechanisms remain poorly characterized. Here, we showed that although the addition of potassium (K+) or nitrate (NO3−) partially alleviated the inhibition of rice root growth caused by ammonium toxicity, the coexistence of K+and NO3−clearly improved the alleviation via a synergistic mechanism. The synergism led to significantly improved alleviation effects on root biomass, length, surface area, number and meristem cell number. The aberrant auxin distribution in root tips, rhizosphere acidification level and abnormal cell morphology in the root cap and elongation zone caused by ammonium toxicity could be recovered by this synergism. RNA sequencing and the weighted gene correlation network analysis (WGCNA) revealed that the mechanism of this synergism involves cellulose synthesis, auxin and gibberellin metabolism regulation at the transcription level.
ANCHOR, a technical approach to monitor single-copy locus localizationin planta
Authors: Meschichi Anis , Ingouff Mathieu , Picart Claire , Mirouze Marie , Desset Sophie , Gallardo Franck , Bystricky Kerstin , Picault Nathalie , Rosa Stefanie , Pontvianne Frédéric
Published: March 2021

RESUME

Gene expression is governed by several layers of regulation which in addition to genome organization, local chromatin structure, gene accessibility and the presence of transcription factors also includes gene positioning. Although basic mechanisms are expected to be conserved in Eukaryotes, surprisingly little information on the role of gene positioning is available in plant cells, mainly due to the lack of a highly resolutive approach. In this manuscript, we adapted the use of the ANCHOR system to perform real-time single-locus detectionin planta.ANCHOR is a DNA-labelling tool derived from the partitioning system. We demonstrate its suitability to monitor a single-locusin plantaand used this approach to track chromatin mobility during cell differentiation in Arabidopsis root epidermal cells. Finally, we discuss the potential of this approach to investigate the role of gene positioning during transcription and DNA repair in plants.
High sensitivity dia-PASEF proteomics with DIA-NN and FragPipe
Authors: Demichev Vadim , Yu Fengchao , Teo Guo Ci , Szyrwiel Lukasz , Rosenberger George A. , Decker Jens , Kaspar-Schoenefeld Stephanie , Lilley Kathryn S. , Mülleder Michael , Nesvizhskii Alexey I. , Ralser Markus
Published: March 2021

The dia-PASEF technology exploits ion mobility separation for high-sensitivity analysis of complex proteomes. Here, we demonstrate neural network-based processing of the ion mobility data, which we implement in the DIA-NN software suite. Using spectral libraries generated with the MSFragger-based FragPipe computational platform, the DIA-NN analysis of dia-PASEF raw data increases the proteomic depth by up to 69% compared to the originally published dia-PASEF workflow. For example, we quantify over 5200 proteins from 10ng of HeLa peptides separated with a 95-minute nanoflow gradient, and over 5000 proteins from 200ng using a 4.8-minute separation with an Evosep One system. In complex samples, featuring a mix of human and yeast lysates, the workflow detects over 11700 proteins in single runs acquired with a 100-minute nanoflow gradient, while demonstrating quantitative precision. Hence, the combination of FragPipe and DIA-NN provides a simple-to-use software platform for dia-PASEF data analysis, yielding significant gains in high-sensitivity proteomics.
Aerodynamics and motor control of ultrasonic vocalizations for social communication in mice and rats
Authors: Håkansson Jonas , Jiang Weili , Xue Qian , Zheng Xudong , Ding Ming , Agarwal Anurag A. , Elemans Coen P.H.
Published: March 2021

Rodent ultrasonic vocalizations (USVs) are crucial to their social communication and a widely used translational tool for linking gene mutations to behavior. To maximize the causal interpretation of experimental treatments, we need to understand how neural control affects USV production. However, both the aerodynamics of USV production and its neural control remain poorly understood. Here we test three intralaryngeal whistle mechanisms - the wall and alar edge impingement, and shallow cavity tone - by combining in vitro larynx physiology and individual-based 3D airway reconstructions with fluid dynamics simulations. Our results show that in the mouse and rat larynx USVs are produced by a glottal jet impinging on the thyroid inner wall. Furthermore, we implemented an empirically based motor control model that predicts motor gesture trajectories of USV call types. Our work provides a quantitative neuromechanical framework to evaluate the contributions of brain and body in shaping USVs, and a first step in linking descending motor control to USV production.
Transgenic mice forin vivoepigenome editing with CRISPR-based systems
Authors: Gemberling Matthew , Siklenka Keith , Rodriguez Erica , Tonn-Eisinger Katherine R. , Barrera Alejandro , Liu Fang , Kantor Ariel , Li Liqing , Cigliola Valentina , Hazlett Mariah F. , Williams Courtney , Bartelt Luke C. , Madigan Victoria J. , Bodle Josephine , Daniels Heather , Rouse Douglas C. , Hilton Isaac B. , Asokan Aravind , Ciofani Maria , Poss Kenneth D. , Reddy Timothy E. , West Anne E. , Gersbach Charles A.
Published: March 2021

The discovery, characterization, and adaptation of the RNA-guided clustered regularly interspersed short palindromic repeat (CRISPR)-Cas9 system has greatly increased the ease with which genome and epigenome editing can be performed. Fusion of chromatin-modifying domains to the nuclease-deactivated form of Cas9 (dCas9) has enabled targeted gene activation or repression in both cultured cells andin vivoin animal models. However, delivery of the large dCas9 fusion proteins to target cell types and tissues is an obstacle to widespread adoption of these tools forin vivostudies. Here we describe the generation and validation of two conditional transgenic mouse lines for targeted gene regulation, Rosa26:LSL-dCas9-p300 for gene activation and Rosa26:LSL-dCas9-KRAB for gene repression. Using the dCas9p300and dCas9KRABtransgenic mice we demonstrate activation or repression of genes in both the brain and liverin vivo, and T cells and fibroblastsex vivo. We show gene regulation and targeted epigenetic modification with gRNAs targeting either transcriptional start sites (TSS) or distal enhancer elements, as well as corresponding changes to downstream phenotypes. These mouse lines are convenient and valuable tools for facile, temporally controlled, and tissue-restricted epigenome editing and manipulation of gene expressionin vivo.
Comparative host interactomes of the SARS-CoV-2 nonstructural protein 3 and human coronavirus homologs
Authors: Almasy Katherine M. , Davies Jonathan P. , Plate Lars
Published: March 2021

Human coronaviruses have become an increasing threat to global health; three highly pathogenic strains have emerged since the early 2000s, including most recently SARS-CoV-2, the cause of COVID-19. A better understanding of the molecular mechanisms of coronavirus pathogenesis is needed, including how these highly virulent strains differ from those that cause milder, common-cold like disease. While significant progress has been made in understanding how SARS-CoV-2 proteins interact with the host cell, non-structural protein 3 (nsp3) has largely been omitted from the analyses. Nsp3 is a viral protease with important roles in viral protein biogenesis, replication complex formation, and modulation of host ubiquitinylation and ISGylation. Herein, we use affinity purification-mass spectrometry to study the host-viral protein-protein interactome of nsp3 from five coronavirus strains: pathogenic strains SARS-CoV-2, SARS-CoV, and MERS-CoV; and endemic common-cold strains hCoV-229E and hCoV-OC43. We divide each nsp3 into three fragments and use tandem mass tag technology to directly compare the interactors across the five strains for each fragment. We find that few interactors are common across all variants for a particular fragment, but we identify shared patterns between select variants, such as ribosomal proteins enriched in the N-terminal fragment (nsp3.1) dataset for SARS-CoV-2 and SARS-CoV. We also identify unique biological processes enriched for individual homologs, for instance nuclear protein important for the middle fragment of hCoV-229E, as well as ribosome biogenesis of the MERS nsp3.2 homolog. Lastly, we further investigate the interaction of the SARS-CoV-2 nsp3 N-terminal fragment with ATF6, a regulator of the unfolded protein response. We show that SARS-CoV-2 nsp3.1 directly binds to ATF6 and can suppress the ATF6 stress response. Characterizing the host interactions of nsp3 widens our understanding of how coronaviruses co-opt cellular pathways and presents new avenues for host-targeted antiviral therapeutics.
Genomic environments scale the activities of diverse core promoters
Authors: Hong Clarice KY , Cohen Barak A
Published: March 2021

A classical model of gene regulation is that enhancers provide specificity while core promoters provide a modular site for the assembly of the basal transcriptional machinery. However, examples of core promoter specificity have led to an alternate hypothesis in which specificity is achieved by core promoters with different sequence motifs that respond differently to genomic environments containing different enhancers and chromatin landscapes. To distinguish between these models, we measured the activities of hundreds of diverse core promoters in four different genomic locations and, in a complementary experiment, six different core promoters at thousands of locations across the genome. While genomic locations had large effects on expression, the intrinsic activities of different classes of promoters were preserved across genomic locations, suggesting that core promoters are modular regulatory elements whose activities are independently scaled up or down by different genomic locations. This scaling of promoter activities is non-linear and depends on the genomic location and the strength of the core promoter. Our results support the classical model of regulation in which diverse core promoter motifs set the intrinsic strengths of core promoters, which are then amplified or dampened by the activities of their genomic environments.
High Transcriptional Activity and Diverse Functional Repertoires of Hundreds of Giant Viruses in a Coastal Marine System
Authors: Ha Anh D , Moniruzzaman Mohammad , Aylward Frank O
Published: March 2021

Viruses belonging to theNucleocytoviricotaphylum are globally-distributed and include members with notably large genomes and complex functional repertoires. Recent studies have shown that these viruses are particularly diverse and abundant in marine systems, but the magnitude of actively replicatingNucleocytoviricotapresent in ocean habitats remains unclear. In this study, we compiled a curated database of 2,431Nucleocytoviricotagenomes and used it to examine the gene expression of these viruses in a 2.5-day metatranscriptomic time-series from surface waters of the California Current. We identified 145 viral genomes with high levels of gene expression, including 90Imiterviralesand 49Algaviralesviruses. In addition to recovering high expression of core genes involved in information processing that are commonly expressed during viral infection, we also identified transcripts of diverse viral metabolic genes from pathways such as glycolysis, the TCA cycle, and the pentose phosphate pathway, suggesting that virus-mediated reprogramming of central carbon metabolism is common in oceanic surface waters. Surprisingly, we also identified viral transcripts with homology to actin, myosin, and kinesin domains, suggesting that viruses may use them to manipulate host cytoskeletal dynamics during infection. We performed phylogenetic analysis on the virus-encoded myosin and kinesin proteins, which demonstrated that most belong to deep-branching viral clades, but that others appear to have been acquired from eukaryotes more recently. Our results highlight a remarkable diversity of activeNucleocytoviricotain a coastal marine system and underscore the complex functional repertoires expressed by these viruses during infection.

Importance

The discovery of giant viruses has transformed our understanding of viral complexity. Although viruses have traditionally been viewed as filterable infectious agents that lack metabolism, giant viruses can reach sizes rivalling cellular lineages and possess genomes encoding central metabolic processes. Recent studies have shown that giant viruses are widespread in aquatic systems, but the activity of these viruses and the extent to which they reprogram host physiologyin situremains unclear. Here we show that numerous giant viruses consistently express central metabolic enzymes in a coastal marine system, including components of glycolysis, the TCA cycle, and other pathways involved in nutrient homeostasis. Moreover, we found expression of several viral-encoded actin, myosin, and kinesin genes, indicating viral manipulation of the host cytoskeleton during infection. Our study reveals a high activity of giant viruses in a coastal marine system and indicates they are a diverse and underappreciated component of microbial diversity in the ocean.
Endothelial Pannexin 1–TRPV4 channel signaling lowers pulmonary arterial pressure
Authors: Daneva Zdravka , Ottolini Matteo , Chen Yen-Lin , Klimentova Eliska , Shah Soham A. , Minshall Richard D. , Seye Cheikh I. , Laubach Victor E. , Isakson Brant E. , Sonkusare Swapnil K.
Published: March 2021

Pannexin 1 (Panx1) is an ATP-efflux channel that controls endothelial function in the systemic circulation. However, the roles of endothelial Panx1 in resistance-sized pulmonary arteries (PAs) are unknown. Extracellular ATP dilates PAs through activation of endothelial TRPV4 (transient receptor potential vanilloid 4) ion channels. We hypothesized that endothelial Panx1–ATP– TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 or TRPV4 increased PA contractility and raised PAP. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase Cα (PKCα), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCα, and TRPV4 channels in PAs, promoting their spatial proximity and enabling signaling interactions. These results indicate that endothelial Panx1–P2Y2R–TRPV4 channel signaling, facilitated by caveolin-1, reduces PA contractility and lowers PAP.
Sortilin-related receptor is a druggable therapeutic target in breast cancer
Authors: Al-Akhrass Hussein , Pietilä Mika , Lilja Johanna , Vesilahti Ella-Maria , Anttila Johanna M. , Haikala Heidi M. , Munne Pauliina M. , Klefström Juha , Peuhu Emilia , Ivaska Johanna
Published: March 2021

In breast cancer, the currently approved anti-receptor tyrosine-protein kinase erbB-2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2-related therapeutic targets could offer means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin-related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2-targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti-SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumabin vitroandin ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cellularity in a mouse xenograft model of HER2-positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient-derived explant three-dimensional cultures. These results provide for the first time proof-of-principle that SorLA is a druggable target in breast cancer.
Structural dynamics of cytochrome P450 3A4 in the presence of substrates and cytochrome P450 reductase
Authors: Ducharme Julie , Sevrioukova Irina F. , Thibodeaux Christopher J. , Auclair Karine
Published: March 2021

Cytochrome P450 3A4 (CYP3A4) is the most important drug-metabolizing enzyme in humans and has been associated with harmful drug interactions. The activity of CYP3A4 is known to be modulated by several compounds, as well as by the electron transfer partner, cytochrome P450 reductase (CPR). The underlying mechanism of these effects however is poorly understood. We have used hydrogen-deuterium exchange mass spectroscopy (HDX-MS) to investigate the impact of CPR and three different substrates (7-benzyloxy-4-trifluoromethyl-coumarin, testosterone and progesterone) on the conformational dynamics of CYP3A4. Here, we report that interaction of CYP3A4 with substrates or with the oxidized or reduced form of CPR leads to a global rigidification of the CYP3A4 structure. This was evident from a suppression of deuterium exchange in several regions of CYP3A4, including those known to be involved in protein-protein interactions (C-helix) as well as substrate binding and specificity (B’-, E-helices and K/β1-loop). Furthermore, the bimodal isotopic distributions observed for some CYP3A4-derived peptides were drastically impacted by CPR and/or substrates, suggesting the existence of stable CYP3A4 conformational populations that are perturbed by ligand/CPR binding. The results have implications for understanding the mechanisms of allostery, ligand binding, and catalysis in CYP enzymes.
Explaining Asian growth paradox through interaction between informal and formal institutions
Authors: Chung Kee Hoon , Kim DaEun
Published: March 2021

Purpose

Much of existing research has attempted to explain Asian Growth Paradox through formal institution – role of the government or rule of law. Therefore, this paper attempts to empirically explain the paradox with informal institution including interaction between informal and formal institutions. Two interrelated research questions summarize this research. First, how can we capture the relationship between informal and formal institutions? Then, how is that relationship different for Asian Paradox states vs non-paradox states?

Design/methodology/approach

To capture the relationship between informal and formal institutions, we use Helmke and Levitsky (2004)'s framework to categorize the interaction as complementing, competing, substituting and accommodating. We perform cross-sectional regression analysis for more than 130 countries.

Findings

We find that the developed, developing and the Asian Paradox states display different patterns of interaction between informal and formal institutions. However, we also find that the interaction effect has a limited value explaining growth for most of these countries, suggesting that Helmke and Levitsky (2004)'s framework has limitations. Finally, we challenge the notion of Asian Paradox states, as countries outside of Asia also qualify as the Paradox states.

Originality/value

Not much empirical effort has examined how different relationships between informal and formal institutions can explain growth internationally across countries. We show that different institutional patterns explain growth across the Paradox states and non-Paradox states.
The narrative strategies of retail spaces: a semio-ethnographic approach
Authors: Welte Jean-Baptiste , Badot Olivier , Hetzel Patrick
Published: March 2021

Purpose

The purpose of this study is to understand how narratives are generated in stores.

Design/methodology/approach

The study design is based on ethnographies documented in 10 sports stores in the Paris region. The ethnographic method enables a precise and in situ observation of how narratives are structured. Narrative structures develop from the accommodation of the narratives specific to retailers and narratives specific to the customer.

Findings

The findings of this study identified four main narratives in retail spaces (the serial, the tale, the epic, the legend), each of which is distinguished by the commercial/non-commercial orientation of the narratives and by a superficial/in-depth modification of the narratives produced outside the store. These four narratives are characterized by the vendors’ roles and by the distinct interactions between customers and retail stores.

Research limitations/implications

The originality of this study is to propose a narrative framework for retail structures. It illustrates the fact that the narrative is not solely a product of experiential marketing, but that it may be found in any retail store. From a practical point of view, it highlights other less costly experiential narrative strategies.

Practical implications

From a practical point of view, it highlights other less costly experiential narrative strategies.

Originality/value

The original value of this study is to apply structural semiotics to analyse narratives in the store.
Drought grade assessment method based on grey cloud incidence clustering model
Authors: Luo Dang , Hu Yan , Sun Decai
Published: March 2021

Purpose

The purpose of this paper is to establish a grey cloud incidence clustering model to assess the drought disaster degree under 15 indexes in 18 cities of Henan province.

Design/methodology/approach

The grey incidence degree between each index and ideal index is used to determine the index weight and combined with the subjective weight, the comprehensive weight is given; the traditional possibility function is transformed into grey cloud possibility function by using the principle of maximum deviation and maximum entropy, which fully reflects the coexistence of multiple decision-making conclusions and constructs the grey cloud incidence clustering model.

Findings

The drought disaster degree of Henan province is divided into four grades under the selected 15 indexes. The drought grades show obvious regional differences. The risk levels of the east and southwest are higher, and the risk levels of the north and southeast are lower. This result is consistent with the study of drought disaster grades in Henan province, which shows the practicability and usefulness of the model.

Practical implications

It provides an effective method for the assessment of drought disaster grade and the basis for formulating disaster prevention and mitigation plan.

Originality/value

By studying the method of multiattribute and multistage decision-making with interval grey number information. The objective weight model of index value is designed, and the subjective weight is given by experts. On the basis of the two, the comprehensive weight of subjective and objective combination is proposed, which effectively weakens the randomness of subjective weight and reasonably reflects the practicality of index decision-making. The time weight reflects the dynamic of the index. The traditional possibility function is transformed into the grey cloud possibility function, which effectively takes advantage of the grey cloud model in dealing with the coexistence of fuzzy information, grey information and random information. Thus, the conflict between the decision-making results and the objective reality is effectively solved. The interval grey number can make full use of the effective information and improve the accuracy of the actual information.
Brand balance: the effect of influencer brand encroachment on interactivity
Authors: Hamdan Lara , Lee Seung Hwan (Mark)
Published: March 2021

Purpose

As social media platforms continue to have an increased presence in influencer marketing, researchers and practitioners are seeking ways to optimize the use of these platforms. The purpose of this study is to investigate the effect of brand encroachment, a level of brand's control over the promotion executed by social media influencers (SMIs), on the importance of interactivity of SMIs.

Design/methodology/approach

This study examined the effect of brand encroachment on interactivity whilst examining the mediating effects of both passion and personal power. The study was an online, one-factor between-subjects design comparing high level of brand encroachment vs low level of brand encroachment.

Findings

The results of the experimental study suggest that as brand encroachment decreases, there is an increasing importance of being interactive. In addition, with lower brand encroachment, SMIs portray more personal power and passion toward the product or service being promoted.

Originality/value

As influencers create communities via increased levels of engagement, authenticity and relatability, it is of paramount importance that SMIs build relationships through interactivity in low-brand encroachment settings. Brands should offer more opportunities for SMIs to be interactive with their audience, while intrinsically building their personal power and passion as sources for these interactions.
Managerial ability and fair value accounting: evidence from nonfinancial firms
Authors: Bradley Wray , Sun Li
Published: March 2021

Purpose

The purpose of this study is to examine the relation between managerial ability and fair value inputs (measured as fair value intensity) for nonfinancial firms.

Design/methodology/approach

This study uses regression analysis to investigate the impact of managerial ability on the level of fair value inputs.

Findings

This study finds significant and positive relations between managerial ability and use of Level 1 and Level 2 fair value inputs. On the other hand, this study finds an insignificant relation between managerial ability and Level 3 inputs.

Originality/value

The findings contribute to two research streams. To the best of the author’s knowledge, this is perhaps the first study that directly examines the link between managerial ability and fair value inputs.
Female sexuality in marketing communication and effects on the millennial buying decisions in fashion industry in Nigeria
Authors: Oniku Ayodele , Joaquim Anthonia Farayola
Published: March 2021

Purpose

The study aims to examine female sexuality in marketing communications and how it shapes the millennial buying decisions in the fashion industry. The focus of the study is to connect fashion industry and marketing communication to understand how female sexuality influence buying behaviours and decisions of the millennial.

Design/methodology/approach

The study was underpinned by the dimensions of skin colour, brand image and market share in sexual appealing marketing communication, and the millennial in the study comprises youths between the age of 21and 40 years and demographically defined by Wells and Guber (1966) as bachelors, Full nests 1 and 2. Multistage stage sampling was used with a structured questionnaire.

Findings

Findings show that youths, 2019 buying decisions and behaviours are strategically influenced by different manifestations of female sexuality in the context of the study and equally affect market share and patronage.

Research limitations/implications

The study shows what shapes the marketing communication strategies of the rising fashion industry but is limited to the millennial buying decisions and not the larger fashion industry consumers.

Practical implications

The needs for fashion industry to understand the influence of increasing use of female sexuality in marketing communication on male and female consumers and the effects on their respective buying behaviours is strategic to the industry as shown in the study.

Social implications

Female sexuality in marketing communication is strategic to fashion industry in today's market among youths.

Originality/value

The millennial constitutes a larger percentage of the developing economy market with rising income thus the need to understand their buying behaviours in the fashion industry
Mass collection of magnetotactic bacteria from the permanently stratified ferruginous Lake Pavin, France
Authors: Busigny Vincent , Mathon François P. , Jézéquel Didier , Bidaud Cécile C. , Viollier Eric , Bardoux Gérard , Bourrand Jean‐Jacques , Benzerara Karim , Duprat Elodie , Menguy Nicolas , Monteil Caroline L. , Lefevre Christopher T.
Published: March 2021

Obtaining high biomass yields of specific microorganisms for culture‐independent approaches is a challenge faced by scientists studying organism's recalcitrant to laboratory conditions and culture. This difficulty is highly decreased when studying magnetotactic bacteria (MTB) since their unique behaviour allows their enrichment and purification from other microorganisms present in aquatic environments. Here, we use Lake Pavin, a permanently stratified lake in the French Massif Central, as a natural laboratory to optimize collection and concentration of MTB that thrive in the water column and sediments. A method is presented to separate MTB from highly abundant abiotic magnetic particles in the sediment of this crater lake. For the water column, different sampling approaches are compared such as in situ collection using a Niskin bottle and online pumping. By monitoring several physicochemical parameters of the water column, we identify the ecological niche where MTB live. Then, by focusing our sampling at the peak of MTB abundance, we show that the online pumping system is the most efficient for fast recovering of large volumes of water at a high spatial resolution, which is necessary considering the sharp physicochemical gradients observed in the water column. Taking advantage of aerotactic and magnetic MTB properties, we present an efficient method for MTB concentration from large volumes of water. Our methodology represents a first step for further multidisciplinary investigations of the diversity, metagenomic and ecology of MTB populations in Lake Pavin and elsewhere, as well as chemical and isotopic analyses of their magnetosomes.
Addressing Australia's collaboration ‘problem’: Is there a Brave New World of innovation policy post COVID‐19?
Authors: George AJ , Tarr Julie‐Anne
Published: March 2021

In a post‐COVID‐19 world, innovation stimuli and well‐aligned policies will assume even greater importance as various sectors seek to recover lost ground and to generate new opportunities. Collaborative partnering in innovation research and development (R&D) between private industry and higher education has increasingly emerged over the last decade as a leading key performance indicator for government policy development, and higher education research funding allocations. Recalibration of R&D‐related policies and incentivisation will require careful consideration, with constructive lessons to be learned from outcomes over the last four decades. This paper presents findings from a new study of stakeholder perceptions as to the National Innovation and Science Agenda's impact on innovation partnerships, and synthesises outcomes from two prior studies. It then examines a newly proposed innovation policy framework, Stimulating Business Investment in Innovation (SBII), set against a background of the shifting mix of paradigms that have comprised Australian innovation policy over the last 40 years. It argues that, following the SBII, any proposed change of policy direction will face significant challenges in its implementation, requiring a fully committed and comprehensive embrace by Government of the new APS engagement framework and greater levels of deliberative democracy.
Influence of circulating testosterone concentration on sperm cryoresistance: The ibex as an experimental model
Authors: Bóveda Paula , Esteso Milagros Cristina , Velázquez Rosario , Castaño Cristina , Toledano‐Díaz Adolfo , López‐Sebastián Antonio , Mejía Octavio , Millán de la Blanca María Gemma , Ungerfeld Rodolfo , Santiago‐Moreno Julián
Published: March 2021

Background

Recent studies have noted that the circulating testosterone concentration may affect the ability of spermatozoa to survive cryopreservation. However, few attempts to confirm such a relationship have been made. Wild ruminant species have very marked seasonal changes in their reproductive function and strong annual changes in their plasma testosterone concentration.

Objectives

The present work examines the influence of induced changes in testosterone secretion on sperm variables following conventional slow freezing and ultra‐rapid freezing, using the Iberian ibex as an experimental model.

Materials and Methods

In a first experiment, testosterone levels were reduced in the middle of the rutting season (December) using the antiandrogen cyproterone acetate (CA). In a second experiment, testosterone levels were increased at the end of the rutting season (January) via the use of the androgen testosterone propionate (TP).

Results

During December, the testosterone concentration was found to be higher in the blood and seminal plasma of untreated males than in those of CA‐treated males (p < 0.001 andp < 0.05, respectively). Compared with controls, the TP‐treated animals had higher blood plasma testosterone concentrations but lower seminal plasma testosterone concentrations during January (p < 0.01 andp < 0.001, respectively). The seminal vesicles of the TP‐treated males were larger than those of untreated males (p < 0.05). When CA was administered, sperm viability improved compared with controls (p < 0.05), irrespective of the freezing protocol followed. For the ultra‐rapid freezing procedure, the cryoresistance ratio for motility decreased when TP was administered (p < 0.05). The values for fresh sperm morphometric variables decreased during the 50 days after the end of CA treatment (p < 0.001) and increased over the same time after the end of TP treatment (p < 0.001).

Discussion and Conclusion

The circulating testosterone concentration appears to influence sperm cryoresistance. This may explain the seasonal changes seen in sperm freezability in some species, independent of fresh sperm quality.