bluuebunny/crossref_metadata_2025 huggingface dataset:
Forecasting COVID-19 infection trends and new hospital admissions in England due to SARS-CoV-2 Variant of Concern Omicron
Authors: Gerli Alberto Giovanni , Centanni Stefano , Soriano Joan B , Ancochea Julio
Published: December 2021

Objectives

On November 26, 2021, WHO designated the variant B.1.1.529 as a new SARS-CoV-2 variant of concern (VoC), named Omicron, originally identified in South Africa. Several mutations in Omicron indicate that it may have an impact on how it spreads, resistance to vaccination, or the severity of illness it causes. We used our previous modelling algorithms to forecast the spread of Omicron in England.

Design

We followed EQUATOR’s TRIPOD guidance for multivariable prediction models.

Setting

England.

Participants

Not applicable.

Interventions

Non-interventional, observational study with a predicted forecast of outcomes.

Main outcome measures

Trends in daily COVID-19 cases with a 7-day moving average and of new hospital admissions.

Methods

Modelling included a third-degree polynomial curve in existing epidemiological trends on the spread of Omicron and a new Gaussian curve to estimate a downward trend after a peak in England.

Results

Up to February 15, 2022, we estimated a projection of 250,000 COVID-19 daily cases of Omicron spread in the worse scenario, and 170,000 in the “best” scenario. Omicron might represent a relative increase from the background daily rates of COVID-19 infection in England of mid December 2021 of 1.9 to 2.8-fold. With a 5-day lag-time, daily new hospital admissions would peak at around 5,063 on January 23, 2022 in the worse scenario.

Conclusion

This warning of pandemic surge of COVID-19 due to Omicron is calling for further reinforcing in England and elsewhere of universal hygiene interventions (indoor ventilation, social distance, and face masks), and anticipating the need of new total or partial lockdowns in England.
Diversity of microglial transcriptional responses during opioid exposure and neuropathic pain
Authors: Sypek Elizabeth I , Collins Hannah Y , McCallum William M , Bourdillon Alexandra T , Barres Ben A , Bohlen Christopher J , Scherrer Grégory
Published: December 2021

Microglia take on an altered morphology during chronic opioid treatment. This morphological change is broadly used to identify the activated microglial state associated with opioid side effects, including tolerance and opioid-induced hyperalgesia (OIH). Following chronic opioid treatment and peripheral nerve injury (PNI) microglia in the spinal cord display similar morphological responses. Consistent with this observation, functional studies have suggested that microglia activated by PNI or opioids engage common molecular mechanisms to induce hypersensitivity. Here we conducted deep RNA sequencing of acutely isolated spinal cord microglia from male mice to comprehensively interrogate transcriptional states and mechanistic commonality between multiple OIH and PNI models. Following PNI, we identify a common early proliferative transcriptional event across models that precedes the upregulation of histological markers of activation, followed by a delayed and injury-specific transcriptional response. Strikingly, we found no such transcriptional responses associated with opioid-induced microglial activation, consistent with histological data indicating that microglia number remain stable during morphine treatment. Collectively, these results reveal the diversity of pain-associated microglial transcriptomes and point towards the targeting of distinct insult-specific microglial responses to treat OIH, PNI, or other CNS pathologies.
Structural and functional characterizations of altered infectivity and immune evasion of SARS-CoV-2 Omicron variant
Authors: Cui Zhen , Liu Pan , Wang Nan , Wang Lei , Fan Kaiyue , Zhu Qianhui , Wang Kang , Chen Ruihong , Feng Rui , Jia Zijing , Yang Minnan , Xu Ge , Zhu Boling , Fu Wangjun , Chu Tianming , Feng Leilei , Wang Yide , Pei Xinran , Yang Peng , Xie Xiaoliang Sunney , Cao Lei , Cao Yunlong , Wang Xiangxi
Published: December 2021

The SARS-CoV-2 Omicron with increased fitness is spreading rapidly worldwide. Analysis of cryo-EM structures of the Spike (S) from Omicron reveals amino acid substitutions forging new interactions that stably maintain an “active” conformation for receptor recognition. The relatively more compact domain organization confers improved stability and enhances attachment but compromises the efficiency of viral fusion step. Alterations in local conformation, charge and hydrophobic microenvironments underpin the modulation of the epitopes such that they are not recognized by most NTD- and RBD-antibodies, facilitating viral immune escape. Apart from already existing mutations, we have identified three new immune escape sites: 1) Q493R, 2) G446S and 3) S371L/S373P/S375F that confers greater resistance to five of the six classes of RBD-antibodies. Structure of the Omicron S bound with human ACE2, together with analysis of sequence conservation in ACE2 binding region of 25 sarbecovirus members as well as heatmaps of the immunogenic sites and their corresponding mutational frequencies sheds light on conserved and structurally restrained regions that can be used for the development of broad-spectrum vaccines and therapeutics.
Computational analysis of transition temperatures (Tts) of proteins fused to elastin-like polypeptide (ELP): deep fake evaluation of proteins, linkers, and trailers features
Authors: Ghafari Mohammad Davoud , Rasooli Iraj , Khajeh Khosro , Dabirmanesh Bahareh , Ghafari Mohammadreza , Owlia Parviz
Published: December 2021

The phase transition temperature (Tt) prediction of the Elastin-like polypeptides (ELPs) is not trivial because it is related to complex sets of variables such as composition, sequence length, hydrophobic characterization, hydrophilic characterization, the sequence order in the fused proteins, linkers and trailer constructs. In this paper, two unique quantitative models are presented for the prediction of the Tt of a family of ELPs that could be fused to different proteins, linkers, and trailers. The lack of need to use multiple software, peptide information, such as PDB file, as well as knowing the second and third structures of proteins are the advantages of this model besides its high accuracy and speed. One of our models could predict the Tt values of the fused ELPs by entering the protein, linker, and trailer features with R2=99%. Also, another model is able to predict the Tt value by entering the fused protein feature with R2=96%. For more reliability, our method is enriched by Artificial Intelligence (AI) to generate similar proteins. In this regard, Generative Adversarial Network (GAN) is our AI method to create fake proteins and similar values. The experimental results show that our strategy for prediction of Tt is reliable in large data.

Author Summary

The application of Elastin-like polypeptides (ELPs) as a protein tag is now developed in a variety of biotechnology aspects especially in proteins purification and drug delivery. ELPs application as a protein tag is owed to retain the phase transition behavior when ELPs fused to other proteins, linkers and tags. ELPs undergo the phase transition behavior by changing from soluble phase to insoluble phase above its inverse transition temperature (Tt) within a short time span. This biophysical behavior is usually reversible at the temperature below the Tt. There are few reports for evaluation of the Tt of ELPs types by using the dissimilar equations and algorithms. Our current predictions are the most accurate calculations presented so far by using the protein, linker and trailer effects and the results were evaluated in accordance with the available experimental data. Furthermore, our results also show that our strategy for prediction of Tt is reliable in large data.
Multi-Wavelength Analytical Ultracentrifugation of Biopolymer Mixtures and Interactions
Authors: Henrickson Amy , Gorbet Gary E. , Savelyev Alexey , Kim Minji , Schultz Sarah K. , Ding Xiaozhe , Hargreaves Jason , Gradinaru Viviana , Kothe Ute , Demeler Borries
Published: December 2021

Multi-wavelength analytical ultracentrifugation (MW-AUC) is a recent development made possible by new analytical ultracentrifuge optical systems. MW-AUC is suitable for a wide range of applications and biopolymer systems and is poised to become an essential tool to characterize macromolecular interactions. It adds an orthogonal spectral dimension to the traditional hydrodynamic characterization by exploiting unique chromophores in analyte mixtures that may or may not interact. Here we illustrate the utility of MW-AUC for representative classes of challenging biopolymer systems, including interactions between mixtures of different sized proteins with small molecules, mixtures of loaded and empty viral AAV capsids contaminated with free DNA, and mixtures of different proteins, where some have identical hydrodynamic properties, all of which are difficult to resolve with traditional AUC methods. We explain the improvement in resolution and information content obtained by this technique compared to traditional single- or dual-wavelength approaches. We discuss experimental design considerations and limitations of the method, and address the advantages and disadvantages of the two MW optical systems available today, and the differences in data analysis strategies between the two systems.
Efficient CRISPR/Cas12a-based genome editing toolbox for metabolic engineering in Methanococcus maripaludis
Authors: Bao Jichen , de Dios Mateos Enrique , Scheller Silvan
Published: December 2021

The rapid-growing and genetically tractable methanogen Methanococcus maripaludis is a promising host organism for the biotechnological conversion of carbon dioxide and renewable hydrogen to fuels and value-added products. Expansion of its product scope through metabolic engineering necessitates reliable and efficient genetic tools, particularly for genome edits to the primary metabolism that affect cell growth. Here, we have designed a genome editing toolbox by utilizing Cas12a from Lachnospiraceae bacterium ND2006 (LbCas12a) in combination with the homology-directed repair machinery endogenously present in M. maripaludis. Remarkably, this toolbox can knock out target genes with a success rate of up to 95%, despite the hyper-polyploidy of M. maripaludis. For the purposes of demonstrating a large-sized deletion, we have replaced the flagellum operon (ca. 8.9 kbp) by the β-glucuronidase gene. To facilitate metabolic engineering and flux balancing in M. maripaludis, the relative strength of 15 different promoters were quantified in the presence of the two common growth substrates, formate or carbon dioxide and hydrogen. This CRISPR/LbCas12a toolbox can be regarded as a reliable and fast method for genome editing in a methanogen.
m7G cap-eIF4E interaction stimulates polysome formation by enhancing first-round initiation kinetics
Authors: Sun Lexi , Gaba Anthony , Wang Hongyun , Qu Xiaohui
Published: December 2021

Translation in eukaryotic cells occurs predominantly through a 7-methylguanosine (m7G) cap-dependent mechanism. m7G cap interactions with eukaryotic initiation factor 4E (eIF4E) facilitates 43S recruitment to the mRNA 5’ end and enhances the translation efficiency of mRNA. However, it remains poorly understood how m7G cap-eIF4E interactions affect polysome formation kinetics. Here, we examine the role of the m7G cap in polysome formation by utilizing a single-molecule approach to track individual ribosomes during active translation. Translation was monitored in wheat germ extract with capped and uncapped synthetic mRNAs and in HeLa extract with purified human eIF4E titration. The presence of the m7G cap and the supplementation of eIF4E to eIF4E-deficient extract enhanced the kinetics of the first initiation event of polysomes. Subsequent to the first initiation event, efficient polysome-forming initiation events occurred independent of mRNA m7G capping status and eIF4E concentration. Our results indicate that m7G cap-eIF4E interactions in wheat germ and HeLa extracts promote polysome formation by enhancing first-round initiation kinetics. The dynamics of individual translation events on polysomal mRNAs suggest that first-round initiation events activate mRNAs for efficient subsequent rounds of polysome-forming initiation.
Effect of lipopolysaccharide (LPS) on HAEC cells. Does nicotinamide N-methyltransferase sensitize HAEC cells to LPS?
Authors: Stępińska Oksana , Dymkowska Dorota , Mateuszuk Łukasz , Zabłocki Krzysztof
Published: December 2021

Treatment of endothelial cells with bacterial lipopolysaccharide (LPS) evokes a number of metabolic and functional consequences which built a multifaceted physiological response of endothelium to bacterial infection. Here effects of LPS on human aortic endothelial cells (HAEC) have been investigated. Among the spectrum of biochemical changes substantially elevated N-nicotinamide methyltransferase (NNMT) protein level was particularly intriguing. This important enzyme may potentially affect cellular metabolism by two means: direct regulation of methylnicotinamide level and availability of nicotinamide, that at least potentially may influence NAD+ synthesis, and regulation of S-adenosylmethionine concentration and therefore controlling methylation of many proteins including chromatin. This may have epigenetic consequences. This paper is focused on NNMT, despite the fact that in the presence of LPS additional effects of this compound mask pure (canonical) consequences of the elevated NNMT protein which are an increased MNA synthesis or reduced NAD+ level. On the other hand, however, it has been shown that silencing of the NNMT-encoding gene prevents several changes which are observed in control HAECs treated with LPS. They include significantly increased calcium response to thapsigargin (store-operated calcium entry), altered energy metabolism which is switched to anaerobic glycolysis and rearrangement of the mitochondrial network. However, a biochemical mechanism behind the protective consequences of the NNMT deficiency in cells treated with LPS remains unexplained.
A Combined Immunophenotypic And Transcriptional Single-Cell Map Of First Trimester Human Fetal Liver Hematopoiesis
Authors: Sommarin Mikael N.E. , Olofzon Rasmus , Palo Sara , Dhapola Parashar , Karlsson Göran , Böiers Charlotta
Published: December 2021

Knowledge of human fetal blood development and how it differs from adult is highly relevant for our understanding of congenital blood and immune disorders as well as childhood leukemia, the latter known to originate in utero. Blood production during development occurs in waves that overlap in time and space adding to heterogeneity, which necessitates single cell approaches. Here, a combined single cell immunophenotypic and transcriptional map of first trimester primitive blood development is presented. Using CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) the molecular profile of established immunophenotypic gated progenitors was analyzed in the fetal liver (FL). Classical markers for hematopoietic stem cells (HSCs) such as CD90 and CD49F were largely preserved, whereas CD135 (FLT3) and CD123 (IL3R) had a ubiquitous expression pattern capturing heterogenous populations. Direct molecular comparison with an adult bone marrow (BM) data set revealed that HSC-like cells were less frequent in FL, whereas cells with a lympho-myeloid signature were more abundant. Furthermore, an erythro-myeloid primed multipotent progenitor cluster was identified, potentially representing a transient, FL-specific progenitor. Based on the projection performed, up- and downregulated genes between fetal and adult cells were analyzed. In general, cell cycle pathways, including MYC targets were shown to be upregulated in fetal cells, whereas gene sets involved in inflammation and human leukocyte antigen (HLA) complex were downregulated. Importantly, a fetal core molecular signature was identified that could discriminate certain types of infant and childhood leukemia from adult counterparts.

Our detailed single cell map presented herein emphasizes molecular as well as immunophenotypic differences between fetal and adult primitive blood cells, of significance for future studies of pediatric leukemia and blood development in general.
Dynamic Expedition of Leading Mutations in SARS-CoV-2 Spike Glycoproteins
Authors: Hasan Muhammad , He Zhouyi , Jia Mengqi , Leung Alvin C. F. , Natarajan Kathiresan , Xu Wentao , Yap Shanqi , Zhou Feng , Chen Shihong , Su Hailei , Zhu Kaicheng , Su Haibin
Published: December 2021

Throughout the coronavirus disease 2019 (COVID-19) pandemic, the continuous genomic evolution of its etiological agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has generated many new variants with enhanced transmissibility and immune escape capabilities. Being an essential mediator of infections and a key target of antibodies, mutations of its spike glycoprotein play a vital role in modulating its evolutionary trajectory. Here, we present a time-resolved statistical method, Dynamic Expedition of Leading Mutations (deLemus), to analyze the evolutionary dynamics of the SARS-CoV-2 spike. Together with analysis of its single amino acid polymorphism (SAP), we propose the use ofL-index in quantifying the mutation strength of each amino acid site, such that the evolutionary mutation pattern of the spike glycoprotein can be unravelled.
All-atom molecular dynamics simulations of synaptic vesicle fusion I: a glimpse at the primed state
Authors: Rizo Josep , Sari Levent , Qi Yifei , Im Wonpil , Lin Milo M.
Published: December 2021

Synaptic vesicles are primed into a state that is ready for fast neurotransmitter release upon Ca2+-binding to synaptotagmin-1. This state likely includes trans-SNARE complexes between the vesicle and plasma membranes that are bound to synaptotagmin-1 and complexins. However, the nature of this state and the steps leading to membrane fusion are unclear, in part because of the difficulty of studying this dynamic process experimentally. To shed light into these questions, we performed all-atom molecular dynamics simulations of systems containing trans-SNARE complexes between two flat bilayers or a vesicle and a flat bilayer with or without fragments of synaptotagmin-1 and/or complexin-1. Our results help visualize potential states of the release machinery en route to fusion, and suggest mechanistic features that may control the speed of release. In particular, the simulations suggest that the primed state contains almost fully assembled trans-SNARE complexes bound to the synaptotagmin-1 C2B domain and complexin-1 in a spring-loaded configuration where interactions of the C2B domain with the plasma membrane orient complexin-1 toward the vesicle, avoiding premature membrane merger but keeping the system ready for fast fusion upon Ca2+ influx.
Symphonizing pileup and full-alignment for deep learning-based long-read variant calling
Authors: Zheng Zhenxian , Li Shumin , Su Junhao , Leung Amy Wing-Sze , Lam Tak-Wah , Luo Ruibang
Published: December 2021

Deep learning-based variant callers are becoming the standard and have achieved superior SNP calling performance using long reads. In this paper, we present Clair3, which leveraged the best of two major method categories: pile-up calling handles most variant candidates with speed, and full-alignment tackles complicated candidates to maximize precision and recall. Clair3 ran faster than any of the other state-of-the-art variant callers and performed the best, especially at lower coverage.
The influence of saccades on yaw gaze stabilization in fly flight
Authors: Davis Brock A. , Mongeau Jean-Michel
Published: December 2021

In a way analogous to human vision, the fruit flyD. melanogasterand many other flying insects generate smooth and saccadic movements to stabilize and shift their gaze in flight, respectively. It has been hypothesized that this combination of continuous and discrete movements benefits both flight stability and performance, particularly at high frequencies or visual motion speeds [1]. Here we develop a hybrid control system model to explore the effects of saccades on the yaw gaze stabilization reflex ofD. melanogaster. Inspired from experimental studies, the model includes a first order plant, a Proportional-Integral (PI) continuous controller, and a saccadic reset system that fires based on the integrated error of the continuous controller. We explore the gain, delay and switching threshold parameter space to quantify the optimum regions for yaw stability and performance. We show that the addition of saccades to a continuous controller provides benefits to both stability and performance across a range of visual motion speeds. Our model suggests thatDrosophilaoperates near its optimal switching threshold for its experimental gain set. We also show that based on experimental data,D. melanogasteroperates in a region that trades off performance and stability. This trade-off increases flight robustness, which could facilitate compensation for internal perturbations such as wing damage.
Capturing a crucial ‘disorder-to-order transition’ at the heart of the coronavirus molecular pathology – triggered by highly persistent, interchangeable salt-bridges
Authors: Roy Sourav , Ghosh Prithwi , Bandyopadhyay Abhirup , Basu Sankar
Published: December 2021

The COVID-19 origin debate has greatly been influenced by Genome comparison studies of late, revealing the seemingly sudden emergence of the Furin-Like Cleavage Site at the S1/S2 junction of the SARS-CoV-2 Spike (FLCSSpike) containing its 681PRRAR685 motif, absent in other related respiratory viruses. Being the rate-limiting (i.e., the slowest) step, the host Furin cleavage is instrumental in the abrupt increase in transmissibility in COVID-19, compared to earlier onsets of respiratory viral diseases. In such a context, the current paper entraps a ’disorder-to-order transition’ of the FLCSSpike (concomitant to an entropy arrest) upon binding to Furin. The interaction clearly seems to be optimized for a more efficient proteolytic cleavage in SARS-CoV-2. The study further shows the formation of dynamically interchangeable and persistent networks of salt-bridges at the Spike–Furin interface in SARS-CoV-2 involving the three arginines (R682, R683, R685) of the FLCSSpike with several anionic residues (E230, E236, D259, D264, D306) coming from Furin, strategically distributed around its catalytic triad. Multiplicity and structural degeneracy of plausible salt-bridge network archetypes seems the other key characteristic features of the Spike–Furin binding in SARS-CoV-2 allowing the system to breathe – a trademark of protein disorder transitions. Interestingly, with respect to the homologous interaction in SARS-CoV (2002/2003) taken as a baseline, the Spike–Furin binding events generally in the coronavirus lineage seems to have a preference for ionic bond formation, even with lesser number of cationic residues at their potentially polybasic FLCSSpike patches. The interaction energies are suggestive of a characteristic metastabilities attributed to Spike–Furin interactions generally to the coronavirus lineage – which appears to be favorable for proteolytic cleavages targeted at flexible protein loops. T he current findings not only offer novel mechanistic insights into the coronavirus molecular pathology and evolution but also add substantially to the existing theories of proteolytic cleavages.
Microtubule plus-end regulation by centriolar cap proteins
Authors: Ogunmolu Funso E. , Moradi Shoeib , Volkov Vladimir A. , van Hoorn Chris , Wu Jingchao , Andrea Nemo , Hua Shasha , Jiang Kai , Vakonakis Ioannis , Potočnjak Mia , Herzog Franz , Gigant Benoît , Gudimchuk Nikita , Stecker Kelly E. , Dogterom Marileen , Steinmetz Michel O. , Akhmanova Anna
Published: December 2021

Centrioles are microtubule-based organelles required for the formation of centrosomes and cilia. Centriolar microtubules, unlike their cytosolic counterparts, grow very slowly and are very stable. The complex of centriolar proteins CP110 and CEP97 forms a cap that stabilizes the distal centriole end and prevents its over-elongation. Here, we used in vitro reconstitution assays to show that whereas CEP97 does not interact with microtubules directly, CP110 specifically binds microtubule plus ends, potently blocks their growth and induces microtubule pausing. Cryo-electron tomography indicated that CP110 binds to the luminal side of microtubule plus ends and reduces protofilament peeling. Furthermore, CP110 directly interacts with another centriole biogenesis factor, CPAP/SAS- 4, which tracks growing microtubule plus ends, slows down their growth and prevents catastrophes. CP110 and CPAP synergize in inhibiting plus-end growth, and this synergy depends on their direct binding. Together, our data reveal a molecular mechanism controlling centriolar microtubule plus- end dynamics and centriole biogenesis.
Loss ofGrin2aCauses a Transient Delay in the Electrophysiological Maturation of Hippocampal Parvalbumin Interneurons: A Possible Mechanism for Transient Seizure Burden in Patients with NullGRIN2AVariants
Authors: Camp Chad R. , Vlachos Anna , Klöckner Chiara , Krey Ilona , Banke Tue G. , Shariatzadeh Nima , Ruggiero Sarah M , Galer Peter , Park Kristen L. , Caccavano Adam , Kimmel Sarah , Yuan Xiaoqing , Yuan Hongjie , Helbig Ingo , Benke Tim A. , Lemke Johannes R. , Pelkey Kenneth A. , McBain Chris J. , Traynelis Stephen F.
Published: December 2021

N-methyl-D-aspartate receptors (NMDARs) comprise a family of ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits (encoded by theGRIN1gene) and two GluN2 subunits (encoded by theGRIN2A-GRIN2Dgenes). Sequencing data shows that 43% (297/679) of all currently known NMDAR disease-associated genetic variants are within theGRIN2Agene, which encodes the GluN2A subunit. Here, we show that unlike missenseGRIN2Avariants, individuals affected with disease-associated nullGRIN2Avariants demonstrate a transient period of seizure susceptibility that begins during infancy and diminishes near adolescence. To explore this new clinical finding at that circuit and cellular level, we conducted studies usingGrin2a+/-andGrin2a-/-mice at various stages during neurodevelopment. We show increased circuit excitability and CA1 pyramidal cell output in juvenile mice of bothGrin2a+/-andGrin2a-/-mice. These alterations in somatic spiking are not due to global upregulation otherGRINgenes (includingGrin2b) nor can they be attributed to perturbations in the intrinsic excitability or action-potential firing properties of CA1 pyramidal cells. Deeper evaluation of the developing CA1 circuit led us to uncover age- andGrin2agene dosing-dependent transient delays in the electrophysiological maturation programs of PV interneurons. Overall, we report thatGrin2a+/+mice reach electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, withGrin2a+/-mice not reaching electrophysiological maturation until preadolescence, andGrin2a-/-not reaching electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure burden in disease-associated nullGRIN2Apatients.
Identification of ER/SR resident proteins as biomarkers for ER/SR calcium depletion in skeletal muscle cells
Authors: Greer Lacey K. , Meilleur Katherine G. , Harvey Brandon K. , Wires Emily S.
Published: December 2021

Aberrations to endoplasmic/sarcoplasmic reticulum (ER/SR) calcium concentration can result in the departure of endogenous proteins in a phenomenon termed exodosis. Redistribution of the ER/SR proteome can have deleterious effects to cell function and cell viability, often contributing to disease pathogenesis. Many proteins prone to exodosis reside in the ER/SR via an ER retention/retrieval sequence (ERS) and are involved in protein folding, protein modification, and protein trafficking. While the consequences of their extracellular presence have yet to be fully delineated, the proteins that have undergone exodosis may be useful for biomarker development. Skeletal muscle cells rely upon tightly coordinated ER/SR calcium release for muscle contractions, and perturbations to calcium homeostasis can result in myopathies. Ryanodine receptor type-1 (RYR1) is a calcium release channel located in the SR. Mutations to the RYR1 gene can compromise calcium homeostasis leading to a vast range of clinical phenotypes that include hypotonia, myalgia, respiratory insufficiency, ophthalmoplegia, fatigue and malignant hyperthermia (MH). There are currently no FDA approved treatments for RYR1-related myopathies (RYR1-RM). Here we examine the exodosis profile of skeletal muscle cells following ER/SR calcium depletion. Proteomic analysis identified 4,465 extracellular proteins following ER/SR calcium depletion with 1,280 proteins significantly different than vehicle. A total of 54 ERS proteins were identified and 33 ERS proteins significantly increased following ER/SR calcium depletion. Specifically, ERS protein, mesencephalic astrocyte-derived neurotrophic factor (MANF), was elevated following calcium depletion, making it a potential biomarker candidate for human samples. Despite no significant elevation of MANF in plasma levels among healthy volunteers and RYR1-RM individuals, MANF plasma levels positively correlated with age in RYR1-RM individuals, presenting a potential biomarker of disease progression. Selenoprotein N (SEPN1) was also detected only in extracellular samples following ER/SR calcium depletion. This protein is integral to calcium handling and SEPN1 variants have a causal role in SEPN1-related myopathies (SEPN1-RM). Extracellular presence of ER/SR membrane proteins may provide new insight into proteomic alterations extending beyond ERS proteins. Pre-treatment of skeletal muscle cells with bromocriptine, an FDA approved drug recently found to have anti-exodosis effects, curbed exodosis of ER/SR resident proteins. Changes to the extracellular content caused by intracellular calcium dysregulation presents an opportunity for biomarker development and drug discovery.
Unsupervised genome-wide cluster analysis: nucleotide sequences of the omicron variant of SARS-CoV-2 are similar to sequences from early 2020
Authors: Hahn Georg , Lee Sanghun , Prokopenko Dmitry , Novak Tanya , Hecker Julian , Khurana Surender , Baden Lindsey R. , Randolph Adrienne G. , Weiss Scott T. , Lange Christoph
Published: December 2021

The GISAID database contains more than 1,000,000 SARS-CoV-2 genomes, including sequences of the recently discovered SARS-CoV-2 omicron variant and of prior SARS-CoV-2 strains that have been collected from patients around the world since the beginning of the pandemic. We applied unsupervised cluster analysis to the SARS-CoV-2 genomes, assessing their similarity at a genome-wide level based on the Jaccard index and principal component analysis. Our analysis results show that the omicron variant sequences are most similar to sequences that have been submitted early in the pandemic around January 2020. Furthermore, the omicron variants in GISAID are spread across the entire range of the first principal component, suggesting that the strain has been in circulation for some time. This observation supports a long-term infection hypothesis as the omicron strain origin.
SARS-CoV-2 diverges from other betacoronaviruses in only partially activating the IRE1α/XBP1 ER stress pathway in human lung-derived cells
Authors: Nguyen Long C. , Renner David M. , Silva Diane , Yang Dongbo , Parenti Nicholas , Medina Kaeri M. , Nicolaescu Vlad , Gula Haley , Drayman Nir , Valdespino Andrea , Mohamed Adil , Dann Christopher , Wannemo Kristin , Robinson-Mailman Lydia , Gonzalez Alan , Stock Letícia , Cao Mengrui , Qiao Zeyu , Moellering Raymond E. , Tay Savas , Randall Glenn , Beers Michael F. , Rosner Marsha Rich , Oakes Scott A. , Weiss Susan R.
Published: December 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed over 6 million individuals worldwide and continues to spread in countries where vaccines are not yet widely available, or its citizens are hesitant to become vaccinated. Therefore, it is critical to unravel the molecular mechanisms that allow SARS-CoV-2 and other coronaviruses to infect and overtake the host machinery of human cells. Coronavirus replication triggers endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), a key host cell pathway widely believed essential for viral replication. We examined the master UPR sensor IRE1α kinase/RNase and its downstream transcription factor effector XBP1s, which is processed through an IRE1α-mediated mRNA splicing event, in human lung-derived cells infected with betacoronaviruses. We found human respiratory coronavirus OC43 (HCoV-OC43), Middle East respiratory syndrome coronavirus (MERS-CoV), and murine coronavirus (MHV) all induce ER stress and strongly trigger the kinase and RNase activities of IRE1α as well as XBP1 splicing. In contrast, SARS-CoV-2 only partially activates IRE1α through autophosphorylation, but its RNase activity fails to splice XBP1. Moreover, while IRE1α was dispensable for replication in human cells for all coronaviruses tested, it was required for maximal expression of genes associated with several key cellular functions, including the interferon signaling pathway, during SARS-CoV-2 infection. Our data suggest that SARS-CoV-2 actively inhibits the RNase of autophosphorylated IRE1α, perhaps as a strategy to eliminate detection by the host immune system.

IMPORTANCE

SARS-CoV-2 is the third lethal respiratory coronavirus after MERS-CoV and SARS-CoV to emerge this century, causing millions of deaths world-wide. Other common coronaviruses such as HCoV-OC43 cause less severe respiratory disease. Thus, it is imperative to understand the similarities and differences among these viruses in how each interacts with host cells. We focused here on the inositol-requiring enzyme 1α (IRE1α) pathway, part of the host unfolded protein response to virus-induced stress. We found that while MERS-CoV and HCoV-OC43 fully activate the IRE1α kinase and RNase activities, SARS-CoV-2 only partially activates IRE1α, promoting its kinase activity but not RNase activity. Based on IRE1α-dependent gene expression changes during infection, we propose that SARS-CoV-2 prevents IRE1α RNase activation as a strategy to limit detection by the host immune system.
Prolactin action is necessary for parental behavior in male mice
Authors: Smiley Kristina O. , Brown Rosemary S.E. , Grattan David R.
Published: December 2021

Parental care is critical for successful reproduction in mammals. In comparison to maternal care, the neuroendocrine mechanisms supporting paternal care are less well-studied. Laboratory mice show a mating-induced suppression of infanticide (normally observed in virgins) and onset of paternal behavior. Using this model, we sought to investigate whether the hormone prolactin plays a role in paternal behavior, as it does for maternal behavior. First, using c-fos immunoreactivity in Prlr-IRES-Cre-tdtomato reporter mouse sires, we show that the circuitry activated during paternal interactions contains prolactin-responsive neurons, including the medial preoptic area, bed nucleus of the stria terminalis, and medial amygdala. To evaluate whether prolactin action is required for the establishment and display of paternal behavior, we conditionally deleted the prolactin receptor (Prlr) from 3 distinct cell types: glutamatergic, GABAergic, and CaMKIIα-expressing forebrain neurons. Prlr-deletion from CaMKIIα-expressing forebrain neurons, but not from glutamatergic or GABAergic cells, resulted in a profound effect on paternal behavior, as none of these males completed the pup retrieval task. Finally, although sires do not show an acute increase in circulating prolactin levels in response to pups, pharmacological blockade of prolactin-release at the time of pup exposure resulted in failure to retrieve pups, similar to when the Prlr was deleted from CaMKIIα neurons, with prolactin administration rescuing this behavior. Taken together, our data show that paternal behavior in sires is dependent on basal levels of circulating prolactin acting at the Prlr on CaMKIIα-expressing neurons. These new data in male mice demonstrate that prolactin has a similar action in both sexes to promote parental care.
Gut mélange à trois: fluctuating selection modulated by microbiota, host immune system, and antibiotics
Authors: Barreto Hugo C. , Abreu Beatriz , Gordo Isabel
Published: December 2021

Iron is critical in host-microbe interactions, and its availability is tightly regulated in the mammalian gut. Antibiotics and inflammation can perturb iron availability in the gut, which could alter host-microbe interactions. Here, we show that an adaptive allele of iscR, a major regulator of iron homeostasis of Escherichia coli, is under fluctuating selection in the mouse gut. In vivo competitions in immune-competent, immune-compromised, and germ-free mice reveal that the selective pressure on an iscR mutant E. coli is modulated by the presence of antibiotics, the microbiota, and the immune system. In vitro assays show that iron availability is an important mediator of the iscR allele fitness benefits or costs. We identify Lipocalin-2, a host’s immune protein that prevents bacterial iron acquisition, as a major host mechanism underlying fluctuating selection of iscR. Our results provide a remarkable example of strong fluctuating selection acting on bacterial iron regulation in the mammalian gut.
A review of methodologies for performance evaluation of automated construction processes
Authors: Krishnamoorthi Sundararaman , Raphael Benny
Published: December 2021

Purpose

The aim of this paper is to synthesize knowledge related to performance evaluation of automated construction processes during the planning and execution phases through a theme-based literature classification. The primary research question that is addressed is “How to quantify the performance improvement in automated construction processes?”

Design/methodology/approach

A systematic literature review of papers on automated construction was conducted involving three stages-planning, conducting and reporting. In the planning stage, the purpose of the review is established through key research questions. Then, a four-step process is employed consisting of identification, screening, shortlisting and inclusion of papers. For reporting, observations were critically analysed and categorized according to themes.

Findings

The primary conclusion from this study is that the effectiveness of construction processes can only be benchmarked using realistic simulations. Simulations help to pinpoint the root causes of success or failure of projects that are either already completed or under execution. In automated construction, there are many complex interactions between humans and machines; therefore, detailed simulation models are needed for accurate predictions. One key requirement for simulation is the calibration of the models using real data from construction sites.

Research limitations/implications

This study is based on a review of 169 papers from a database of peer-reviewed journals, within a time span of 50 years.

Originality/value

Gap in research in the area of performance evaluation of automated construction is brought out. The importance of simulation models calibrated with on-site data within a methodology for performance evaluation is highlighted.
An examination of social media advertising features, brand engagement and purchase intention in the fast food industry
Authors: Hanaysha Jalal Rajeh
Published: December 2021

Purpose

This study aimed to investigate the impact of social media advertising features (interactivity, perceived relevance, informativeness and entertainment) on brand engagement in the fast food industry. It was also designed to identify the effect of brand engagement on purchase intention.

Design/methodology/approach

The data was gathered from 258 customers of fast food restaurants in United Arab Emirates using an online survey. The collected data was analyzed via the partial least square approach (PLS-SEM) to verify the hypotheses and reach at conclusions.

Findings

The findings indicated that social media advertising features have positive effects on brand engagement. In particular, it was found that interactivity, perceived relevance, informativeness and entertainment are positively associated with brand engagement. The results also confirmed that brand engagement has a positive effect on purchase intention.

Originality/value

This study provides a noteworthy contribution to the literature by examining the effect of four unique social media advertising features on consumer engagement. By looking at previous studies, it can also be observed there is a limited empirical research on the effect of perceived relevance and informativeness on brand engagement. It further focuses on covering existing gaps in the literature concerning the effect of brand engagement on purchase intention in the fast food industry setting. This is one of the earlier studies that collectively examined these factors in model; particularly, in fast food industry setting with empirical data from a Middle East country.
Consumer attitudes toward facial recognition payment: an examination of antecedents and outcomes
Authors: Dang Van Thac , Nguyen Ninh , Nguyen Hoang Viet , Nguyen Hoang , Van Huy Le , Tran Viet Thao , Nguyen Tran Hung
Published: December 2021

Purpose

Facial recognition payment (FRP) has been recently introduced as a new cashless payment method in retail store context. Anchored on information systems and consumer theories, this research aims to investigate the key antecedents and outcomes of consumer attitudes toward this innovative payment method.

Design/methodology/approach

This research used a survey method to obtain data from 795 consumers at retail stores in China. The data were then analyzed by different statistical methods, including descriptive statistics, reliability analysis and structural equation modeling.

Findings

Results show that perceived usefulness, perceived ease of use and perceived innovativeness positively affect consumer attitudes toward FRP, while perceived risk negatively impacts such attitudes. In addition, consumer attitudes enhance store satisfaction, and hedonic shopping value plays a mediating role in this relationship.

Practical implications

This study encourages retailers to adopt FRP that can enhance consumer hedonic shopping value and satisfaction.

Originality/value

This study contributes to the literature by explaining both the antecedents and the outcomes of consumer attitudes toward FRP in retail context. The study also provides fresh insights into how such attitudes can improve consumers' shopping values and satisfaction in an emerging market.
Working from home and long-term housing wealth inequality in large cities of advanced economies
Authors: Tajaddini Reza , Gholipour Hassan F. , Arjomandi Amir
Published: December 2021

Purpose

The purpose of this study is to explain the potential long-term impacts of working from home on housing wealth inequality in large cities of advanced economies.

Design/methodology/approach

This study is descriptive research and It supports the arguments by providing some emerging evidence from property markets in developed countries.

Findings

The authors argue that due to the unique nature of the COVID-19 crisis, it will have a different and long-term impact on housing wealth inequality. Changes in the working arrangements of many professionals will change the housing demand dynamic across different suburbs and may lead to a reduction of the housing wealth gap in the long term. In this paper, the authors propose five mechanisms that may impact housing wealth inequality.

Research limitations/implications

Long-term data is required to test the proposed conceptual model in this study and the effect of the COVID-19 pandemic on housing wealth across and within suburbs of large cities.

Practical implications

Policymakers and regulators may benefit from the discussions and suggestions provided in this study and consider the proposed avenues on how new changes in the working environment (remote working) may result in a reduction of housing wealth inequality.

Originality/value

This study presents a new perspective about the potential long-term impacts of working from home that is posed by the COVID-19 pandemic on housing wealth inequality in large cities of developed economies.
Employability of job applicants in skilful jobs: commonality in employer and employee perspectives
Authors: Murrar Abdullah , Batra Madan , Paz Veronica , Asfour Bara , Balmakhtar Marouane
Published: December 2021

Purpose

The purpose of this research is to explore the employer and employee perspectives about the employability skills of skilful jobs. The research is conducted in a developing country (Palestine) which has a high percentage of university graduates, high unemployment rate and intense job competition. This paper defines skilful jobs as those that require employees who have attended a college or university and have completed a two-year diploma or a four-year degree.

Design/methodology/approach

This research integrates the components of discussion with local experts in the skilled labour market, primary data from employers (N = 415) and primary data from employees (N = 880). Binary logistic regression is used to measure the relationship between the dependent variable (likelihood of hire or not hire) and independent variables (job applicants' hard and soft skills).

Findings

The results from both employer and employee data revealed that the previous work experience, computer skills, professional certifications and high grade point average have significant impact on hiring and recruitment in the skilful jobs. In addition to these, the employers seek applicants who have communication skills. However, the employees consider personal relationship with employers to be a highly significant factor in accepting job offers.

Practical implications

To increase their likelihood of obtaining a skilful job, and then sustaining it, the job seekers should hone their soft skills and acquire professional certifications. The universities should adapt their curriculum to match these skills and move their focus from disciplinary knowledge to competencies. The public policy makers should design awareness and capacity building programmes that will facilitate the recent graduates' integration into the labour market. The empirical model in this study shows that previous work experience is the most important recruitment factor for employers – accordingly, creating internships and apprenticeship opportunities would be its clear policy implication.

Originality/value

The study contributes to the literature by providing a parsimonious employability model of skilful jobs, which fits as much as possible the perspectives of the employers and employees about the employability skills in a developing country.