bluuebunny/crossref_metadata_2025 huggingface dataset:
The SARS-CoV-2 variants associated with infections in India, B.1.617, show enhanced spike cleavage by furin
Authors: Peacock Thomas P. , Sheppard Carol M. , Brown Jonathan C. , Goonawardane Niluka , Zhou Jie , Whiteley Max ,   PHE Virology Consortium, de Silva Thushan I. , Barclay Wendy S.
Published: May 2021

The spike (S) glycoprotein of the SARS-CoV-2 virus that emerged in 2019 contained a suboptimal furin cleavage site at the S1/S2 junction with the sequence 681PRRAR/S686. This cleavage site is required for efficient airway replication, transmission, and pathogenicity of the virus. The B.1.617 lineage has recently emerged in India, coinciding with substantial disease burden across the country. Early evidence suggests that B.1.617.2 (a sublineage of B.1.617) is more highly transmissible than contemporary lineages. B.1.617 and its sublineages contain a constellation of S mutations including the substitution P681R predicted to further optimise this furin cleavage site. We provide experimental evidence that virus of the B.1.617 lineage has enhanced S cleavage, that enhanced processing of an expressed B.1.617 S protein in cells is due to P681R, and that this mutation enables more efficient cleavage of a peptide mimetic of the B.1.617 S1/S2 cleavage site by recombinant furin. Together, these data demonstrate viruses in this emerging lineage have enhanced S cleavage by furin which we hypothesise could be enhancing transmissibility and pathogenicity.
Group II truncated haemoglobin YjbI prevents reactive oxygen species-induced protein aggregation in Bacillus subtilis
Authors: Imai Takeshi , Tobe Ryuta , Honda Koji , Tanaka Mai , Kawamoto Jun , Mihara Hisaaki
Published: May 2021

Oxidative stress–mediated formation of protein hydroperoxides can induce irreversible fragmentation of the peptide backbone and accumulation of cross-linked protein aggregates, leading to cellular toxicity, dysfunction, and death. However, how bacteria protect themselves from damages caused by protein hydroperoxidisation is unknown. Here we show that YjbI, a group II truncated haemoglobin from Bacillus subtilis, prevents oxidative aggregation of cell-surface proteins by its biologically unprecedented protein hydroperoxide peroxidase-like activity, which removes hydroperoxide groups from oxidised proteins. Disruption of the yjbI gene in B. subtilis lowered biofilm water repellence and the mechanical stiffness of the cell surface, which associated with the cross-linked aggregation of the biofilm matrix protein TasA. YjbI was localised to the cell surface, and the sensitivity of planktonically grown cells to generators of reactive oxygen species was significantly increased upon yjbI disruption, suggesting that YjbI pleiotropically protects labile cell-surface proteins from oxidative damage. YjbI removed hydroperoxide residues from a model oxidised protein substrate, bovine serum albumin, and prevented its oxidative aggregation in vitro. These findings provide new insights into the role of truncated haemoglobin and the importance of hydroperoxide removal from proteins in the survival of aerobic bacteria.
Global analysis of the zinc homeostasis network in Pseudomonas aeruginosa and its gene expression dynamics
Authors: Ducret Verena , Abdou Melina , Milho Catarina Goncalves , Leoni Sara , Martin--Pelaud Oriane , Sandoz Antoine , Campos Inés Segovia , Tercier-Waeber Mary-Lou , Valentini Martina , Perron Karl
Published: May 2021

Zinc is one of the most important trace elements for life and its deficiency, like its excess, can be fatal. In the bacterial opportunistic pathogen Pseudomonas aeruginosa, Zn homeostasis is not only required for survival, but also for virulence and antibiotic resistance. Thus, the bacterium possesses multiple Zn import/export/storage systems. In this work, we determine the expression dynamics of the entire P. aeruginosa Zn homeostasis network at both transcript and protein levels. Precisely, we followed the switch from a Zn-deficient environment, mimicking the initial immune strategy to counteract bacterial infections, to a Zn-rich environment, representing the phagocyte metal boost used to eliminate an engulfed pathogen. Thanks to the use of the NanoString technology, we timed the global silencing of Zn import systems and the orchestrated induction of Zn export systems. We show that the induction of Zn export systems is hierarchically organized as a function of their impact on Zn homeostasis. Moreover, we identify PA2807 as a novel Zn resistance component in P. aeruginosa and highlight new regulatory links among Zn-homeostasis systems. Altogether, this work unveils a sophisticated and adaptive homeostasis network, which complexity is key in determining a pathogen spread in the environment and during host-colonization.
Rapid evolution of bacterial AB5 toxin B subunits independent of A subunits: sialic acid binding preferences correlate with host range and toxicity
Authors: Khan Naazneen , Sasmal Aniruddha , Khedri Zahra , Secrest Patrick , Verhagen Andrea , Srivastava Saurabh , Varki Nissi , Chen Xi , Yu Hai , Beddoe Travis , Paton Adrienne W. , Paton James C. , Varki Ajit
Published: May 2021

Cytotoxic A subunits of bacterial AB5 toxins enter the cytosol following B subunit binding to host cell glycans. We report that A subunit phylogeny evolves independently of B subunits and suggest a future B subunit nomenclature based on species name. Phylogenetic analysis of B subunits that bind sialic acids (Sias) with homologous molecules in databases also show poor correlation with phylogeny. These data indicate ongoing lateral gene transfers between species, with mixing of A and B subunits. Some B subunits are not even associated with A subunits e.g., YpeB of Yersinia pestis, the etiologic agent of plague epidemics. Plague cannot be eradicated because of Y. pestis’ adaptability to numerous hosts. YpeB shares 58% identity/79% similarity with the homo-pentameric B subunit of E. coli Subtilase cytotoxin, and 48% identity/68% similarity with the B subunit of S. Typhi typhoid toxin. We previously showed selective binding of B5 pentamers to a sialoglycan microarray, with Sia preferences corresponding to hosts e.g., N-acetylneuraminic acid (Neu5Ac; prominent in humans) or N-glycolylneuraminic acid (Neu5Gc; prominent in ruminant mammals and rodents). Consistent with much broader host range of Y. pestis, YpeB binds all mammalian sialic acid types, except for 4-O-acetylated ones. Notably, YpeB alone causes dose-dependent cytotoxicity, abolished by a mutation (Y77F) eliminating Sia recognition, suggesting cell proliferation and death via lectin-like cross-linking of cell surface sialoglycoconjugates. These findings help explain the host range of Y. pestis and could be important for pathogenesis. Overall, our data indicate ongoing rapid evolution of both host Sias and pathogen toxin-binding properties.
GIGANTEA gene expression influence leaf senescence in Populus in two different ways
Authors: Fataftah Nazeer , Bag Pushan , André Domenique , Lihavainen Jenna , Zhang Bo , Ingvarsson Pär K , Nilsson Ove , Jansson Stefan
Published: May 2021

GIGANTEA (GI) genes have a central role in plant development and influence several processes such as light signaling, circadian rhythm and abiotic stress tolerance. Hybrid aspen T89 (Populus tremula x tremuloides) trees with low GI expression through RNAi have a severely compromised growth. In order to study the effect of reduced GI expression on leaf traits with special emphasis on leaf senescence, we grafted GI-RNAi scions onto wild type (WT) rootstocks and managed to restore scions’ growth. The RNAi line had distorted leaf shape and reduced photosynthesis, probably caused by modulating phloem or stomatal function, increased starch accumulation, higher carbon-to-nitrogen (C/N) ratio and a reduced capacity to withstand moderate light stress. GI-RNAi also induced senescence under long day (LD) and moderate light conditions. Furthermore, the GI-RNAi lines were affected in their capacity to respond to “autumn environmental cues” inducing senescence, a type of leaf senescence with characteristics different from senescence induced directly by stress under LD conditions. Whereas Overexpression of GI delayed senescence. The two different effects on leaf senescence were not affected by the expression of FT (Flowering locus T), were “local” – they followed the genotype of the branch independent on the position in the tree – and trees with modified gene expression grown in the field were affected in a similar way as under controlled conditions. Taken together, GI plays a central role to sense the environmental changes during autumn and determine the appropriate timing for leaf senescence in Populus.

One sentence summary

Leaf senescence is a complex process that is not well understood, but this paper shows that changing the expression of one gene could influence leaf senescence in Populus trees in two separate ways.
Metabolic design in a model of extreme mammalian metabolism, the North American least shrew (Cryptotis parva)
Authors: Chung Dillon J. , Madison Grey P. , Aponte Angel M. , Singh Komudi , Li Yuesheng , Pirooznia Mehdi , Bleck Christopher K. E. , Darmani Nissar A. , Balaban Robert S.
Published: May 2021

Mitochondrial adaptations are fundamental to differentiated function and energetic homeostasis in mammalian cells. But the mechanisms that underlie these relationships remain poorly understood. Here, we investigated organ-specific mitochondrial morphology, connectivity and protein composition in a model of extreme mammalian metabolism, the Least shrew (Cryptotis parva). This was achieved through a combination of high-resolution 3D focused-ion-beam EM imaging and tandem-mass-tag MS proteomics. We demonstrate that liver and kidney mitochondrial content are equivalent to the heart permitting assessment of mitochondrial adaptations in different organs with similar metabolic demand. Muscle mitochondrial networks (cardiac and skeletal) are extensive, with a high incidence of nanotunnels – which collectively support the metabolism of large muscle cells. Mitochondrial networks were not detected in the liver and kidney as individual mitochondria are localized with sites of ATP consumption. This configuration is not observed in striated muscle, likely due to a homogenous ATPase distribution and the structural requirements of contraction. These results demonstrate distinct, fundamental mitochondrial structural adaptations for similar metabolic demand that are dependent on the topology of energy utilization process in a mammalian model of extreme metabolism.
Simple and practical sialoglycan encoding system reveals vast diversity in nature and identifies a universal sialoglycan-recognizing probe derived from AB5 toxin B subunits
Authors: Sasmal Aniruddha , Khan Naazneen , Khedri Zahra , Kellman Benjamin P. , Srivastava Saurabh , Verhagen Andrea , Yu Hai , Bruntse Anders Bech , Diaz Sandra , Varki Nissi , Beddoe Travis , Paton Adrienne W. , Paton James C. , Chen Xi , Lewis Nathan E. , Varki Ajit
Published: May 2021

Vertebrate sialic acids (Sias) display much diversity in modifications, linkages and underlying glycans. Slide microarrays allow high-throughput explorations of sialoglycan-protein interactions. A microarray presenting ∼150 structurally-defined sialyltrisaccharides with various Sias linkages and modifications still poses challenges in planning, data sorting, visualization and analysis. To address these issues, we devised a simple 9-digit code for sialyltrisaccharides with terminal Sias and underlying two monosaccharides assigned from the non-reducing end, with three digits assigning a monosaccharide, its modifications, and linkage. Calculations based on the encoding system reveals >113,000 likely linear sialyltrisaccharides in nature. Notably a biantennary N-glycan with two terminal sialyltrisaccharides could thus have >1010 potential combinations and a triantennary N-glycan with three terminal sequences, >1015 potential combinations. While all possibilities likely do not exist in nature, sialoglycans encode enormous diversity. While glycomic approaches are used to probe such diverse sialomes, naturally-occurring bacterial AB5 toxin B subunits are simpler tools to track the dynamic sialome in biological systems. Sialoglycan microarray was utilized to compare sialoglycan-recognizing bacterial toxin B subunits. Unlike the poor correlation between B subunits and species phylogeny, there is stronger correlation with Sia-epitope preferences. Further supporting this pattern, we report a B subunit (YenB) from Yersinia enterocolitica (broad host range) recognizing almost all sialoglycans in the microarray, including 4-O-acetylated-Sias not recognized by a Y. pestis orthologue (YpeB). Differential Sia-binding patterns were also observed with phylogenetically-related B subunits from Escherichia coli (SubB), Salmonella Typhi (PltB), S. Typhimurium (ArtB), extra-intestinal E.coli (EcPltB), Vibrio cholera (CtxB), and cholera family homologue of E. coli (EcxB).
Mapping the biosynthetic pathway of a hybrid polyketide-nonribosomal peptide in a metazoan
Authors: Feng Likui , Gordon Matthew T. , Liu Ying , Basso Kari B. , Butcher Rebecca A.
Published: May 2021

Hybrid polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) systems typically use complex protein-protein interactions to facilitate direct transfer of intermediates between megasynthases. In the nematode Caenorhabditis elegans, PKS-1 and NRPS-1 produce the nemamides, the only known hybrid polyketide-nonribosomal peptides in animals, through a poorly understood mechanism. Here, we use genome editing and mass spectrometry to map the roles of individual PKS-1 and NRPS-1 enzymatic domains in nemamide biosynthesis. Furthermore, we show that nemamide biosynthesis requires at least five additional stand-alone enzymes that are encoded by genes distributed across the worm genome. We identify the roles of these enzymes in the biosynthetic pathway and discover a novel mechanism of trafficking intermediates between a PKS and an NRPS. Specifically, we show that the enzyme PKAL-1 activates an advanced polyketide intermediate as an adenylate and directly loads it onto a carrier protein in NRPS-1. This trafficking provides a means by which a PKS-NRPS system can expand its biosynthetic potential and is likely important for the regulation of nemamide biosynthesis.
Genomic characterization of world’s longest selection experiment in mouse reveals the complexity of polygenic traits
Authors: Palma-Vera Sergio E. , Reyer Henry , Langhammer Martina , Reinsch Norbert , Derežanin Lorena , Fickel Jörns , Qanbari Saber , Weitzel Joachim , Franzenburg Sören , Hemmrich-Stanisak Georg , Schön Jennifer
Published: May 2021

A unique set of mouse outbred lines has been generated through selective breeding in the longest selection experiment ever conducted on mice. Over the course of >140 generations, selection on the control line has given rise to two extremely fertile lines (>20 pups per litter each), two giant growth lines (one lean, one obese) and one long-distance running line. Genomic analysis revealed line-specific patterns of genetic variation among lines and high levels of homozygosity within lines as a result of long-term intensive selection, genetic drift and isolation. Detection of line-specific patterns of genetic differentiation and structural variation revealed multiple candidate genes behind the improvement of the selected traits. We conclude that the genomes of these lines are rich in beneficial alleles for the respective selected traits and represent an invaluable resource for unraveling the polygenic basis of fertility, obesity, muscle growth and endurance fitness.
Two Type VI Secretion Systems in Vibrio coralliilyticus RE22Sm exhibit differential target specificity for bacteria prey and oyster larvae
Authors: Schuttert Christian W. , Gomez-Chiarri Marta , Rowley David C. , Nelson David R.
Published: May 2021

Vibrio coralliilyticus is an extracellular bacterial pathogen and a causative agent of vibriosis in larval oysters. Host mortality rates can quickly reach 100% during vibriosis outbreaks in oyster hatcheries. Type VI Secretion Systems (T6SS) are rapidly polymerizing, contact dependent injection apparatus for prey cell intoxication and play important roles in pathogenesis. DNA sequencing of V. coralliilyticus RE22Sm indicated the likely presence of two functional T6SSs with one on each of two chromosomes. Here, we investigated the antibacterial and anti-eukaryotic roles of the two T6SSs (T6SS1 and T6SS2) against E. coli Sm10 cells and Crassostrea virginica larvae, respectively. Mutations in hcp and vgrG genes were created and characterized for their effects upon bacterial antagonism and eukaryotic host virulence. Mutations in hcp1 and hcp2 resulted in significantly reduced antagonism against E. coli Sm10, with the hcp2 mutation demonstrating the greater impact. In contrast, mutations in vgrG1 or vgrG2 had little effect on E. coli killing. In eastern oyster larval challenge assays, T6SS1 mutations in either hcp1 or vgrG1 dramatically attenuated virulence against C. virginica larvae. Strains with restored wild type hcp or vgrG genes reestablished T6SS-mediated killing to that of wild type V. coralliilyticus RE22Sm. These data suggest that the T6SS1 of V. coralliilyticus RE22Sm principally targets eukaryotes and secondarily bacteria, while the T6SS2 primarily targets bacterial cells and secondarily eukaryotes. Attenuation of pathogenicity was observed in all T6SS mutants, demonstrating the requirement for proper assembly of the T6SS systems to maintain maximal virulence.

Importance

Vibriosis outbreaks lead to large-scale hatchery losses of oyster larvae (product and seed) where Vibrio sp. associated losses of 80 to 100 percent are not uncommon. Practical and proactive biocontrol measures can be taken to help mitigate larval death by Vibrio sp. by better understanding the underlying mechanisms of virulence in V. coralliilyticus. In this study, we demonstrate the presence of two Type VI Secretion Systems (T6SS) in V. coralliilyticus RE22Sm and interrogate the roles of each T6SS in bacterial antagonism and pathogenesis against a eukaryotic host. Specifically, we show that the loss of T6SS1 function results in the loss of virulence against oyster larvae.
Reconstruction of metagenome-assembled genomes from aquaria
Authors: Ettinger Cassandra L. , Bryan Jordan , Tokajian Sima , Jospin Guillaume , Coil David , Eisen Jonathan A.
Published: May 2021

We report 11 metagenome-assembled genomes (MAGs) reconstructed from freshwater and saltwater aquaria including representatives of Polynucleobacter, Anaerolinae, Roseobacter, Flavobacteriia, Octadecabacter, Mycobacterium and Candidate Phyla Radiation (CPR) members. These MAGs can serve as a resource for aquatic research and elucidating the role of CPR taxa in the built environment.
Complete genomes of clade G6 Saccharibacteria suggest a divergent ecological niche and lifestyle
Authors: Baker Jonathon L.
Published: May 2021

Abstract

Saccharibacteria (formerly TM7) have reduced genomes, a small size, and appear to have a parasitic lifestyle dependent on a bacterial host. Although there are at least 6 major clades of Saccharibacteria inhabiting the human oral cavity, cultured isolates or complete genomes of oral Saccharibacteria have been previously limited to the G1 clade. In this study, nanopore sequencing was used to obtain three complete genome sequences from clade G6. Phylogenetic analysis suggested the presence of at least 3-5 distinct species within G6, with two discrete taxa represented by the 3 complete genomes. G6 Saccharibacteria were highly divergent from the more well-studied clade G1, and had the smallest genomes and lowest GC-content of all Saccharibacteria. Pangenome analysis showed that although 97% of shared pan-Saccharibacteria core genes and 89% of G1-specific Core Genes had putative functions, only 50% of the 244 G6-specific Core Genes had putative functions, highlighting the novelty of this group. Compared to G1, G6 encoded divergent metabolic pathways. G6 genomes lacked an F1F0 ATPase, the pentose phosphate pathway, and several genes involved in nucleotide metabolism, which were all core genes for G1. G6 genomes were also unique compared to G1 in that they encoded lactate dehydrogenase, adenylate cyclase, limited glycerolipid metabolism, a homolog to a lipoarabinomannan biosynthesis enzyme, and the means to degrade starch. These differences at key metabolic steps suggest a distinct lifestyle and ecological niche for clade G6, possibly with alternative hosts and/or host-dependencies, which would have significant ecological, evolutionary, and likely pathogenic, implications.

Importance

Saccharibacteria are ultrasmall, parasitic bacteria that are common members of the oral microbiota and have been increasingly linked to disease and inflammation. However, the lifestyle and impact on human health of Saccharibacteria remains poorly understood, especially for the 5 clades (G2-G6) with no complete genomes or cultured isolates. Obtaining complete genomes is of particular importance for Saccharibacteria, because they lack many of the “essential” core genes used for determining draft genome completeness and few references exist outside of clade G1. In this study, complete genomes of 3 G6 strains, representing two candidate species, were obtained and analyzed. The G6 genomes were highly divergent from G1, and enigmatic, with 50% of the G6 core genes having no putative functions. The significant difference in encoded functional pathways is suggestive of a distinct lifestyle and ecological niche, probably with alternative hosts and/or host-dependencies, which would have major implications in ecology, evolution, and pathogenesis.
Amphiphilic proteins coassemble into multiphasic condensates and act as biomolecular surfactants
Authors: Kelley Fleurie M. , Favetta Bruna , Regy Roshan M. , Mittal Jeetain , Schuster Benjamin S.
Published: May 2021

Cells contain membraneless compartments that assemble due to liquid-liquid phase separation, including biomolecular condensates with complex morphologies. For instance, certain condensates are surrounded by a film of distinct composition, such as Ape1 condensates coated by a layer of Atg19, required for selective autophagy in yeast. Other condensates are multiphasic, with nested liquid phases of distinct compositions and functions, such as in the case of ribosome biogenesis in the nucleolus. The size and structure of such condensates must be regulated for proper biological function. We leveraged a bio-inspired approach to discover how amphiphilic, surfactant-like proteins may contribute to the structure and size regulation of biomolecular condensates. We designed and examined families of amphiphilic proteins comprising one phase-separating domain and one non-phase separating domain. In particular, these proteins contain the soluble structured domain glutathione S-transferase (GST) or maltose binding protein (MBP), fused to the intrinsically disordered RGG domain from P granule protein LAF-1. When one amphiphilic protein is mixed in vitro with RGG-RGG, the proteins assemble into enveloped condensates, with RGG-RGG at the core, and the amphiphilic protein forming the surface film layer. Importantly, we found that MBP-based amphiphiles are surfactants and control droplet size, with increasing surfactant concentration resulting in smaller droplet radii. In contrast, GST-based amphiphiles at increased concentrations co-assemble with RGG-RGG into multiphasic structures. We propose a mechanism for these experimental observations, supported by molecular simulations of a minimalist model. We speculate that surfactant proteins may play a significant role in regulating the structure and function of biomolecular condensates.
Diverse mating phenotypes impact the spread of wtf meiotic drivers in S. pombe
Authors: López Hernández José Fabricio , Helston Rachel M. , Lange Jeffrey J. , Billmyre R. Blake , Schaffner Samantha H. , Eickbush Michael T. , McCroskey Scott , Zanders Sarah E.
Published: May 2021

Meiotic drivers are genetic loci that break Mendel’s law of segregation to be transmitted into more than half of the offspring produced by a heterozygote. The success of a driver relies on outcrossing because drivers gain their advantage in heterozygotes. It is, therefore, curious that Schizosaccharomyces pombe, a species reported to rarely outcross, harbors many meiotic drivers. To address this paradox, we measured mating phenotypes in S. pombe natural isolates. We found that the propensity to inbreed varies between natural isolates and can be affected both by cell density and by the available sexual partners. Additionally, we found that the observed level of inbreeding slows, but does not prevent, the spread of a wtf meiotic driver in the absence of additional fitness costs. These analyses reveal parameters critical to understanding the evolution of S. pombe and help explain the success of meiotic drivers in this species.
More than just oil droplets in water: surface tension and viscosity of protein condensates quantified by micropipette aspiration
Authors: Wang Huan , Kelley Fleurie M. , Milovanovic Dragomir , Schuster Benjamin S. , Shi Zheng
Published: May 2021

The material properties of biomolecular condensates play pivotal roles in many biological and pathological processes. Despite the rapid increase in the number of biomolecules identified that undergo liquid-liquid phase separation (LLPS), quantitative studies of the resulting condensates have been severely lagging behind. Here, we develop a micropipette-based technique, which uniquely allows quantifications of both the surface tension and viscosity of biomolecular condensates, independent of labeling and surface wetting effects. We demonstrate the accuracy and versatility of this technique by measuring condensates of LAF-1 RGG domains and a polymer-based aqueous two-phase system (ATPS). We anticipate this technique will be widely applicable to biomolecular condensates and will resolve several limitations regarding current approaches.
A meta-analysis of gRNA library screens enables an improved understanding of the impact of gRNA folding and structural stability on CRISPR-Cas9 activity
Authors: Moreb E.A. , Lynch Michael D.
Published: May 2021

CRISPR systems are known to be inhibited by unwanted secondary structures that form within the guide RNA (gRNA). The minimum free energy of predicted secondary structures has been used in prediction algorithms. However, the types of structures as well as the degree to which a predicted structure can inhibit Cas9/gRNA activity is not well characterized. Here we perform a meta-analysis of published CRISPR-Cas9 datasets to better understand the role of secondary structures in inhibiting gRNA activity. We identify two inhibitory structures and provide estimated free energy cutoffs at which they become impactful. Further, we identify the prevalence of these structures in existing datasets. The cutoffs provided help to explain conflicting impacts of free energy values in different datasets as well as providing a guideline for future gRNA designs.

Highlights

Clearly define two secondary structures that inhibit CRISPR-Cas9 activity

Provide free energy calculations and cutoffs at which each structure begins to inhibit activity

Evaluate impact of these structures in published datasets
Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor
Authors: Cong Zhaotong , Chen Li-Nan , Ma Honglei , Zhou Qingtong , Zou Xinyu , Ye Chenyu , Dai Antao , Liu Qing , Huang Wei , Sun Xianqiang , Wang Xi , Xu Peiyu , Zhao Lihua , Xia Tian , Zhong Wenge , Yang Dehua , Xu H. Eric , Zhang Yan , Wang Ming-Wei
Published: May 2021

The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer the structural basis of ago-allosterism at GLP-1R and new knowledge to design better therapeutics.
Src activation in lipid rafts confers epithelial cells with invasive potential to escape from apical extrusion during cell competition
Authors: Kajiwara Kentaro , Chen Ping-Kuan , Kon Shunsuke , Fujita Yasuyuki , Okada Masato
Published: May 2021

Abnormal/cancerous cells within healthy epithelial tissues undergo apical extrusion to protect against carcinogenesis, while they acquire invasive capacity once carcinogenesis progresses. However, the molecular mechanisms by which cancer cells escape from apical extrusion and invade surrounding tissues remain elusive. We found that during competition within epithelial cell layers, Src-transformed cells underwent basal delamination by Src activation within lipid rafts, whereas they were apically extruded when Src was outside of lipid rafts. Comparative analysis of contrasting phenotypes revealed that activation of the Src-STAT3-MMP axis through lipid rafts was required for basal delamination. CUB domain-containing protein 1 (CDCP1) was identified as an Src activating scaffold in lipid rafts, and its overexpression induced basal delamination. In renal cancer spheroids, CDCP1 promoted HGF-dependent invasion by activating the Src-STAT3-MMP axis. Overall, these results suggest that Src activation in lipid raft confers resistance to apical extrusion and invasive potential on epithelial cells to promote carcinogenesis.
DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations
Authors: Peycheva Mihaela , Neumann Tobias , Malzl Daniel , Nazarova Mariia , Schoeberl Ursula , Pavri Rushad
Published: May 2021

Chromosomal translocations result from the joining of DNA double-strand breaks (DSBs) and frequently cause cancer. Yet, the steps linking DSB formation to DSB ligation remain undeciphered. We report that DNA replication timing (RT), mediated by replication origin activity, directly regulates the genesis of lymphomagenic Myc translocations during antibody maturation in B cells. Reduced levels of the replicative helicase, the minichromosome-maintenance (MCM) complex, decreases translocations and globally abrogates the RT program. Ablating a single replication origin at Myc causes an early-to-late RT switch with major loss of translocations, a phenotype that is reversed by restoring early RT. Finally, this novel RT-regulated mechanism occurs after DSB formation and independently of DSB frequency. Thus, RT constitutes a distinct regulatory event in translocation biogenesis linking DSB formation to DSB ligation.
The effect of TQM practices on INGOs' staff work-related attitudes
Authors: Karia Noorliza , Mahmoud Saleh Firas Izzat
Published: May 2021

Purpose

This paper aims to investigate the impact of total quality management (TQM) practices on the work-related attitudes of International Non-Governmental Organisations (INGOs) staff, including job involvement, job satisfaction, career satisfaction and organisational commitment.

Design/methodology/approach

The paper developed and tested 16 hypotheses on the relationship between TQM practices and work-related attitudes. Out of 295 targeted staff working for 59 INGOs operating in Jordan, 126 staff have responded to the research questionnaire. The collected dataset has been analysed using the structural equation modelling-partial least square (SEM-PLS) technique.

Findings

Analysis of the data revealed the significant positive effect of TQM practices. Beneficiary focus, empowerment-teamwork and continuous improvement impact 35% of job involvement. Meanwhile, beneficiary focus and empowerment-teamwork affect 34 and 47% of career satisfaction and organisational commitment, respectively. Significantly, empowerment-teamwork and continuous improvement determine 62% of job satisfaction. However, the low extent of training and education is challenging to enhance employees' positive emotions.

Practical implications

This research provides further evidence on the importance of TQM practices to the leaders of INGOs. Therefore, to orient their resources towards TQM implementation to enhance work-related attitudes, and in turn, the performance of interventions in this challenging sector.

Originality/value

This research extends the knowledge regarding certain TQM practices that naturally and variably empower job and career satisfaction, job involvement, and organisational commitment within the INGOs. Therefore, to confirm the validity of this research direction in a new uncovered sector, which has its own specificities.
Network diversity, distance and economic impact in a cluster: visualising linkages and assessing network capital
Authors: Byrne Eoin , Doyle Eleanor , Hobbs John
Published: May 2021

Purpose

Effective policy to support business ecosystems should build on evidence-based analyses of firm-level activities and outcomes. This paper aims to contribute to this requirement and makes three contributions. The first contribution is to extend the application of the network capital concept to a variety of eight distinct linkage categories (e.g. suppliers, customers and business support agencies) that support networking and clustering, in both activity and impact terms. The second contribution is outlining a novel method of network visualisation (V-LINC) based on the collection of primary and qualitative data. The third contribution is in applying the method to one cluster, information and communications technologies.

Design/methodology/approach

Qualitative research on the nature and extent of organisational network linkages was undertaken. Structured interviews with a set of focal firms followed a tailored design approach. The concept of network capital was extended and applied to the cluster context by measuring network inputs and output (i.e. investments and impact). The approach was operationalised via a novel impact measurement approach, denoted as V-LINC, an acronym for visualising linkages in networks and clusters.

Findings

The authors develop a business impact framework exploiting novel linkage visualisations and qualitative data from firms in a cluster in one city region across eight linkage types to capture distinct network capital elements. Organisational inputs into network development, measured as investment and involvement indicators and organisational outcomes from those networks, measured as importance and intensity indicators, are used to assess network performance. A comprehensive, systematic and robust analysis of network elements and performance is possible. Distance is found to interact differently across linkage types. Targeted recommendations may be made from the analysis of local or regional business ecosystems in light of measured business impacts of linkages.

Research limitations/implications

Due to the resource-intensive nature of data collection, the current study engages a limited sample of firms and interviewees. Applications of this approach in other contexts will permit further research into its usefulness in evaluating business impacts generated through networking activities.

Originality/value

The method introduced here (V-LINC) offers a novel means to include both geography network theory into an understanding of knowledge relationships and networks within clusters. Accounting for both distance and linkage type reveals which categories of intra-regional and extra-regional linkages generate the greatest impact, given their frequency. The approach adds to available cluster visualisation and analysis approaches through identifying patterns of disaggregated knowledge flows and their impacts, with application to evaluation demands of policy.
Psychological empowerment and individual performance: the mediating effect of intrapreneurial behaviour
Authors: Mahmoud Mahmoud Ahmad , Ahmad Shuhymee , Poespowidjojo Donny Abdul Latief
Published: May 2021

Purpose

The purpose of this study is to extend the existing literature on the relationship between psychological empowerment and individual performance (IP) through the mediating role of intrapreneurial behaviour (IB). Therefore, the empowerment theory (ET) and psychological entrepreneurship theory (PET) were integrated to nurture the IP of medium enterprises (MEs) production/operations managers by analyzing the mediating influence of IB on the psychological empowerment–IP relationship.

Design/methodology/approach

Survey method was engaged by means of self-administered questionnaire. Data were collected from a sample of 355 MEs production/operations managers and analysed with partial least square (PLS) structural equation modelling (SEM).

Findings

According to the results, Psychological empowerment (PE) has a significant direct relationship with both IB and IP. Equally, IB has a positive significant impact on IP. Moreover, the mediating influence of IB on the psychological empowerment–IP relationship was established.

Practical implications

The result implies that MEs can stimulate the IP of production/operations managers by encouraging IB through psychological empowerment–IP relationship. Therefore, the psychological empowerment–IP relationship will manifest better when IB is invigorated among production/operations managers.

Originality/value

To the best of the authors’ knowledge, this paper is the first to examine the mediating influence of IB on the psychological empowerment–IP relationship, which revealed a significant contribution to both entrepreneurship and organizational behaviour literature. The IB literature is relatively lacking, particularly among developing countries and in particular Nigeria.
Views of utilizing sustainable tourism to improve community sustenance: a case study of the impoverished rural communities of Musina Municipality
Authors: Ramaano Azwindini Isaac
Published: May 2021

Purpose

This study assesses the “possibilities of utilizing sustainable tourism to improve community sustenance in Musina Municipality, Limpopo, South Africa.”

Design/methodology/approach

Therefore, to competently discern the implications of tourism in Musina Municipality, data got accumulated by questionnaire surveys, interviews, focus group discussions, document reviews and field observations. Thus, Microsoft Excel, Spreadsheet and Cross-Tabulation Analysis provided both quantitative and qualitative data analyses.

Findings

The study identified immense tourism potentials attached to low tourism influences and privileges on the local community's advancement. The relationships and contributory factors pointing to the present and latent tourism situations in Musina Municipality got critiqued. The study inferred that the Musina Municipality is well enriched with tourism potentials and necessitates a fitting tourism plan to profits the locals.

Originality/value

Musina Municipality is one of the driest districts in the remote North of Limpopo Province, South Africa. It is aggregated by meager livelihoods of rural communities, as do most rural communities abroad. However, the Municipality exemplifies some of the numerous tourism-based areas in the Vhembe District of Limpopo. The undertakings of tourism, community sustenance and sustainable promotion have been more proceeding to the lead. However, diverse investigations neglect to efficiently estimate the fundamental points and the complete functions of multiple forms of tourism in community development within many rural expanses.
Staging city events in public spaces: an urban design perspective
Authors: Smith Andrew , Vodicka Goran , Colombo Alba , Lindstrom Kristina N. , McGillivray David , Quinn Bernadette
Published: May 2021

Purpose

There are two main aims of this conceptual paper. The first is to explore the issues associated with staging events in public spaces, and to produce a typology of different event spaces. The second is to explore if and how events should be designed into parks, streets and squares and whether this might reduce some of the negative impacts and associated user conflicts.

Design/methodology/approach

The paper analyses the history, drivers and effects of using public spaces as venues and examines the reciprocal relationships between events and the spaces that host them. To explain the range and dynamics of contemporary events, a typology of event spaces is developed. This typology highlights nine different types of event spaces which are differentiated by the level of public accessibility (free entry, sometimes free, paid entry), and the mobility of event audiences (static, limited mobility, mobile). Using this typology, the paper discusses ways that public spaces might be adapted to make them better suited to staging events. This discussion is illustrated by a range of examples.

Findings

The paper finds that it makes practical sense to adapt some urban public spaces to make them better equipped as venues, but designing in events presents new issues and does not necessarily resolve many of the problems associated with staging events. Disputes over events are inevitable and constituent features of public spaces.

Originality/value

This paper makes an original contribution by developing a new classification of event spaces and by synthesising ideas from urban design with ideas from the events literature.
Land value impacts of Airbnb listings on single-family homes in Austin, Texas, USA
Authors: Jiao Junfeng , Hansen Kent , Azimian Amin
Published: May 2021

Purpose

This study aims to explore the impacts of Airbnb listings on land values in the Austin, Texas, USA area, particularly on single-family homes. The goal of the analysis is to shed light on how greatly and in what direction Airbnb is affecting the housing market, with an emphasis on the spatial distribution of its effects.

Design/methodology/approach

The analysis in this paper is performed using three distinct models on a data set of land parcel data within Travis County: an ordinary least squares regression model, a geographically weighted regression (GWR) aimed at detecting the influence of variables at the census tract level, and a Bayesian approach, which describes spatial and temporal effects on the data.

Findings

The findings of the analysis indicate that across the years 2013 to 2019, higher numbers of Airbnb listings were associated with lower percentage increases in land value in certain tracts in the northern and eastern parts of the city. Additionally, the results of the Bayesian model indicated that much of the change in land value can be attributed to unobserved factors within census tracts.

Originality/value

The contribution of this study to the existing literature is its analysis of the spatial and temporal analysis of the effects of Airbnb listings on land value using a GWR and a Bayesian model. Also, as the negative correlation found in the study departs from previous research, this paper may provide policymakers insight into the complex spatial distribution and conflicting effects of Airbnb listings across distinct parts of cities.
Investigating the relationships between uncertainty types and risk management strategies in cross-border e-commerce logistics
Authors: Giuffrida Maria , Jiang Hai , Mangiaracina Riccardo
Published: May 2021

Purpose

Due to its fast growth, cross-border e-commerce (CBEC) is becoming a popular internationalization model, especially in those destination markets with impressive e-commerce development like China. However, CBEC also brings new logistics challenges and uncertainty. This paper aims to understand how companies cope with logistics uncertainty in this field and whether the different types of uncertainty influence the risk management strategies adopted to face them.

Design/methodology/approach

A survey targeting online exporters to China and third-party forwarding logistics service providers (3PFLs) is conducted. A structural equation model (SEM) analysis is performed to test the possible relationship between the adopted risk management strategies and the types of uncertainty. The type, industry and size of the company, as well as the distance between the company's home country and China, are used as control variables in the study. Survey results are enriched via interviews with some of the respondents.

Findings

The risk management strategies adopted are dependent on the type of logistics uncertainty that the companies face and, to a minor extent, on the industry the company operates in. Conversely, no significant influence is exerted by other types of control factors, i.e. home country, company size or company type.

Originality/value

The paper investigates logistics uncertainty and risk management approaches in the novel context of CBEC. A systematic review of relevant sources of uncertainty is offered to help both scholars and practitioners understand the current complexities of CBEC. From a theoretical perspective, the paper models the investigated concepts in light of the contingency approach. From a practical perspective, results can be of interest since the list of proposed items can support risk identification and evaluation while the interviews with managers can provide insights on risk management practices.
Positive effects of negative reviews: an eye-tracking perspective
Authors: Luan Jing , Xiao Jie , Tang Pengfei , Li Meng
Published: May 2021

Purpose

A counterintuitive finding of existing research is that negative reviews can produce positive effects; for example, they can increase purchase likelihood and sales by increasing product awareness. It is important to continue highlighting this fact and to develop further insights into this positive effect, as a more thorough analysis can provide online retailers with a more comprehensive understanding of how to effectively manage and use negative reviews. Thus, by using an eye-tracking method, this paper attempts to provide a further thorough analysis of positive effects of negative reviews from a cognitive perspective.

Design/methodology/approach

An eye-tracking experiment with two tests over a time delay was performed to examine whether negative reviews have some positive effects. Review valence (positive vs. negative), brand popularity (popular vs. unpopular) and advertising exposure (no repetition vs. repetition) were considered in the experiment.

Findings

The results show that a cognitive process of attention allocation happens when consumers deal with brand popularity cues and that arousal evoking and attention allocation occur when handling review valence. Allocation of more attention to unpopular brands helps improve brand awareness and enhance brand memory, and larger arousal from negative reviews narrows attention and leads to a better memory of products and brands. However, with the passage of time, the memory of review valence can dissociate and fade, and the remaining awareness of and familiarity with unpopular brands with negative reviews contribute to a positive reversion, which leads to the production of positive effects from negative reviews.

Originality/value

This paper contributes to the literature on online reviews by examining the visual processing of review valence and brand popularity with an eye-tracking method and by revealing the cognitive mechanism of positive effects of negative reviews from a visual attention perspective.