bluuebunny/crossref_metadata_2025 huggingface dataset:
Topological data analysis reveals a core heteroblastic program embedded in leaves of grapevine and maracuyá
Authors: Percival Sarah , Chitwood Daniel H. , Husbands Aman Y.
Published: July 2023

Leaves have a single shape. However, embedded in that shape are a multitude of latent shapes arising from evolutionary, developmental, environmental, and other effects. These confounded effects manifest at distinct developmental time points and evolve at different tempos. Here, revisiting datasets comprised of thousands of leaves of vining grapevine (Vitaceae) and maracuyá (Passifloraceae) species, we apply a technique from the mathematical field of topological data analysis to comparatively visualize the structure of heteroblastic effects on leaf shape in each group. Consistent with a morphologically closer relationship, members of the grapevine dataset possess a strong core heteroblasty program with little deviation between species. Remarkably, we found that most members of the maracuyá family also share a core heteroblasty program despite dramatic species-to-species leaf shape differences. This conservation was not detected using traditional analyses. We also identify two morphotypes of maracuyá that deviate from the core structure, suggesting the evolution of new heteroblastic properties in this phylogenetically related sub-group. Our findings illustrate how topological data analysis can be used to disentangle previously confounded developmental and evolutionary effects to visualize latent shapes and hidden relationships, even ones embedded in complex, high-dimensional datasets.
Investigating bacteria-phage interaction dynamics using droplet-based technology
Authors: Nikolic Nela , Anagnostidis Vasileios , Tiwari Anuj , Chait Remy , Gielen Fabrice
Published: July 2023

An alarming rise in antimicrobial resistance worldwide has spurred efforts into the search for alternatives to antibiotic treatments. The use of bacteriophages, bacterial viruses harmless to humans, represents a promising approach with potential to treat bacterial infections (phage therapy). Recent advances in microscopy-based single-cell techniques have allowed researchers to develop new quantitative approaches for assessing the interactions between bacteria and phages, especially the ability of phages to eradicate bacterial pathogen populations. Here we combine droplet microfluidics with fluorescence time-lapse microscopy to characterize the growth and lysis dynamics of the bacteriumEscherichia coliconfined in droplets when challenged with phage. We investigated phages that promote lysis of infectedE. colicells, specifically, a phage species with DNA genome, T7 (Escherichia virus T7) and two phage species with RNA genomes, MS2 (Emesvirus zinderi) and Qβ (Qubevirus durum). Our microfluidic trapping device generated and immobilized picoliter-sized droplets, enabling stable imaging of bacterial growth and lysis in a temperature-controlled setup. Temporal information on bacterial population size was recorded for up to 25 hours, allowing us to determine growth rates of bacterial populations helping us uncover the extent and speed of phage infection. In the long-term, the development of novel microfluidic and single-cell techniques will expedite research towards understanding the genetic and molecular basis of rapid phage-induced lysis, preempting bacterial resistance to phages and ultimately identifying key factors influencing the success of phage therapy.
Brain network reconfiguration during prediction error processing
Authors: Bonna Kamil , Hulme Oliver James , Meder David , Duch Włodzisław , Finc Karolina
Published: July 2023

Learning from experience is driven by reward prediction errors—signals that reflect updates to our expectations of reward. Despite numerous studies on neural correlates of reward prediction errors, the question of how large-scale brain networks reconfigure in response to reward prediction error signalling remains open. Here we ask how functional networks change in response to reward prediction errors depending on the context. In our study participants performed the probabilistic reversal learning task in functional magnetic resonance imaging (fMRI) scanner in two experimental contexts: a reward-seeking setting and a punishment-avoiding. We found that the participants’ learning speed depended on the sign of the prediction error but not on the experimental context. Whole-brain network analysis revealed a multi-scale community structure with a separate striatal reward network emerging at a finer topological scale and a ventromedial prefrontal network emerging at a coarser scale. We also found that the integration between large-scale networks increased when switching from positive to negative prediction error events. This pattern of large-scale network reconfiguration aligns with the broad range of research showing increased network integration with increased cognitive demands. Our findings offer a first sketch of how processing reward prediction error affects the functional connectivity of brain-wide networks.
Decrypting the languages of allostery in membrane-bound K-Ras4B using four complementaryin silicoapproaches
Authors: Castelli Matteo , Marchetti Filippo , Osuna Sílvia , F. Oliveira A. Sofia , Mulholland Adrian J. , Serapian Stefano A. , Colombo Giorgio
Published: July 2023

Proteins are evolved molecular machines whose diverse biochemical functions can be dynamically regulated by allostery, through which even faraway protein residues can conformationally communicate. Allostery can express itself in different ways, akin to different “languages”: allosteric control pathways predominating in an unperturbed protein are superseded by others as soon as a perturbation arises—e.g., a mutation—that alters its function (pathologically or not). Accurately modeling these often-unintuitive phenomena could therefore help explain functional changes in a specific protein whenever they are unclear. Unbiased molecular dynamics (MD) simulations are a possibility; however, since allostery can operate at longer timescales than those accessible by MD, simulations require integration with a reliable method able to,e.g., detect regions of incipient allosteric change or likely perturbation pathways. Several methods exist but are typically applied singularly: we argue their joint application, in a “multilingual” approach, could significantly enrich this picture. To prove this, we perform unbiased MD simulations (∼100 µs) of the widely studied, allosterically active oncotarget K-Ras4B, solvated and embedded in a phospholipid membrane, proceeding to decrypt its allostery using four showcase “languages”:Distance Fluctuationanalysis and theShortest Path Mapcapture allosteric communication hotspots at equilibrium;Anisotropic Thermal DiffusionandDynamical Non-Equilibrium MDsimulations assess them once the GTP that oncogenically activates K-Ras4B is, respectively, either superheated or hydrolyzed. “Languages” provide a uniquely articulate, mutually coherent, experimentally consistent picture of allostery in K-Ras4B. At equilibrium, pathways stretch from the membrane-embedded hypervariable region all the way to the active site, touching known flexible allosteric “switches” and proposed pockets. Upon GTP cleavage/perturbation, known to inactivate K-Ras4B, allosteric signals most reverberate on switches and interfaces that recruit effector proteins. Our work highlights the benefits of integrating different allostery detection methods with unbiased MD.
Performance of amplicon and capture based next-generation sequencing approaches for the epidemiological surveillance of Omicron SARS-CoV-2 and other variants of concern
Authors: Daviña-Núñez Carlos , Pérez-Castro Sonia , Cabrera-Alvargonzález Jorge Julio , Rincón-Quintero Anniris , Treinta-Álvarez Ana , Godoy-Diz Montse , Suárez-Luque Silvia , Regueiro-García Benito
Published: July 2023

To control the SARS-CoV-2 pandemic, healthcare systems have focused on ramping up their capacity for epidemiological surveillance through viral whole genome sequencing. In this paper, we tested the performance of two protocols of SARS-CoV-2 nucleic acid enrichment, an amplicon enrichment using different versions of the ARTIC primer panel and a hybrid-capture method using KAPA RNA Hypercap. We focused on the challenge of the Omicron variant sequencing, the advantages of automated library preparation and the influence of the bioinformatic analysis in the final consensus sequence. All 94 samples were sequenced using Illumina iSeq 100 and analysed with two bioinformatic pipelines: a custom-made pipeline and an Illumina-owned pipeline. We were unsuccessful in sequencing six samples using the capture enrichment due to low reads. On the other hand, amplicon dropout and mispriming caused the loss of mutationG21987Aand the erroneous addition of mutationT15521Arespectively using amplicon enrichment. Overall, we found high sequence agreement regardless of method of enrichment, bioinformatic pipeline or the use of automation for library preparation in eight different SARS-CoV-2 variants. Automation and the use of a simple app for bioinformatic analysis can simplify the genotyping process, making it available for more diagnostic facilities and increasing global vigilance.
Ectopical expression of bacterial collagen-like protein supports its role as adhesin in host-parasite coevolution
Authors: Huessy Benjamin , Bumann Dirk , Ebert Dieter
Published: July 2023

For a profound understanding of the mechanisms of antagonistic coevolution, it is necessary to identify the coevolving genes. The spore-forming bacteriumPasteuria ramosaand its host, the microcrustaceanDaphnia, are a well-characterized paradigm for co-evolution, but the underlying genes remain largely unknown. A genome-wide association study identified a polymorphic carboxy-terminal globular domain ofPasteuriacollagen-like protein 7 (Pcl7) as a candidate mediating parasite attachment and driving its coevolution with the host. SinceP. ramosacannot currently be genetically manipulated, we usedBacillus thuringiensisas a surrogate parasite to express a fusion protein of a Pcl7 carboxy-terminus fromP. ramosaand the amino-terminal domain of aB. thuringiensiscollagen-like protein. MutantB. thuringiensis(Pcl7-Bt) spores but not wild-typeB. thuringiensis(WT-Bt) spores, attached to the same site of susceptible hosts asP. ramosa. Furthermore, Pcl7-Btspores attached readily to host genotypes that were susceptible to theP. ramosaclone that was the origin of the Pcl7 C-terminus, but only slightly to resistant host genotypes. These findings indicated that the fusion protein was properly expressed and folded and demonstrated that indeed the C-terminus of Pcl7 mediates attachment in a host genotype-specific manner. These results provide strong evidence for the involvement of a CLP in the coevolution ofDaphniaandP. ramosaand opens new avenues for genetic epidemiological studies of host-parasite interactions.

150-word “Importance” paragraph

During host-parasite coevolution, hosts evolve to evade the damaging effect of the parasite, while parasites evolve to maximize their benefits by exploiting the host. The genes underlying this coevolution remain largely unknown. For the prime model-system for coevolutionary research, the crustaceanDaphniaand the parasitePasteuria ramosa, collagen-like proteins (CLPs) inPasteuriawere suggested to play a crucial role for host-parasite interactions. Here we report that transferring part of a CLP coding gene from the unculturableP. ramosatoBacillus thuringiensis(Bt), confirmed the function of this protein as a genotype-specific adhesin to the host’s cuticle. Our finding highlights the importance of a CLP in host-parasite interactions and will enable us to explore the population genetic dynamics of coevolution in this system.
Social influences on delayed gratification in New Caledonian crows and Eurasian jays
Authors: Miller Rachael , Davies James , Schiestl Martina , Garcia-Pelegrin Elias , Gray Russell D. , Taylor Alex H. , Clayton Nicola S.
Published: July 2023

Self-control underlies goal-directed behaviour in humans and other animals. Delayed gratification - a measure of self-control - requires the ability to tolerate a delay and/or invest more effort to obtain a reward of higher value over one of lower value, such as food or mates. Social context, in particular, the presence of competitors, may influence delayed gratification. We adapted the ‘rotating-tray’ paradigm, where subjects need to forgo an immediate, lower-quality (i.e. less preferred) reward for a delayed, higher-quality (i.e. more preferred) one, to test social influences on delayed gratification in two corvid species: New Caledonian crows and Eurasian jays. We compared choices for immediate vs. delayed rewards while alone, in the presence of a competitive conspecific and in the presence of a non-competitive conspecific. We found that species differed: jays were more likely to select the immediate, less preferred reward than the crows. We also found that jays were more likely to select the immediate, less preferred reward when a competitor or non-competitor was present than when alone, or when a competitor was present compared to a non- competitor, while the crows selected the delayed, highly preferred reward irrespective of social presence. We discuss our findings in relation to species differences in socio-ecological factors (adult sociality and food caching) and wider implications of social influences on self-control.
Generative and predictive neural networks for the design of functional RNA molecules
Authors: Riley Aidan T. , Robson James M. , Green Alexander A.
Published: July 2023

RNA is a remarkably versatile molecule that has been engineered for applications in therapeutics, diagnostics, andin vivoinformation-processing systems. However, the complex relationship between the sequence and structural properties of an RNA molecule and its ability to perform specific functions often necessitates extensive experimental screening of candidate sequences. Here we present a generalized neural network architecture that utilizes thesequenceand structureofRNAmolecules (SANDSTORM) to inform functional predictions. We demonstrate that this approach achieves state-of-the-art performance across several distinct RNA prediction tasks, while learning interpretable abstractions of RNA secondary structure. We paired these predictive models withgenerativeadversarialRNAdesignnetworks (GARDN), allowing the generative modelling of novel mRNA 5’ untranslated regions and toehold switch riboregulators exhibiting a predetermined fitness. This approach enabled the design of novel toehold switches with a 43-fold increase in experimentally characterized dynamic range compared to those designed using classic thermodynamic algorithms. SANDSTORM and GARDN thus represent powerful new predictive and generative tools for the development of diagnostic and therapeutic RNA molecules with improved function.
Differential laboratory passaging of SARS-CoV-2 viral stocks impacts the in vitro assessment of neutralizing antibodies
Authors: Avila-Herrera Aram , Kimbrel Jeffrey A. , Marti Jose Manuel , Thissen James , Saada Edwin A. , Weisenberger Tracy , Arrildt Kathryn T. , Segelke Brent , Allen Jonathan E. , Zemla Adam , Borucki Monica K.
Published: July 2023

Viral populations in natural infections can have a high degree of sequence diversity, which can directly impact immune escape. However, antibody potency is often tested in vitro with a relatively clonal viral populations, such as laboratory virus or pseudotyped virus stocks, which may not accurately represent the genetic diversity of circulating viral genotypes. This can affect the validity of viral phenotype assays, such as antibody neutralization assays. To address this issue, we tested whether recombinant virus carrying SARS-CoV-2 spike (VSV-SARS-CoV-2-S) stocks could be made more genetically diverse by passage, and if a stock passaged under selective pressure was more capable of escaping monoclonal antibody (mAb) neutralization than unpassaged stock or than viral stock passaged without selective pressures. We passaged VSV-SARS-CoV-2-S four times concurrently in three cell lines and then six times with or without polyclonal antiserum selection pressure. All three of the monoclonal antibodies tested neutralized the viral population present in the unpassaged stock. The viral inoculum derived from serial passage without antiserum selection pressure was neutralized by two of the three mAbs. However, the viral inoculum derived from serial passage under antiserum selection pressure escaped neutralization by all three mAbs. Deep sequencing revealed the rapid acquisition of multiple mutations associated with antibody escape in the VSV-SARS-CoV-2-S that had been passaged in the presence of antiserum, including key mutations present in currently circulating Omicron subvariants. These data indicate that viral stock that was generated under polyclonal antiserum selection pressure better reflects the natural environment of the circulating virus and may yield more biologically relevant outcomes in phenotypic assays.
Ebola Virus VP35 Interacts Non-Covalently with Ubiquitin Chains to Promote Viral Replication Creating New Therapeutic Opportunities
Authors: Rodríguez-Salazar Carlos A. , van Tol Sarah , Mailhot Olivier , Galdino Gabriel , Teruel Natalia , Zhang Lihong , Warren Abbey N. , González-Orozco María , Freiberg Alexander N. , Najmanovich Rafael J. , Giraldo María I. , Rajsbaum Ricardo
Published: July 2023

Ebolavirus (EBOV) belongs to a family of highly pathogenic viruses that cause severe hemorrhagic fever in humans. EBOV replication requires the activity of the viral polymerase complex, which includes the co-factor and Interferon antagonist VP35. We previously showed that the covalent ubiquitination of VP35 promotes virus replication by regulating interactions with the polymerase complex. In addition, VP35 can also interact non-covalently with ubiquitin (Ub); however, the function of this interaction is unknown. Here, we report that VP35 interacts with free (unanchored) K63-linked polyUb chains. Ectopic expression of Isopeptidase T (USP5), which is known to degrade unanchored polyUb chains, reduced VP35 association with Ub and correlated with diminished polymerase activity in a minigenome assay. Using computational methods, we modeled the VP35-Ub non-covalent interacting complex, identified the VP35-Ub interacting surface and tested mutations to validate the interface. Docking simulations identified chemical compounds that can block VP35-Ub interactions leading to reduced viral polymerase activity that correlated with reduced replication of infectious EBOV. In conclusion, we identified a novel role of unanchored polyUb in regulating Ebola virus polymerase function and discovered compounds that have promising anti-Ebola virus activity.

Significance Statement

Ebola virus infection can result in high mortality rates with extreme risk of person-to-person transmission. Sporadic outbreaks in Africa have resulted in thousands of fatal cases, highlighting that there is still insufficient knowledge to develop effective antiviral therapies. Like other viruses, Ebola utilizes the host machinery to replicate. Understanding how viral and host proteins interact can help identifying targets for the rational design of antiviral drugs. Here, we identified interactions between the cellular ubiquitin machinery and the Ebola virus polymerase cofactor protein VP35, which are important for efficient virus replication. We developed an approach to identify and block these virus-host interactions using small chemical compounds, which provides a useful tool to study functional molecular mechanisms and at the same time a potential approach to antiviral therapies.
Postsynaptic mitochondria are positioned to support functional diversity of dendritic spines
Authors: Thomas Connon I. , Ryan Melissa A. , Kamasawa Naomi , Scholl Benjamin
Published: July 2023

Postsynaptic mitochondria are critical to the development, plasticity, and maintenance of synaptic inputs. However, their relationship to synaptic structure and functional activity is unknown. We examined a correlative dataset from ferret visual cortex within vivotwo-photon calcium imaging of dendritic spines during visual stimulation and electron microscopy (EM) reconstructions of spine ultrastructure, investigating mitochondrial abundance near functionally- and structurally-characterized spines. Surprisingly, we found no correlation to structural measures of synaptic strength. Instead, we found that mitochondria are positioned near spines with orientation preferences that are dissimilar to the somatic preference. Additionally, we found that mitochondria are positioned near groups of spines with heterogeneous orientation preferences. For a subset of spines with mitochondrion in the head or neck, synapses were larger and exhibited greater selectivity to visual stimuli than those without a mitochondrion. Our data suggest mitochondria are not necessarily positioned to support the energy needs of strong spines, but rather support the structurally and functionally diverse inputs innervating the basal dendrites of cortical neurons.
Comparative genomics of clinicalStenotrophomonas maltophiliaisolates reveals regions of diversity which correlate with colonization and persistence in vivo
Authors: McDaniel Melissa S. , Sumpter Nicholas A. , Lindgren Natalie R. , Billiot Caitlin E. , Swords W. Edward
Published: July 2023

Stenotrophomonas maltophiliais a Gram-negative emerging opportunistic pathogen often found in respiratory diseases such as cystic fibrosis (CF). Patients with CF experience lifelong polymicrobial infections of the respiratory mucosa. Our prior work showed thatP. aeruginosapromotes persistence ofS. maltophiliamouse respiratory infections. As is typical for environmental opportunistic pathogens,S. maltophiliahas a large genome and a high degree of genetic diversity. In this study, we evaluated the genomic content ofS. maltophilia,combining short and long read sequencing to construct complete genomes of 10 clinical isolates which were then compared with the larger phylogeny ofS. maltophiliagenomic sequence data, and compared colonization/persistence in vivo, alone and in coinfection withP. aeruginosa. We found that while the overall genome size and GC content were fairly consistent, there was considerable variability in arrangement and gene content. Similarly, there was significant variability inS. maltophiliacolonization and persistence in vivo in experimental mouse respiratory infection. Ultimately, this study gives us a greater understanding of the genomic diversity ofS. maltophiliaisolated from patients, and how this genomic diversity relates to interactions with other pulmonary pathogens, and to host disease progression. Identifying the molecular determinants of infection withS. maltophiliacan facilitate development of novel antimicrobial strategies for a highly drug-resistant pathogen.
Bacterial and fungal components of the gut microbiome have distinct, sex-specific roles in HawaiianDrosophilareproduction
Authors: Medeiros Matthew J. , Seo Laura , Macias Aziel , Price Donald K. , Yew Joanne Y.
Published: July 2023

Gut microbiomes provide numerous physiological benefits for host animals. The role of bacterial members of microbiomes in host physiology is well-documented. However, much less is known about the contributions and interactions of fungal members of the microbiome even though fungi are significant components of many microbiomes, including those of humans and insects. Here, we used antibacterial and antifungal drugs to manipulate the gut microbiome of a Hawaiian picture-wingDrosophilaspecies,D. grimshawi, and identified distinct, sex-specific roles for the bacteria and fungi in microbiome community stability and reproduction. Female oogenesis, fecundity and mating drive were significantly diminished when fungal communities were suppressed. By contrast, male fecundity was more strongly affected by bacterial but not fungal populations. For males and females, suppression of both bacteria and fungi severely reduced fecundity and altered fatty acid levels and composition, implicating the importance of interkingdom interactions on reproduction and lipid metabolism. Overall, our results reveal that bacteria and fungi have distinct, sexually-dimorphic effects on host physiology and interkingdom dynamics in the gut help to maintain microbiome community stability and enhance reproduction.
Flagellar motor remodeling during swarming requires FliL
Authors: Partridge Jonathan D. , Dufour Yann , Hwang YuneSahng , Harshey Rasika M.
Published: July 2023

FliL is an essential component of the flagellar machinery in some bacteria, but a conditional one in others. The conditional role is for optimal swarming in some bacteria. During swarming, physical forces associated with movement on a surface are expected to exert a higher load on the flagellum, requiring more motor torque to move. Bacterial physiology and morphology are also altered during swarming to cope with the challenges of surface navigation. FliL was reported to enhance motor output in several bacteria and observed to assemble as a ring around ion-conducting stators that power the motor. In this study we identify a common new function for FliL in diverse bacteria –Escherichia coli, Bacillus subtilisandProteus mirabilis. During swarming, all these bacteria show increased cell speed and a skewed motor bias that suppresses cell tumbling. We demonstrate that these altered motor parameters, or ‘motor remodeling’, require FliL. Both swarming and motor remodeling can be restored in anE. coli fliLmutant by complementation withfliLgenes fromP. mirabilisandB. subtilis, showing conservation of swarming-associated FliL function across phyla. In addition, we demonstrate that the strong interaction we reported earlier between FliL and the flagellar MS-ring protein FliF is confined to the RBM-3 domain of FliF that links the periplasmic rod to the cytoplasmic C-ring. This interaction may explain several phenotypes associated with the absence of FliL.
Proguanil and chlorhexidine augment the antibacterial activities of clarithromycin and rifampicin againstAcinetobacter baumannii
Authors: Wang Chuandong , Zhang Tingting , Wang Yan , Wang Yipeng , Pan Hongwei , Dong Xinyu , Liu Siyu , Cao Meng , Wang Shuhua , Wang Mingyu , Li Yuezhong , Zhang Jian , Hu Wei
Published: July 2023

The emergence ofAcinetobacter baumanniiinfections as a significant healthcare concern in hospital settings, coupled with their association with poorer clinical outcomes, has prompted extensive investigation into novel therapeutic agents and innovative treatment strategies. Proguanil and chlorhexidine, both categorized as biguanide compounds, have displayed clinical efficacy as antimalarial and topical antibacterial agents, respectively. In this study, we conducted an investigation to assess the effectiveness of combining proguanil and chlorhexidine with clarithromycin or rifampicin against both laboratory strains and clinical isolates ofA. baumannii. The combination therapy demonstrated rapid bactericidal activity against planktonic multidrug-resistantA. baumannii, exhibiting efficacy in eradicating mature biofilms and impeding the development of antibiotic resistancein vitro. Additionally, when administered in conjunction with clarithromycin or rifampicin, proguanil enhanced the survival rate of mice afflicted with intraperitonealA. baumanniiinfections, and chlorhexidine expedited wound healing in mice with skin infections. These findings are likely attributable to the disruption ofA. baumanniicell membrane integrity by proguanil and chlorhexidine, resulting in heightened membrane permeability and enhanced intracellular accumulation of clarithromycin and rifampicin. Overall, this study underscores the potential of employing proguanil and chlorhexidine in combination with specific antibiotics to effectively combatA. baumanniiinfections and improve treatment outcomes in clinically challenging scenarios.

IMPORTANCE

A. baumanniihas emerged as a globally significant nosocomial pathogen due to its remarkable ability to acquire antibiotic resistance and develop biofilms on both biotic and abiotic surfaces. Recent research has demonstrated that the antidiabetic drug metformin has a potentiation effect on doxycycline and minocycline against certain multidrug-resistant bacterial pathogens, suggesting the potential of this biguanide agent as a novel tetracyclines adjuvant. In this study, we provide evidence showing that the combination of proguanil and chlorhexidine with clarithromycin or rifampicin exhibits rapid bactericidal activities against both planktonic cells and mature biofilms ofA. baumannii, the capacity to inhibit the development of antibiotic resistance and improvement of the treatment outcomes inA. baumannii-infected mice. Given the advantages of repurposing non-antibiotic drugs as antibiotic adjuvants, proguanil and chlorhexidine show promise as adjuvants of specific antibiotics in combating clinically significant pathogenicA. baumannii.
De novo purine metabolism is a metabolic vulnerability of cancers with low p16 expression
Authors: Tangudu Naveen Kumar , Buj Raquel , Wang Hui , Wang Jiefei , Cole Aidan R. , Uboveja Apoorva , Fang Richard , Amalric Amandine , Sajjakulnukit Peter , Lyons Maureen A. , Cooper Kristine , Hempel Nadine , Snyder Nathaniel W. , Lyssiotis Costas A. , Chandran Uma R. , Aird Katherine M.
Published: July 2023

p16 is a tumor suppressor encoded by theCDKN2Agene whose expression is lost in ∼50% of all human cancers. In its canonical role, p16 inhibits the G1-S phase cell cycle progression through suppression of cyclin dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. Whether other nucleotide metabolic genes and pathways are affected by p16/CDKN2Aloss and if these can be specifically targeted in p16/CDKN2A-low tumors has not been previously explored. Using CRISPR KO libraries in multiple isogenic human and mouse melanoma cell lines, we determined that many nucleotide metabolism genes are negatively enriched in p16/CDKN2Aknockdown cells compared to controls. Indeed, many of the genes that are required for survival in the context of low p16/CDKN2Aexpression based on our CRISPR screens are upregulated in p16 knockdown melanoma cells and those with endogenously lowCDKN2Aexpression. We determined that cells with low p16/Cdkn2aexpression are sensitive to multiple inhibitors ofde novopurine synthesis, including anti-folates. Tumors with p16 knockdown were more sensitive to the anti-folate methotrexatein vivothan control tumors. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16/CDKN2A-low tumors as loss of p16/CDKN2Amay provide a therapeutic window for these agents.
Predicting on restaurant's hygiene rating: Does customer review emotion and content matter?
Authors: Jeon Jiyeon , Kim Eojina , Wang Xi , Tang Liang(Rebecca)
Published: July 2023

Purpose

The hygiene factor is always imperative when customers consider a certain restaurant, and the information contained in customer reviews can be an efficient approach to gauge a restaurant's hygiene during gaps in the official inspection. Therefore, the purpose of this study was to investigate whether information obtained from online reviews could predict the upcoming hygiene rating, specifically, evaluating the impact of both qualitative and quantitative content of reviews on the restaurant hygiene rating.

Design/methodology/approach

The quantitative research method with big data analytic techniques was applied in this study. In total, 127,656 pieces of data collected from 1,710 restaurants in four major cities in the USA were used in the analysis. Both quantitative factors (i.e. reviewer's numerical rating, days to review, readability, useful/funny/cool) and qualitative factors (i.e. eight emotional dimensions of textual reviews) were analyzed from the online customer reviews and considered in predicting the restaurant's hygiene rating.

Findings

Six out of eight emotional dimensions including anger, disgust, fear, sadness, surprise and trust were identified as having significant influences on the restaurant hygiene ratings. While three quantitative variables including days to review, readability and usefulness were identified with significant impacts on the dependent variable of restaurant hygiene rating.

Originality/value

This study opens an avenue for innovative research that establishes a connection between customers' reviews and restaurants' inspection systems. The results allow restaurants to predict an impending hygiene inspection rating upon dynamic assessment of review content and aid in adjusting hygiene measures accordingly.
Inventory sharing in healthcare supply chains: systematic literature review and future research agenda
Authors: Atcha Panniphat , Vlachos Ilias , Kumar Satish
Published: July 2023

Purpose

Ineffective management inventory of medical products such as blood and vaccines can create severe repercussions for hospitals, clinics or medical enterprises, such as surgery delays and postponements. Inventory sharing is a form of horizontal collaboration that can provide solutions to key actors of the healthcare supply chain (HSC), yet no prior study reviewed this topic.

Design/methodology/approach

This study conducts a systematic literature review of thirty-nine inventory-sharing studies in the context of HSCs published from 2012 until early 2022. The descriptive and thematic analyses include chronological distribution, geographical location, comparison between developed/developing regions, stakeholder and incident analysis.

Findings

Thematic analysis classified inventory sharing among five product supply chains (blood, medical supplies, medicines, vaccines and generic medical products). Benefits include shortage reduction, cost minimisation, and wastage mitigation. Barriers include (1) IT infrastructure, (2) social systems, (3) cost and (4) supply chain operations. Perishable inventory policies include Fresher-First (FF), Last-Expire-First-Out (LEFO), First-In-First-Out (FIFO) and First-Expire-First-Out (FEFO). The analysis also showed differences between developed and developing countries. The study identifies several future research opportunities that include (1) product utilisation rate, (2) cost reductions, (3) shortage mitigation and (4) waste reduction.

Originality/value

No prior study has systematically reviewed inventory sharing in HSCs to reveal benefits, barriers, patterns and gaps in the current literature. It makes five propositions and develops a research model to guide future research. The study concludes with theoretical and managerial implications.
Does gratuitous behaviour promote workplace nonviolence? Exploring the mediating role of constructive deviance
Authors: Garg Naval , Sharma Nidhi
Published: July 2023

Purpose

This study evaluates gratitude's role in developing nonviolent work behaviour. It also examines the mediating effect of constructive deviance in the relationship between gratitude and nonviolent work behaviour.

Design/methodology/approach

The study is based on responses from 424 working professionals engaged in different Indian industries: banks, insurance, IT, manufacturing, hotel and software. The respondents were approached both physically and electronically using convenience sampling. Also, the data were collected in three phases four months apart, utilizing the benefits of a repeated cross-sectional research design. Structural equation modelling examines the relationship between gratitude and nonviolent work behaviour. Model fit indices are also assessed for two models (without a mediator and with a mediator). Total, direct and indirect effects are calculated using AMOS 21 to study the mediating effect of constructive deviance.

Findings

Findings reveal that all three dimensions of gratitude (lack of sense of deprivation, simple appreciation and appreciation for others) are positively associated with nonviolent work behaviour. The results also confirm the mediating effect of constructive deviance.

Originality/value

This is one of the pioneer studies exploring gratitude's role in ensuring nonviolent work behaviour.
How prone are emerging markets' sectoral indices to global uncertainties? Evidence from the quantile connectedness approach with portfolio implications
Authors: Khan Shabeer , Rehman Mohd Ziaur , Shahzad Mohammad Rahim , Khan Naimat U , Abdul Razak Lutfi
Published: July 2023

Purpose

There has been a burgeoning interest in exploring the impact of uncertainty factors on share returns. However, studies on the influence of global financial uncertainties on emerging market sectoral indices are scarce. Thus, there is a need to have a thorough investigation of the connection between global financial uncertainties and emerging market sectoral indices. To fill this gap, using the theoretical framework of international portfolio diversification (IPD) and utilizing data from 2008 to 2021, this study examines the spillover connection between global uncertainty indices (GUIs) and leading sectoral indices of 28 emerging markets.

Design/methodology/approach

The authors employ the quantile spillover-based connectedness approach and minimum connectedness portfolio approach to explore the dynamic connectedness among sectoral indices and global uncertainty indices (GUIs) as well as portfolio implication.

Findings

The study found high connectedness among all indices, especially at higher and lower quantiles. Among GUIs, the authors find that stock market volatility (VIX) and oil volatility index (OVX) are strongly interconnected with all leading emerging markets' sectoral indices. Among sectoral indices, the linkage between the financial (F-Index), information technology (IT-Index), and consumer discretionary (CD-Index) sectors shows moderate interconnectedness. In contrast, the communication services (CS-Index) sector has low interconnectedness with the system. In terms of spillover effects, the authors find EVZ, OVX, and the IT sectors to be net recipients for the entire period. The authors also explored portfolio diversification benefits by employing a minimum connectedness portfolio approach. The cumulative returns' findings show a slight decline in the portfolio's value after 2010; during 2012, the pattern remained stable; from 2014 to 2020, the portfolio performed negatively, that is, underperformance due to different events in that period, including COVID-19. The Consumer Discretionary sector is found to be significant because of having the largest weight, 51%, in the portfolio during the study period.

Practical implications

The study suggests that investors should invest in the communication services sector as it is the least connected. However, the connectedness increases during COVID-19, which implies that it may be difficult for investors to benefit from IPD in a crisis period. Hence, to obtain the benefits from IPD, the evidence suggests that investors need to consider Consumer Discretionary sector while considering assets for investment.

Originality/value

The study's uniqueness is that the authors have investigated spillover between GUIs and 28 emerging markets sectoral indices by employing a quantile spillover-based connectedness approach and minimum connectedness portfolio approach with a special focus on portfolio implication.
Impact pathways: just transition in fashion operations and supply chain management
Authors: Karaosman Hakan , Marshall Donna
Published: July 2023

Purpose

This impact pathways paper proposes that operations and supply chain management (OSCM) can help to ensure that the transition from a high-carbon to low-carbon fashion industry takes place in a just, inclusive and fair way. By immersion in fashion brands, suppliers and workers' realities across multiple supply chains, the authors identify challenges and issues related to just transitions, whilst proposing research pathways to inspire future OSCM research and collaboration using innovative and creative methods to answer complex questions related to just transition.

Design/methodology/approach

The research the authors introduce used a multi-level field research approach to investigate multiple fashion supply chains in transition.

Findings

The authors uncovered that in the pursuit of lowering carbon emissions, fast-fashion giants work with industrial associations to create top-down governance tools, leading to severe problems in supply chain data and paradoxical demands. These demands are cascaded onto the workers in these supply chains. The goals and tools dictated by the fashion giants exclude workers, whilst the physiological and psychological effects on the workers are routinely ignored. These issues impede a just transition to a low-carbon fashion industry.

Originality/value

The authors introduce concepts largely missing from OSCM literature and ensure representation of the most marginalised group, supply chain workers, in a novel setting in a call for research in this emerging area.
Does the integration of lean production and Industry 4.0 in green supply chains generate a better operational performance?
Authors: Maldonado-Guzmán Gonzalo , Pinzón-Castro Sandra Yesenia , Garza-Reyes Jose Arturo
Published: July 2023

Purpose

The tightening of environmental measures and policies in various countries around the world is forcing manufacturing companies, particularly those that make up the automotive industry, to improve their production processes, through the implementation of approaches such as lean production (LP) and Industry 4.0 (I4.0) technologies, to reduce industrial waste. However, the literature indicates that the implementation of LP and I4.0 does not always lead to an improvement in the level of operational performance (OP). Therefore, this study analyzes the effects of the implementation of LP practices and I4.0 on a green supply chain (GSC) and the operational performance of manufacturing companies in the Mexican automotive industry.

Design/methodology/approach

A theoretical research framework consisting of six hypotheses was developed and validated by applying partial least squares structural equation modeling (PLS-SEM) and using a sample of 460 companies from the Mexican automotive industry.

Findings

The results show that the level of OP of manufacturing companies increases substantially with the implementation of LP and I4.0 practices, as well as a GSC.

Practical implications

Managers of manufacturing companies will be able to use the results of this study to improve their production systems and to demonstrate the effects of these practices on OP.

Originality/value

This study contributes to the literature on LP and I4.0 by providing robust empirical evidence of the positive effects of implementing these approaches on the GSC and OP of manufacturing companies.
Wide‐spectrum reconstruction of a velocity model based on the wave equation reflection inversion method and its application
Authors: Xu Xiugang , Zhang Haonan , Xu Wencai , Liu Bin , Tong Siyou , Wang Yifan , Xie Shuxue
Published: July 2023

Most seismic data used for conventional exploration lack far‐offset signals and effective low‐frequency components. This makes it difficult for conventional full waveform inversion methods to recover the low‐wavenumber components of mid‐ and deep‐layer models. To resolve the bottleneck of ray‐theoretical reflection traveltime tomography, wave equations, such as reflection inversion methods, are receiving increasing attention. We reconstructed a wide‐spectrum velocity model based on the multiscale wave‐equation reflection inversion method for model decomposition. First, using the dynamic image warping method to obtain reflection traveltime residuals, the wave‐equation reflection traveltime inversion was used to recover the low‐wavenumber components of the background model, which also solved the cycle‐skipping problem. Second, the medium‐wavenumber component of the model is then supplemented by the reflection waveform inversion, while the reflectivity model is obtained relying on the least‐squares reverse time migration method. Based on this method, the background and perturbation models are updated alternately and iteratively. At the same time, the stratum structural tensor information was extracted using the perturbed model image to construct a preconditioned operator for the stratum structural constraint, suppress unreasonably high‐wavenumber components in the generalized gradient and improve the geological consistency of the inversion results. Testing of the model using the Sigsbee2b model and seismic field data from the East China Sea showed that, compared with the conventional reflection traveltime tomography method based on prestack depth migration, the wave‐equation reflection inversion strategy with well‐matched information from traveltimes to waveforms significantly improved the accuracy of the middle and deep velocity modelling and enhanced the imaging quality of the whole body.
Ginsenoside Rh4 inhibits the malignant progression of multiple myeloma and induces ferroptosis by regulating SIRT2
Authors: Ying Qiuhua , Lou Jinjie , Zheng Daibo
Published: July 2023

Multiple myeloma (MM) has a high mortality rate, and the exploration of therapeutic drugs for MM with low side effects is a hot topic at the moment. Ginsenoside Rh4 has been shown to inhibit tumour growth in many cancers. However, the role of ginsenoside Rh4 in MM and its reaction mechanism have not been reported so far. After the treatment with different concentrations of ginsenoside Rh4, the proliferation of NCI‐H929 cells was detected by Cell Counting Kit‐8 and 5‐ethynyl‐2′‐deoxyuridine staining. The cell apoptosis and cycle arrest were detected by flow cytometry and western blot. The thiobarbituric acid‐reactive substances (TBARS) production was assessed with TBARS assay, whereas Fe2+ fluorescence assay was used for the measurement of Fe2+ level. The production of reactive oxygen species was evaluated with dichloro‐dihydro‐fluorescein diacetate staining, and western blot was applied for the estimation of ferroptosis‐related proteins. The potential targets of ginsenoside Rh4 were predicted by molecular docking technology and verified by western blot. The transfection efficacy of overexpression‐SIRT2 was examined with quantitative reverse transcription polymerase chain reaction and western blot. To figure out the detailed reaction mechanism between ginsenoside Rh4 and SIRT2 in MM, rescue experiments were conducted. We found that ginsenoside Rh4 inhibited cell proliferation, induced cell apoptosis, promoted cycle arrest and facilitated ferroptosis in MM. Moreover, ginsenoside Rh4 inhibited SIRT2 expression in MM cells. The overexpression of SIRT2 reversed the effects of ginsenoside Rh4 on cell proliferation, cell apoptosis, cycle arrest and ferroptosis in MM. Overall, ginsenoside Rh4 inhibited the malignant progression of MM and induced ferroptosis by regulating SIRT2.