bluuebunny/crossref_metadata_2025 huggingface dataset:
A role for Flipons and miRNAs in Promoter Specification during Development
Authors: Herbert Alan , Pavlov Fedor , Konovalov Dmitrii , Poptsova Maria
Published: June 2022

The classical view of gene regulation is based on prokaryotic models and the operon concept with protein-based transcription factors controlling the expression of metabolic pathways essential for bacterial adaptations in response to environmental changes. A new view for establishing cell identity is emerging in eukaryotes where RNA-based pathways provide the framework for the readout of genomic information. Another perspective poses that alternative DNA structures encoded by flipons enable switching of cellular responses from one state to another. Here we provide evidence that these RNA and DNA mechanisms are deeply connected. We present data supporting a model where flipons open up binding sites for microRNAs (miRNAs), leading to the establishment of bivalent promoters early in development whose location structures lineage-specific events. These outcomes are potentially influenced by ovarian and spermatozoan miRNAs, transmissions with evident evolutionary ramifications. The data supports a new perspective on genetic regulation, one in which the genome provides a canvas framed by flipons, sketched with miRNAs and embellished by proteins.
Thymic Rejuvenation by Adult Grafts in the Lymph Node
Authors: Rao Aparna , Gupta Avni , Lagasse Eric
Published: June 2022

Immunologic aging is defined as a process in which the immune system undergoes tremendous decline in T cell numbers and function, thus affecting one’s ability to effectively mount an immune response. The degeneration of the thymus, the primary immune organ responsible for T cell development, is central to immunologic aging. Various studies have assessed thymic regeneration as an effective way to offset immune function decline. In this study, we determined the effect of mouse adult thymus transplants in the lymph node of athymic nude mice to rejuvenate thymus function. We transplanted thymuses of increasing ages and assessed engrafted ectopic thymuses by histology as well as for blood T cell numbers and function. We observed that transplanting aged thymuses, up to 8 months old, in the lymph node regenerated thymus function and corresponding T cell activation with some thymic rejuvenation when compared to the expected native thymus in control animals. However, transplanting 11- and 14-month old thymus in the lymph node had decreased-to-limited thymic function with no thymic rejuvenation detected. These observations provide important insights into the plasticity and regenerative capabilities of the thymus during age-associated involution.
Efficient isolation of rare B cells using next-generation antigen barcoding
Authors: Hurtado Jonathan , Flynn Claudia , Lee Jeong Hyun , Salcedo Eugenia , Cottrell Christopher A. , Skog Patrick D. , Nemazee David , Schief William R. , Landais Elise , Sok Devin , Briney Bryan
Published: June 2022

The ability to efficiently isolate antigen-specific B cells in high throughput will greatly accelerate the discovery of therapeutic monoclonal antibodies (mAbs) and catalyze rational vaccine development. Traditional mAb discovery is a costly and labor-intensive process, although recent advances in single-cell genomics using emulsion microfluidics allow simultaneous processing of thousands of individual cells. Here we present a streamlined method for isolation and analysis of large numbers of antigen-specific B cells, including next generation antigen barcoding and an integrated computational framework for B cell multi-omics. We demonstrate the power of this approach by recovering thousands of antigen-specific mAbs, including the efficient isolation of extremely rare precursors of VRC01-class and IOMA-class broadly neutralizing HIV mAbs.
Selective degradation of an ER stress-induced protein by ER-associated degradation mechanism during stress recovery
Authors: Wang Yi , Ma Zhihui , Zhang Congcong , Chen Yongwu , Lin Liangguang , Mao Juan , Zhang Jianjun , Liu Linchuan , Wang Pengcheng , Li Jianming
Published: June 2022

Unfolded protein response (UPR) is a conserved signaling pathway that is activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER) and stimulates production of ER chaperones to restore ER proteostasis. However, little is known how UPR-induced proteins return to their pre-stress levels upon removal of ER stress. TUNICAMYCIN-INDUCED1 (TIN1) is an Arabidopsis protein that is normally expressed in pollen but is rapidly induced by ER stresses in vegetative tissues. Here we show that the ER stress-induced TIN1 is rapidly degraded in the UPR recovery phase. We found that TIN1 degradation depends on its asparagine-linked glycans and requires both EMS-mutagenized bri1 suppressor 5 (EBS5) and EBS6 for its recruitment to the ER-associated degradation (ERAD) complex. Loss-of-function mutations in Arabidopsis ERAD components greatly stabilize TIN1. Interestingly, two other UPR-induced proteins that are coexpressed with TIN1 remained stable upon removal of ER stress, suggesting that rapid degradation during the stress-recovery phase likely applies to a subset of UPR-induced proteins. Further investigation should uncover the mechanisms by which the ERAD machinery differentially recognizes UPR-induced ER proteins.
ECPAS/Ecm29-Mediated 26S Proteasome Disassembly is an Adaptive Response to Glucose Starvation
Authors: Choi Won Hoon , Yun Yejin , Byun Insuk , Lee Seho , Sim Jiho , Levi Shahar , Kim Sumin , Park Seo Hyeong , Jun Jeongmoo , Kim Kwang Pyo , Kwon Yong Tae , Han Dohyun , Chiba Tomoki , Seok Chaok , Glickman Michael H. , Lee Min Jae
Published: June 2022

The 26S proteasome consists of loosely associated 20S catalytic and 19S regulatory complexes. Approximately half of the proteasomes in eukaryotic cells exist as free 20S complexes; however, our mechanistic and physiological understanding of what determines the ratio of 26S to 20S species remains incomplete. Here, we show that glucose starvation in mammalian cells results in the uncoupling of 26S holoenzymes into intact 20S and 19S subcomplexes. Subcomplex affinity-purification and quantitative mass spectrometry revealed that Ecm29 proteasome adaptor and scaffold (ECPAS) is a crucial mediator of this structural remodeling. The loss of ECPAS abrogated 26S dissociation, leading to decreased degradation of 20S proteasome substrates such as puromycylated polypeptides and lysine-less cyclin B. In silico modeling analysis suggested that the conformational changes of ECPAS may commence the disassembly process. ECPAS was also essential for proper endoplasmic reticulum stress response and cell survival during glucose starvation. In addition, we evaluated the role of ECPAS in vivo using the mouse xenograft model and observed that glucose-deprived tumor tissues had significantly elevated 20S proteasome levels. Collectively, our results indicate that the 20S-19S disassembly mediated by ECPAS is a novel mechanism adapting global proteolysis to physiological needs and an effective cellular strategy against proteotoxic stress.
COVID-MVP: an interactive visualization for tracking SARS-CoV-2 mutations, variants, and prevalence, enabled by curated functional annotations and portable genomics workflow
Authors: Anwar Muhammad Zohaib , Gill Ivan S , Iseminger Madeline , Sehar Anoosha , Igwacho Kenyi D , Vora Khushi , Van Domselaar Gary , Gordon Paul M. K. , Hsiao William WL
Published: June 2022

The SARS-CoV-2 pandemic has reemphasized the importance of genomic epidemiology to track the evolution of the virus, dynamics of epidemics, geographic origins, and the emerging variants. It is vital in understanding the epidemiological spread of the virus on global, national, and local scales. Several analytical (bioinformatics) resources have been developed for molecular surveillance. However, a resource that combines genetic mutations and functional annotations on the impact of these mutations has been lacking in SARS-CoV-2 genomics surveillance. COVID-MVP provides an interactive visualization application that summarizes the mutations and their prevalence in SARS-CoV-2 viral lineages and provides functional annotations from the literature curated in an ongoing effort, Pokay. COVID-MVP is a tool that can be used for routine surveillance including spatio-temporal analyses. We have powered the visualization through a scalable and reproducible genomic analysis workflow nf-ncov-voc wrapped in Nextflow. COVID-MVP allows users to interactively explore data and download summarized surveillance reports. COVID-MVP, Pokay, and nf-ncov-voc are open-source tools available under the Massachusetts Institute of Technology (MIT) and GPL-3.0 licenses. COVID-MVP source code is available athttps://github.com/cidgoh/COVID-MVPand an instance is hosted athttps://covidmvp.cidgoh.ca.
The genomics of linkage drag in sunflower
Authors: Huang Kaichi , Jahani Mojtaba , Gouzy Jérôme , Legendre Alexandra , Carrere Sebastien , Lázaro-Guevara José Miguel , González Segovia Eric Gerardo , Todesco Marco , Mayjonade Baptiste , Rodde Nathalie , Cauet Stéphane , Dufau Isabelle , Staton S Evan , Pouilly Nicolas , Boniface Marie-Claude , Tapy Camille , Mangin Brigitte , Duhnen Alexandra , Gautier Véronique , Poncet Charles , Donnadieu Cécile , Mandel Tali , Hübner Sariel , Burke John M. , Vautrin Sonia , Bellec Arnaud , Owens Gregory L. , Langlade Nicolas , Muños Stéphane , Rieseberg Loren H.
Published: June 2022

Crop wild relatives represent valuable sources of alleles for crop improvement, including adaptation to climate change and emerging diseases. However, introgressions from wild relatives might have deleterious effects on desirable traits, including yield, due to linkage drag. Here we comprehensively analyzed the genomic and phenotypic impacts of wild introgressions into cultivated sunflower to estimate the impacts of linkage drag. First, we generated new reference sequences for seven cultivated and one wild sunflower genotype, as well as improved assemblies for two additional cultivars. Next, relying on previously generated sequences from wild donor species, we identified introgressions in the cultivated reference sequences, as well as the sequence and structural variants they contain. We then used a ridge regression model to test the effects of the introgressions on phenotypic traits in the cultivated sunflower association mapping population. We found that introgression has introduced substantial sequence and structural variation into the cultivated sunflower gene pool, including > 3,000 new genes. While introgressions reduced genetic load at protein-coding sequences and positively affected traits associated with abiotic stress resistance, they mostly had negative impacts on yield and quality traits. Introgressions found at high frequency in the cultivated gene pool had larger effects than low frequency introgressions, suggesting that the former likely were targeted by artificial selection. Also, introgressions from more distantly related species were more likely to be maladaptive than those from the wild progenitor of cultivated sunflower. Thus, pre-breeding efforts should focus, as far as possible, on closely related and fully compatible wild relatives.
Development of an Escape-resistant SARS CoV-2 Neutralizing Synthetic Nanobody
Authors: Dormeshkin Dmitri , Shapira Michail , Dubovik Simon , Kavaleuski Anton , Katsin Mikalai , Migas Alexandr , Meleshko Alexander , Semyonov Sergei
Published: June 2022

An emerging COVID-19 pandemic resulted in a global crisis, but also accelerated vaccine development and antibody discovery. In this work, we identified a number of nanomolar-range affinity VHH binders to SARS-CoV-2 variants of concern (VoC) receptor binding domains (RBD), by screening synthetic humanized antibody library with more than 1011 diversity. In order to explore the most robust and fast method for affinity improvement, we performed affinity maturation by CDR1 and CDR2 shuffling and avidity engineering by multivalent trimeric VHH fusion protein construction. As a result, H7-Fc and G12×3-Fc binders were developed with the affinities in nM and pM range respectively. Importantly, their affinities are weakly influenced by SARS-CoV-2 VoC mutations. The plaque reduction neutralization test (PRNT) resulted in IC50 = 100 ng\ml and 9.6 ng\ml for H7-Fc and G12×3-Fc antibodies respectively for emerging Omicron variant. Therefore, these VHH could expand the present landscape of SARS-CoV-2 neutralization binders with the therapeutic potential for present and future SARS-CoV-2 variants.
Mitotic exchange in female germline stem cells is the major source of Sex Ratio chromosome recombination in Drosophila pseudoobscura
Authors: Koury Spencer
Published: June 2022

Sex Ratio chromosomes in Drosophila pseudoobscura are selfish X chromosome variants associated with three non-overlapping inversions. In the male germline, Sex Ratio chromosomes distort segregation of X and Y chromosomes (99:1), thereby skewing progeny sex ratio. In the female germline, segregation of Sex Ratio chromosomes is mendelian (50:50), but non-overlapping inversions strongly suppress recombination establishing a 26 Megabase haplotype (constituting ~20% of the haploid genome). Rare crossover events located between non-overlapping inversions can disrupt this haplotype, and recombinants have sometimes been found in natural populations. We recently reported on the first lab-generated Sex Ratio recombinants occurring at a rate of 0.0012 crossovers per female meiosis. An improved experimental design presented here reveals these recombination events were 6.5-fold more frequent than previously estimated. Furthermore, recombination events were strongly clustered, indicating the majority arose from mitotic exchange in female germline stem cells and not from meiotic crossing-over in primary oocytes. Finally, recombination-induced viability defects consistent with unequal exchange caused asymmetric recovery rates of complementary recombinant classes. Incorporating these experimental results into population models for Sex Ratio chromosome evolution provided a substantially better fit to natural population frequencies and allowed maintenance of the highly differentiated 26 Megabase Sex Ratio haplotype without invoking strong epistatic selection. This study provides the first estimate of spontaneous mitotic exchange for naturally-occurring chromosomes in Drosophila female germline stem cells, reveals a much higher Sex Ratio chromosome recombination rate, and develops a mathematical model that accurately predicts the rarity of recombinant Sex Ratio chromosomes in natural populations.
Fully Transient CRISPR/Cas12f system in plants capable of broad-spectrum resistance against Begomovirus
Authors: Haider Sibtain , Faiq Ali , Khan Muhammad Zuhaib , Mansoor Shahid , Amin Imran
Published: June 2022

CRISPR/Cas system has emerged as the most efficient genome editing technology for both eukaryotic and prokaryotic cells. Recently, biologist have started using CRISPR/Cas9 as a defence machinery in plants against DNA viruses by targeting conserve regions of their genome. Considerable resistance requires formation of stable transgenic lines with multiple gRNAs, targeting specific viruses. Development of such transgenic plants is not only time consuming but also there will always be some uncertainty of their efficiency and off targets in plant genome. Newly discovered miniature CRISPR/Cas12f (Cas14a) system has unique ability to chop down every ssDNA fragment once activated through targeted cleavage. Here we report first fully functional transient CRISPR/Cas12f system in plants. We also show that Cas12f with just one gRNA is enough for substantial broad-spectrum resistance against Gemini viruses. Plant phenotype showed nearly complete recovery and qPCR results showed multifold decrease infection of CLCuV in CRISPR/Cas12f treated plants compare to the infected plants (infected with CLCuMuV and CLCuKV). Smaller size, broad range and more efficiency make Cas12f a superior alternative of Cas9 against diverse group of ssDNA viruses.
Histone malonylation is regulated by SIRT5 and KAT2A
Authors: Zhang Ran , Bons Joanna , Bielska Olga , Carrico Chris , Rose Jacob , Heckenbach Indra , Scheibye-Knudsen Morten , Schilling Birgit , Verdin Eric
Published: June 2022

The posttranslational modification lysine malonylation is found in many proteins, including histones. However, it remains unclear whether histone malonylation is regulated or functionally relevant. Here, we report that availability of malonyl-co-enzyme A (malonyl-CoA), an endogenous provider of malonyl groups, affects lysine malonylation, and that the deacylase SIRT5 selectively reduces malonylation of histones. To determine if histone malonylation is enzymatically catalyzed, we knocked down each of the 22 lysine acetyltransferases (KATs) to test their malonyltransferase potential. KAT2A knockdown in particular reduced histone malonylation levels. By mass spectrometry, H2B_K5 was highly malonylated and significantly regulated by SIRT5 in mouse brain and liver. Acetyl-CoA carboxylase (ACC), the malonyl-CoA producing enzyme, was partly localized in the nucleolus, and histone malonylation increased nucleolar area and ribosomal RNA expression. Levels of global lysine malonylation and ACC expression were higher in older mouse brains than younger mice. These experiments highlight the role of histone malonylation in ribosomal gene expression.
Abasic site ring opening and DNA-protein crosslink reversal by the SRAP protein YedK
Authors: Paulin Katherine A. , Cortez David , Eichman Brandt F.
Published: June 2022

Apuirinic/apyrimidinic (AP, or abasic) sites in DNA are one of the most common forms of DNA damage. AP sites are reactive and form crosslinks to both proteins and DNA, are prone to strand breakage, and inhibit DNA replication and transcription. The protein HMCES protects cells from strand breaks, inhibits mutagenic translesion synthesis, and participates in repair of interstrand DNA crosslinks derived from AP sites by forming a stable thiazolidine DNA-protein crosslink (DPC) to AP sites in single-stranded DNA (ssDNA). Despite the importance of HMCES to genome maintenance and the evolutionary conservation of its catalytic SRAP (SOS Response Associated Peptidase) domain, the enzymatic mechanisms of DPC formation and resolution are unknown. Using the bacterial homolog YedK, we show that the SRAP domain catalyzes conversion of the AP site to its reactive, ring-opened aldehyde form, and provide structural evidence for the Schiff base intermediate that forms prior to the more stable thiazolidine. We also report two new activities, whereby SRAP reacts with polyunsaturated aldehydes at DNA 3’-ends generated by bifunctional DNA glycosylases and catalyzes direct reversal of the DPC to regenerate the AP site, which provide insight into possible mechanisms by which HMCES DPCs are resolved in cells.
Single-cell Multi-omics Integration for Unpaired Data by a Siamese Network with Graph-based Contrastive Loss
Authors: Liu Chaozhong , Wang Linhua , Liu Zhandong
Published: June 2022

Single-cell omics technology is being rapidly developed to measure the epigenome, genome, and transcriptome across a range of cell types. However, integrating omics data from different modalities is still challenging. Here, we propose a variation of the Siamese neural network framework called MinNet, which is trained to integrate multi-omics data on the single-cell resolution by utilizing graph-based contrastive loss. By training the model and testing it on several benchmark datasets, we showed its accuracy and generalizability in integrating scRNA-seq with scATAC-seq, and scRNA-seq with epitopes data. Further evaluation demonstrated our model’s unique capacity in removing the batch effect, which is a common problem in actual practice. To show how the integration impacts downstream analysis, we established model-based smoothing and cis-regulatory element inferring method and validated it with external pcHi-C evidence. Finally, the framework was applied to a COVID-19 dataset to compensate the original work with integration-based analysis, showing its necessity in single-cell multi-omics research.
The Genetic Architecture of Morphological Scaling
Authors: Wilcox Austin S. , Vea Isabelle M. , Frankino W. Anthony , Shingleton Alexander W.
Published: June 2022

Morphological scaling relationships between the sizes of individual traits and the body captures the characteristic shape of a species, and the evolution of scaling is the primary mechanism of morphological diversification. However, we have almost no knowledge of the genetic architecture of scaling, critical if we are to understand how scaling evolves. Here we explore the genetic architecture of population-level morphological scaling relationships – the scaling relationship fit to multiple genetically-distinct individuals in a population – by describing the distribution of individual scaling relationships – genotype-specific scaling relationships that are unseen or cryptic. These individual scaling relationships harbor the genetic variation that determines relative trait growth within individuals, and theoretical studies suggest that their distribution dictates how the population scaling relationship will respond to selection. Using variation in nutrition to generate size variation within 197 isogenic lineages of Drosophila melanogaster, we reveal extensive variation in the slopes of the wing-body and leg-body scaling relationships among individual genotypes. This genetic variation reflects variation in the nutritionally-induced size plasticity of the wing, leg and body. Surprisingly, we find that variation in the slope of individual scaling relationships primarily results from variation in nutritionally-induced plasticity of body size, not leg or wing size. These data allow us to predict how different selection regimes alter scaling in Drosophila and is the first step in identifying the genetic targets of such selection. More generally, our approach provides a framework for understanding the genetic architecture of scaling, an important prerequisite to explaining how selection changes scaling and morphology.
A cell-permeant nanobody-based degrader that induces fetal hemoglobin
Authors: Shen Fangfang , Zheng Ge , Setegne Mekedlawit , Tenglin Karin , Izada Manizheh , Xie Henry , Zhai Liting , Orkin Stuart H. , Dassama Laura M. K.
Published: June 2022

Proximity-based strategies to degrade proteins have enormous therapeutic potential in medicine, but the technologies are limited to proteins for which small molecule ligands exist. The identification of such ligands for therapeutically relevant but “undruggable” proteins remains challenging. Herein, we employed yeast surface display of synthetic nanobodies to identify a protein ligand selective for BCL11A, a critical repressor of fetal globin gene transcription. Fusion of the nanobody to a cell-permeant miniature protein and an E3 adaptor creates a degrader that depletes cellular BCL11A in erythroid precursor cells, thereby inducing the expression of fetal hemoglobin, a modifier of clinical severity of sickle cell disease and β-thalassemia. This work establishes a new paradigm for the targeted degradation of previously intractable proteins using cell-permeant nanobody-based degraders.

One sentence summary

A cell-permeant, protein-based degrader is used for the induction of fetal hemoglobin.
Electrophysiological indices of individual differences in adult language learning
Authors: Nalaye Halima , Cross Zachariah R. , Schlesewsky Matthias , Bornkessel-Schlesewsky Ina
Published: June 2022

Individual differences in second language (L2) learning can offer insights into the neurobiological bases of learning aptitude. One neurophysiological marker of inter-individual differences in cognition is the individual alpha frequency (IAF), a trait-like measure correlated with cognition. Further, the N400 is an electrophysiological marker indexing stimulus irregularity and has been used to study L2 learning; however, its relationship with IAF and L2 learning remains unknown. To examine the relation between IAF and L2 learning (indexed by N400 amplitude), we report data from a modified miniature language learning study. After a vocabulary learning period, participants (N = 38, Mage = 25.3, SD = 7.13) judged the grammaticality of classifier-noun pairs, with mixed-effects modelling revealing lower IAF individuals were better than higher IAF individuals at grammaticality judgements. N400 amplitude also reduced across the experiment in low relative to high IAF individuals, indicating the relationship between IAF and language learning is more complex than initially postulated.
Mutations in NBEAL2 do not impact Weibel-Palade body biogenesis and Von Willebrand factor secretion in Gray Platelet Syndrome Endothelial Colony Forming Cells
Authors: Kat Marije , van Moort Iris , Bürgisser Petra E. , Kuijpers Taco W. , Hofman Menno , Favier Marie , Favier Rémi , Margadant Coert , Voorberg Jan , Bierings Ruben
Published: June 2022

Background

Gray Platelet Syndrome (GPS) patients with Neurobeachin-like 2 (NBEAL2) deficiency produce platelets lacking alpha-granules (AGs) and present with lifelong bleeding symptoms. AGs are lysosome-related organelles (LROs) and store the hemostatic protein Von Willebrand factor (VWF) and the transmembrane protein P-selectin. Weibel-Palade bodies (WPBs) are LROs of endothelial cells and also store VWF and P-selectin. In megakaryocytes, NBEAL2 links P-selectin on AGs to the SNARE protein SEC22B on the endoplasmic reticulum (ER), thereby preventing premature release of cargo from AG precursors. In endothelial cells, SEC22B drives VWF trafficking from ER to Golgi and promotes the formation of elongated WPBs, but it is unclear if this requires NBEAL2.

Objectives

To investigate a potential role for NBEAL2 in WPB biogenesis and VWF secretion using NBEAL2 deficient endothelial cells.

Methods

Interaction of SEC22B with NBEAL2 in endothelial cells was investigated by interactomic mass spectrometry and pull down analysis. Endothelial Colony Forming Cells (ECFCs) were isolated from healthy controls and 3 unrelated GPS patients with mutations inNBEAL2.

Results

We show that SEC22B binds to NBEAL2 in ECs. GPS patient-derived ECFCs are deficient of NBEAL2, but reveal normal formation and maturation of WPBs and normal WPB cargo recruitment. Neither basal nor histamine-induced VWF secretion are altered in the absence of NBEAL2.

Conclusions

While NBEAL2 deficiency causes absence of AGs in GPS patients, it has no impact on WPB functionality in ECs. Our data highlight the difference in regulatory mechanisms between these two hemostatic storage compartments.

Essentials

We characterized Gray Platelet Syndrome patient-derived endothelial cells with biallelic NBEAL2 mutationsex vivo.

NBEAL2 is not essential for Weibel-Palade body biogenesis, maturation, and Von Willebrand factor secretion from endothelial cells.
Single-cell metabolic profiling reveals subgroups of primary human hepatocytes showing heterogeneous responses to drug challenge
Authors: Sanchez-Quant E. , Richter M. L. , Colomé-Tatché M. , Martinez-Jimenez C.P.
Published: June 2022

Xenobiotics are primarily metabolized by hepatocytes in the liver, and primary human hepatocytes (PHHs) are the gold standard model for the assessment of drug efficacy, safety and toxicity in the early phases of drug development. Recent advances in single-cell genomics have shown liver zonation and ploidy as main drivers of cellular heterogeneity. However, little is known about the impact of hepatocyte specialization on liver function upon metabolic challenge, including hepatic metabolism, detoxification, and protein synthesis. Here, we investigate the metabolic capacity of individual human hepatocytesin vitro, and assess how chronic accumulation of lipids enhances cellular heterogeneity and impairs the metabolisms of drugs. A phenotyping five-probe cocktail was used to identify four functional subgroups of hepatocytes that respond differently to drug challenge and fatty acid accumulation. These four subgroups display differential gene expression profiles upon cocktail treatment and xenobiotic metabolism-related specialization. Notably, intracellular fat accumulation leads to increased transcriptional variability and diminished the drug-related metabolic capacity of hepatocytes. Our results demonstrate that, upon a metabolic challenge such as exposure to drugs or intracellular fat accumulation, hepatocyte subgroups lead to different and heterogeneous transcriptional responses.
Loss of Spindly sensitizes EML4-ALK v3 lung cancer cells to HSP90 inhibitors
Authors: Licciardello Marco P. , Zhang Chi , Le Anh T. , Doebele Robert C. , Clarke Paul A. , Workman Paul
Published: June 2022

Heat Shock Protein 90 inhibitors (HSP90i) have shown activity in EML4-ALK+ non-small cell lung cancer (NSCLC) patients but clinical responses have been heterogeneous. It has been suggested that distinct EML4-ALK variants may have a differential impact on the response to HSP90 inhibition. Here, we show that NSCLC cells harboring the most common EML4-ALK variant 1 (v1) or variant 3 (v3) are in fact similarly sensitive to HSP90i. To discover new genetic alterations that could be involved in stratifying sensitivity, we performed a genome-wide CRISPR/Cas9 knockout screen and found that loss of Spindly increases the sensitivity of EML4-ALK v3, but not v1, NSCLC cells to low concentrations of HSP90i from three distinct chemical families. Upon loss of Spindly, prolonged exposure to low concentrations of HSP90i impairs chromosome congression and cellular fitness. Collectively, our data suggest that mutations leading to loss of Spindly in EML4-ALK v3 NSCLC patients may increase sensitivity to low doses of HSP90i.
Effect of reinforcement of mixed metal oxide nanoparticles in polyurethane resin for barrier and dynamic mechanical properties of steel structures
Authors: Xavier Joseph Raj
Published: June 2022

Purpose

This study aims to study the effect of the reinforcement of mixed CeO2-ZrO2 nanoparticles in the polyurethane (PU) for protection properties of steel structures.

Design/methodology/approach

Electrochemical techniques were used to study the anticorrosion properties of the generated PU/CeO2-ZrO2 nanocomposite coated steel. Dynamic mechanical testing was done to investigate the mechanical properties.

Findings

In natural seawater, Electrochemical impedance spectroscopy experiments indicated outstanding protective behaviour for the PU/CeO2-ZrO2-coated steel. The coating resistance of the PU/CeO2-ZrO2 nanocomposite coating was found to be roughly 30% greater than that of the PU coating. Scanning electron microscopy with energy dispersive X-ray spectroscopy and X-ray diffraction analyses of the coated steel surface revealed that the CeO2-ZrO2 was accumulated at the corrosion products, preventing the corrosion. Dynamic mechanical analysis revealed that when the nanoparticle concentration was 3 Wt.%, the PU/CeO2-ZrO2 nanocomposite coating had improved dynamic mechanical parameters.

Originality/value

The coating resistance of the PU/CeO2-ZrO2 nanocomposite was determined to be 2999.17 kΩ.cm2. The perceived current by scanning electrochemical microscopy analysis across the PU/CeO2-ZrO2 coating was 1.7 nA. The PU/CeO2-ZrO2 nanocomposite had a good hydrophobic behaviour (WCA: 101o). The newly synthesised PU/CeO2-ZrO2 composite offered great barrier and mechanical properties, preventing material degradation and increase the lifespan of the coated steel. Hence, this form of coating could be used as a viable coating material for industrial purposes.
Development and validation of scale to measure responsible consumption
Authors: Jain Vijay Kumar , Dahiya Aditi , Tyagi Vikas , Sharma Preeti
Published: June 2022

Purpose

The objective of this paper is to identify dimensions of responsible consumption from consumer perspective and develop a reliable and valid measurement scale.

Design/methodology/approach

This paper has employed mixed methodology to develop items for responsible consumption. In first phase, experts' interviews were carried out to unearth the dimensions of responsible consumption. In second phase, quantitative survey was carried out to among consumers to measure their response. This was done using five-point Likert scale. The reliability and validity were ensured through empirical data online. Structural equation modeling was used to test the structural model.

Findings

The result showed that consumer perception of responsible consumption consists of five dimensions (Rationality, Sustainable Consumption, Local Consumption, Ethical Consumption and Minimalism). The result also showed strong relationship among satisfaction and responsible consumption dimensions.

Practical implications

It will help policymakers to measure and promote responsible consumption thereby improving environmental performance and reducing carbon footprint.

Originality/value

This is the first study to develop valid and reliable instrument for responsible consumption. The findings will have several implications both theoretical and practical for policymakers and society.
CEO power and CSR: the moderating role of CEO characteristics
Authors: Chu Hsuan-Lien , Liu Nai-Yng , Chiu She-Chih
Published: June 2022

Purpose

The purpose of this study is to examine the moderating role of the characteristics of the chief executive officer (CEO) on the association between CEO power and corporate social responsibility (CSR) performance.

Design/methodology/approach

This paper conducts multiple regression analyses to empirically test the proposed hypotheses based on a sample of US-based publicly held companies. The sample period extends from 2000 to 2018. Firm-level CSR ratings are obtained from the Kinder, Lydenberg and Domini (KLD) database (currently known as MSCI ESG STATS). Financial data and CEO data are retrieved from Compustat and ExecuComp databases, respectively. Additional test and robustness analysis are performed.

Findings

This paper shows that firms with more powerful CEOs are less likely to engage in CSR activities. The negative association between CEO power and CSR is found to be exacerbated by CEOs who are younger, more competent and overconfident; however, this negative association is mitigated by CEOs who are female. This paper also finds that gender plays a more important role among CEO characteristics. Collectively, the findings highlight the potential opportunities to better understand the role of various CEO characteristics that jointly affect CSR.

Originality/value

First, this is the first study providing a comprehensive empirical analysis of how various CEO characteristics jointly affect CSR. Prior studies that focus on standalone CEO characteristics offer an incomplete picture of the relation between a single CEO characteristic and a firm's CSR performance. The current study thus extends the research field by examining the association between seemingly unrelated CEO characteristics and CSR performance. The results also highlight that gender is the critical factor moderating the relationship between CEO power and CSR performance when it is compared with CEO age, ability and overconfidence. Second, the authors add to the literature on employee selection by showing that female CEOs mitigate the negative effect of managerial power on CSR performance. Although the currently available empirical research in management control systems focuses on ex-post analyses of moral hazard mitigation for incumbent employees, both the economics and management literature acknowledge ex ante evidence suggesting that employee selection is even more important. Our findings may provide insight into the selection of CEOs.
Understanding the (lack of) utilization of work-family practices: a multilevel perspective
Authors: Lee Yin , Kramer Amit
Published: June 2022

Purpose

Many employees do not use work-family practices to their full extent, even when they are in need of them. Drawing on the concept of psychological safety the authors propose a new construct: psychological accessibility– employees' sense of embracing the benefits of work-family practices without experiencing a fear of using them. The authors argue that the psychological accessibility of work-family practices could explain the variations in the utilization of work-family practices among employees with similar levels of family needs. Furthermore, the authors propose multilevel contextual factors that could affect the psychological accessibility of work-family practices.

Design/methodology/approach

The authors develop a theoretical multilevel framework for work-family practices that places psychological accessibility at its core and addresses accessibility of work-family practices from a macro level that includes institutions and the different attributes of the national culture, a meso level that includes work time norms in organizations, and a micro level, that includes the social context at the team level in organizations.

Findings

As part of the conceptual development the authors offer 10 propositions.

Originality/value

The authors' multilevel model of psychological accessibility could explain the variations in the utilization of work-family practices across different national, organizational and group contexts. This paper refocuses scholarly attention to the psychological antecedents of the utilization of work-family practices. The authors offer some practical recommendations to make the utilization of work-family practices a psychologically safe activity.
How did supply chain networks handle the COVID-19 pandemic? Empirical evidence from an automotive case study
Authors: Spieske Alexander , Gebhardt Maximilian , Kopyto Matthias , Birkel Hendrik , Hartmann Evi
Published: June 2022

Purpose

The coronavirus disease 2019 (COVID-19) pandemic unveiled resilience deficits in supply chains. Scholars and practitioners aim to identify supply chain resilience (SCRES) measures suitable for this unique disruption; however, empirical evidence on a pandemic's specific characteristics, resulting challenges, and suitable countermeasures is scarce.

Design/methodology/approach

A single-case study on an automotive supply chain network (ASCN), including eight nodes, was conducted. Based on current research and interviews with 35 experts, characteristic pandemic challenges for the ASCN were identified. Moreover, promising SCRES measures were determined along the most prominent SCRES levers. The findings lead to five central propositions and advance organizational information processing theory in the context of SCRES.

Findings

This study’s results confirm unique pandemic characteristics along the supply chain disruption's duration, severity, propagation, and volatility. The resulting unprecedented challenges made the ASCN apply novel SCRES measures, particularly regarding collaboration and risk management culture. However, well-known visibility and flexibility strategies were also suitable. Overall, agility and collaboration measures showed the highest capacity to address characteristic pandemic challenges. A lack of preparedness impeded some measures' application, calling for enhanced proactive risk management following the pandemic.

Originality/value

This paper addresses several research calls by providing in-depth empirical evidence on hitherto conceptually researched pandemic characteristics, challenges, and suitable SCRES measures from a network perspective. The study uncovers the different perceptions of individual tiers, emphasizing the need to analyze supply chain disruptions from multiple angles.
Investigating the performance of the sustainable cold supply chain in the pharmaceutical industry
Authors: Turan Cansu , Ozturkoglu Yucel
Published: June 2022

Purpose

This study focuses on identifying potential challengers affecting cold chain performance in the pharmaceutical industry. Considering the history of humanity, every pandemic experienced could only be controlled with the vaccine found. While the world is fighting the unforgettable epidemic called COVID-19, scientists are also working to find the therapeutic vaccine. The vaccines studied have different temperature storage and transport properties. In the pharmaceutical industry, it is necessary to know and analyse every step of the cold supply chain to provide the most appropriate and safe cooling level. In addition, it is important to understand the relationship between all the facilities, equipment, tools and materials needed to avoid mistakes along the chain.

Design/methodology/approach

Hence, this study focuses on identifying potential challengers affecting sustainable cold supply chain performance in the pharmaceutical industry and proposing a conceptual framework that involves these main challengers. In this study, firstly, different main and sub-factors are defined from the literature, and fuzzy Decision Making Trial and Evaluation Laboratory method is applied to analyse the causal link between these factors for an effective application.

Findings

Results showed that packaging, transportation and shipping, storage specifications and handling practices, inventory management, technical issues and delivery delay are the most affected factors during the sustainable cold supply chain performance in the pharmaceutical industry. This study offers both managerial implications and a roadmap that are designed with a holistic view to guide manufacturer, logistics parties and even policymakers.

Originality/value

Some of the studies related to the pharmaceutical industry are monitoring and controlling the temperature in the cold supply chain steps; the other part is the studies where the chain steps are examined with a focus on production or transportation. While these issues are the focus, the requirements and conditions of each stage of the supply chain must be studied for a safe, effective and sustainable cold chain beyond the current global pandemic crisis. To the best of the authors’ knowledge, this is the first study that highlights identifying the potential challengers that affect cold supply chain performance for the pharmaceutical industry both theoretically and empirically, solving the causal relationships among these challengers and designing a holistic framework.
Creating a Nexus between Dark Triad Personalities, Non-Performing Assets, Corporate Governance and Frauds in the Indian Banking sector
Authors: Murthy Nilaya , Gopalkrishnan Santosh
Published: June 2022

Purpose

The banking sector requires a major comeback with the series of bank frauds that has shook the nation. The rising non-performing assets (NPAs) and corporate frauds find their roots in the top-level management or executive levels. The purpose of this study to analyse the behavioural component with corporate governance lapses for creating a trail and to what extent it can contribute to forensic analysis to help reduce and prevent fraud in the future.

Design/methodology/approach

This study is investigative in nature. This study uses case study approach by taking into account the major Advance–NPA–Fraud cases over period of 2010–2022. RBI data for bank advances, NPAs and advances-relate frauds from 2005 to 2019 were studies and interpreted for creating a trend and pattern for the reduction and prevention of frauds.

Findings

The authors found that behavioural factors and personalities affect the systems and culture of the company, thereby giving a jolt to the corporate governance mechanisms along with various entities like depositors, consumers and shareholders.

Practical implications

Assessing the behavioural aspects for risk mitigation remains unexplored in the banking sector. The personality dimension can help in contributing to comprehending the mental aspects and the reasons behind the combination of dark triads with economic offences.

Originality/value

This study is beneficial to all the beneficiaries of the banking sector and the economy at large in understanding the implications of risks because of patterns formed by emotions and vulnerability towards economic and fugitive economic crimes.
Drivers of facility management strategies used in multi-tenanted office buildings in Ghana
Authors: Tannor Oliver , Attakora-Amaniampong Elvis , Derbile Emmanuel Kanchebe
Published: June 2022

Purpose

This study aims to assess the facilities management (FM) strategies used in multi-tenanted purpose-built office buildings (Mt-POBs) in Ghana and the drivers that influence the decision to use such strategies.

Design/methodology/approach

This study was conducted via a survey and key informant interviews. The survey was conducted using a questionnaire targeted at 65 multi-tenanted office building owners in the Greater Accra region. The data from the survey revealed the views of building owners on FM strategy and the extent to which 20 facility management decision drivers influenced their decisions to use a particular strategy and the responses were descriptively analysed. The key informant interviews were conducted among six leaders of the property owners’ association who use in-house FM to further understand their perspectives and decisions on using such strategy. The interviews were conducted over telephone using an interview guide and analysed using thematic analysis.

Findings

The results showed that 88% of Mt-POBs in Ghana are managed in-house. The results also showed that the decision to use the in-house strategy was driven by the innovative, strategic and cost-saving advantages associated with the in-house strategy.

Originality/value

This study shows the factors that drive the decision of multi-tenanted office building owners in Ghana to use the in-house strategy. The findings of this study will be useful for prospective owners of office buildings in Ghana.
The concept of the cruise supply chain and its characteristics: an empirical study of China's cruise industry
Authors: Zhou Jingen , (Peggy) Chen Shu-Ling , Shi Wenming (Wendy)
Published: June 2022

Purpose

The cruise industry has witnessed steady growth, with passenger volume increasing from 17.8 million in 2009 to 30 million in 2019. In the context of global competition and an uncertain business environment, competition in business has changed dramatically from battles of “firm versus firm” to “supply chain versus supply chain”. Hence, the purpose of this paper is to understand the cruise industry from a chain perspective, which has not drawn widespread research attention.

Design/methodology/approach

This paper brings together the insights, opinions, concepts and frameworks from a literature review of different disciplines (maritime shipping, tourism management, logistics management, operations management and supply chain management) and analysis results from 22 semi-structured interviews to make an early attempt to conceptualise the cruise supply chain (CSC).

Findings

The cruise supply chain is elaborated on the process, the role of each entity and its characteristics by comparing with the maritime supply chain and tourism supply chain. Based on the understanding of the CSC, two specific characteristics of the Chinese CSC are examined, which need further investigation.

Originality/value

The CSC is articulated with detailed processes and characteristics based on the literature review and empirical study. The findings of this paper not only advance the knowledge of the supply chain in the cruise industry but also highlight the importance of further research on the CSC.