bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct attenuation of Arabidopsis ERECTA signaling by a pair of U-box E3 ligases
Authors: Chen Liangliang , Cochran Alicia M. , Waite Jessica M. , Shirasu Ken , Bemis Shannon M. , Torii Keiko U.
Published: July 2022

Plants sense a myriad of signals through cell-surface receptors to coordinate their development and environmental response. The Arabidopsis ERECTA receptor kinase regulates diverse developmental processes via perceiving multiple EPIDERMAL PATTERNING FACTOR (EPF)/EPF-LIKE peptide ligands. How the activated ERECTA protein is turned over is unknown. Here we identify two closely-related Plant U-box ubiquitin E3 ligases, PUB30 and PUB31, as key attenuators of ERECTA signaling for two distinct developmental processes: inflorescence/pedicel growth and stomatal development. Loss-of-function pub30 pub31 mutant plants exhibit extreme inflorescence/pedicel elongation and reduced stomatal numbers owing to excessive ERECTA protein accumulation. Ligand-activation of ERECTA leads to phosphorylation of PUB30/31 by the co-receptor BRI1 ASSOCIATED KINASE1 (BAK1), which then promotes PUB30/31 to associate with and ubiquitinate ERECTA for eventual degradation. We further show that the PUB30 and PUB31 phosphorylation by BAK1 and their ubiquitination activities are critical for the proper in vivo developmental outputs. Our work highlights PUB30 and PUB31 as integral components of the ERECTA regulatory circuit that ensures optimal signaling strengths upon ligand activation, thereby enabling proper growth and development.
A 2D Fragment-Assisted Protein Mimetic Approach to Rescue α-Synuclein Aggregation Mediated Early and Post-Disease Parkinson’s Phenotypes
Authors: Stillman Nicholas H. , Joseph Johnson A. , Ahmed Jemil , Dohoney Ryan A. , Ball Tyler D. , Thomas Alexandra G. , Fitch Tessa C. , Donnelly Courtney M. , Kumar Sunil
Published: July 2022

We have developed a Oligopyridylamide (OP) based 2-Dimensional Fragment-Assisted Structure-based Technique (2D-FAST) to identify potent antagonists of α-Synuclein (αS) aggregation, a process central to Parkinson’s disease (PD). The 2D-FAST utilizes a fragment-based screening of large chemical space in OPs, which led to the identification of NS132 as an antagonist of the multiple facets of αS aggregation. We also identified a better cell permeability analog (NS163) without sacrificing activity. OPs rescue αS aggregation mediated PD phenotypes in muscle cells and dopaminergic (DA) neurons in C. elegans models. OPs prevent the progression of PD phenotypes in a novel post-disease onset PD model.

This is one of the first examples of a synthetic mimetic-based 2D-FAST to identify antagonists of toxic αS self-assembly. We envision that 2D-FAST will have tremendous potential as it is expandable for other oligoamide scaffolds and for a much larger chemical space to identify lead therapeutics for various diseases.
Polygenic risk score analysis identifies deleterious protein-coding variants in novel immune pathway genesATP8B4, FCGR1A, andLILRB1that associate with Alzheimer’s disease
Authors: Reddy Joseph S. , Wang Xue , Allen Mariet , Carrasquillo Minerva M. , Biernacka Joanna M. , Jenkins Gregory D. , Coombes Brandon J. , Belbin Olivia , Golde Todd E. , Ertekin-Taner Nilüfer , Younkin Steven G.
Published: July 2022

Background

Alterations in innate immunity are pathologically associated with and genetically implicated in Alzheimer’s disease (AD). In the whole exome sequence (WES) dataset generated by the Alzheimer’s Disease Sequencing Project (ADSP), only the previously identified p.R47H variant in the innate immunity gene,TREM2, shows study-wide association with risk of AD. Using a novel approach, we searched the ADSP WES data to identify additional immune pathway genes with deleterious variants that, likeTREM2.pR47H, show strong association with AD.

Methods

Using polygenic risk scores (PRS) to analyze association with AD, we evaluated deleterious variants (CADD Phred-scaled score > 20) with a minor allele count of 20 or more in 228 genes comprising an immune co-expression network containingTREM2(CENTREM2). A significant polygenic component composed of deleterious stop-gain and non-synonymous variants was identified, and false discovery rates were determined for the variants in this component. In genes harboring a significant variant, PRS for all variants in the genes were then analyzed.

Results

The PRS for the 182 deleterious variants in CENTREM2showed significant association with AD that was driven by 142 deleterious variants (136 non-synonymous, 6 stop-gain). In the 142 variant polygenic component, four variants had significant AD risk association:TREM2.pR47H, two deleterious stop-gain variants (FCGR1A.pR92X, andLILRB1.pY331X) in novel AD genes and 1 non-synonymous variant(ATP8B4.pG395S). Remarkably, PRS for the 36 additional variants in these four genes also showed significant association with AD. The PRS for all 40 variants in the 4 genes, showed significant, replicable association with AD and 3 additional variants in this polygenic component had significant false discovery rates:ATP8B4.pR1059Q,LILRB1.pP7P, andLILRB1.pY327Y.

Conclusions

Here, we identify 3 immune pathway genes (ATP8B4, LILRB1, andFCGR1A) with a variant that associates with AD. LikeTREM2.pR47H, each of the variants has a minor allele frequency less than 1% and is a deleterious, protein altering variant with a strong effect that increases or decreases (LILRB1.pY331X) risk of AD. Additional variants in these genes also alter risk of AD. The variants identified here are ideally suited for studies aimed at understanding how the innate immune system may be modulated to alter risk of AD.
Rare missense variants in the SH3 domain of PSTPIP1 are associated with hidradenitis suppurativa
Authors: Morales-Heil David J. , Cao Li , Sweeney Cheryl , Malara Anna , Brown Frank , Anadkat Milan , Kaffenberger Jessica , Kaffenberger Benjamin , Nagele Peter , Kirby Brian , Roberson Elisha D.O.
Published: July 2022

Hidradenitis suppurativa (HS) is a chronic, debilitating skin disease estimated to affect ∼1% of the population, for which few treatment options are available. Risk factors associated with HS include smoking, obesity, and some high penetrance genetic variants. Some rare families have autosomal dominant inheritance. Previous studies have shown that rare loss-of-function variants in genes of the gamma-secretase complex, particularly nicastrin, segregate with autosomal dominant HS in some kindred. However, these gamma-secretase variants do not explain much of the overall genetic risk for HS. We performed targeted DNA sequencing of 21 candidate genes in a cohort of 117 individuals with HS to test for an increased burden of rare genetic variants. Candidates included the genes of the gamma-secretase complex, Notch signaling genes, and PSTPIP1, a known risk factor for PAPA syndrome. We discovered two pathogenic loss-of-function variants in nicastrin that to the best of our knowledge have not been described in HS before. We did not identify significant enrichment of rare missense variants in any gamma-secretase gene, further supporting that loss-of-function in gamma-secretase genes is not a common risk factor. We did, however, identify a statistically significant enrichment of rare variants in the SH3 domain of PSTPIP1. Clinical overlap between HS and PSTPIP1 syndromic features has been noted clinically. Our data suggest that there is shared genetic risk as well, and highlights the need for further population-scale HS genetic research.
Single-cell analysis of chromatin and expression reveals age- and sex-associated alterations in the human heart
Authors: Read David F , Booth Gregory T , Daza Riza M , Jackson Dana L , Gladden Rula Green , Srivatsan Sanjay R , Ewing Brent , Franks Jennifer M , Spurrell Cailyn H , Gomes Anne Roshella , O’Day Diana , Gogate Aishwarya A , Martin Beth K , Starita Lea , Lin Yiing , Shendure Jay , Lin Shin , Trapnell Cole
Published: July 2022

Sex differences and age-related changes in the human heart at the tissue, cell, and molecular level have been well-documented and many may be relevant for cardiovascular disease. However, how molecular programs within individual cell types vary across individuals by age and sex remains poorly characterized. To better understand this variation, we performed single-nucleus combinatorial indexing (sci) ATAC- and RNA-Seq in human heart samples from nine donors. We identify hundreds of differentially expressed genes by age and sex. Sex dependent alterations include pathways such as TGFβ signaling and metabolic shifts by sex, evident in both transcriptional alterations and differing presence of transcription factor (TF) motifs in accessible chromatin. Age was associated with changes such as immune activation-related transcriptional and chromatin accessibility differences, as well as changes in the relative proportion of cardiomyocytes, neurons, and perivascular cells. In addition, we compare our adult-derived ATAC-Seq profiles to analogous fetal cell types to identify putative developmental-stage-specific regulatory factors. Finally, we train predictive models of cell-type-specific RNA expression levels utilizing ATAC-Seq profiles to link distal regulatory sequences to promoters, quantifying the predictive value of a simple TF-to-expression regulatory grammar and identifying cell-type-specific TFs.
Peptide binding specificity prediction using fine-tuned protein structure prediction networks
Authors: Motmaen Amir , Dauparas Justas , Baek Minkyung , Abedi Mohamad H. , Baker David , Bradley Philip
Published: July 2022

Peptide binding proteins play key roles in biology, and predicting their binding specificity is a long-standing challenge. While considerable protein structural information is available, the most successful current methods use sequence information alone, in part because it has been a challenge to model the subtle structural changes accompanying sequence substitutions. Protein structure prediction networks such as AlphaFold model sequence-structure relationships very accurately, and we reasoned that if it were possible to specifically train such networks on binding data, more generalizable models could be created. We show that placing a classifier on top of the AlphaFold network and fine-tuning the combined network parameters for both classification and structure prediction accuracy leads to a model with strong generalizable performance on a wide range of Class I and Class II peptide-MHC interactions that approaches the overall performance of the state-of-the-art NetMHCpan sequence-based method. The peptide-MHC optimized model shows excellent performance in distinguishing binding and non-binding peptides to SH3 and PDZ domains. This ability to generalize well beyond the training set far exceeds that of sequence only models, and should be particularly powerful for systems where less experimental data is available.

Significance statement

Peptide binding proteins carry out a variety of biological functions in cells and predicting their binding specificity could significantly improve our understanding of molecular pathways. Deep neural networks have achieved high structure prediction accuracy, but are not trained to predict binding specificity. Here we describe an approach to extending such networks to jointly predict protein structure and binding specificity. We incorporate AlphaFold into this approach, and fine-tune its parameters on peptide-MHC Class I and II structural and binding data. The fine-tuned model approaches state-of-the-art classification accuracy on peptide-MHC specificity prediction and generalizes to other peptide-binding systems such as the PDZ and SH3 domains.
Gene regulation modules in non-alcoholic fatty liver disease revealed by single-nucleus ATAC-seq
Authors: Takeuchi Fumihiko , Liang Yi-Qiang , Shimizu-Furusawa Hana , Isono Masato , Ang Mia Yang , Mori Kotaro , Mori Taizo , Kakazu Eiji , Yoshio Sachiyo , Kato Norihiro
Published: July 2022

We investigated the progression of non-alcoholic fatty liver disease (NAFLD) from fatty liver to steatohepatitis using single-nucleus and bulk ATAC-seq on the livers of rats fed a high-fat diet (HFD). Rats fed HFD for 4 weeks developed fatty liver, and those fed HFD for 8 weeks further progressed to steatohepatitis. We observed an increase in the proportion of inflammatory macrophages, consistent with the pathological progression. Utilizing machine learning, we divided global gene regulation into modules, wherein transcription factors within a module could regulate genes within the same module, reaffirming known regulatory relationships between transcription factors and biological processes. We identified core genes—central to co-expression and protein-protein interaction—for the biological processes discovered. Notably, a large part of the core genes overlapped with genes previously implicated in NAFLD. Single-nucleus ATAC-seq, combined with data-driven statistical analysis, offers insight intoin vivoglobal gene regulation as a combination of modules and assists in identifying core genes of relevant biological processes.

Summary blurb

This study uncovers cell type-specific global gene regulation in NAFLD progression, identifying core genes and shedding light on the disease’s molecular mechanisms.
Macroscopic and microscopic study on floral biology and pollination of Cinnamomum verum Blume (Sri Lankan)
Authors: Hathurusinghe Bhagya M. , Pushpakumara D.K.N.G. , Bandaranayake Pradeepa C. G.
Published: July 2022

Cinnamomum verum Blume (syn Cinnamomum zeylanicum) commonly known as Ceylon cinnamon, has gained worldwide attention and well supported by experimental data. Maintaining the yield quality and quantity are essential, especially for high-end value-added products. Breeding superior varieties and producing good quality planting materials are critical for commercial cultivation efforts. However, limited literature is available on the floral development and biology of C. verum. We assessed the seasonal flowering, floral development and pollination of type A and type B varieties of C. verum. Both macroscopic and microscopic data were collected on floral biology, pollination, male and female floral organs before and after pollination. Cinnamomum verum is morpho-anatomically, structurally, and physiologically adapted for cross-pollination, possible between the two cultivars; type A (Sri Gemunu) and type B (Sri Wijaya) flowers; naturally evolved with Protogynous Dichogamy. It possesses a dry stigma, which changes its surface characteristics after pollination. During close-pollination, a higher percentage of pollen shrink and shrivel on stigma while it develops callose plugs to obstruct the growth of the pollen tube. However, during changes in environmental conditions, female and male stages in the same tree overlap for about 45-60 min suggesting possible close-pollination within the same plant. Moreover, 4-8% of the flowers formed fruits after natural close and hand pollination. pollen was found fully hydrated even after close-pollination. Although C. verum is adapted for cross-pollination, natural close-pollination is also possible. The data suggest the complex nature of the sexual reproduction of C. verum. Well-managed breeding attempts will develop superior C. verum varieties.
Development of aXenopus-based assay for high-throughput evaluation of mucociliary flow
Authors: Antoniades Ioanna , Koulle Andria , Chatzifrangkeskou Maria , Konstantinou Timothea , Skourides Paris
Published: July 2022

Motile cilia are organelles lining the surfaces of major organs of the human body and generate directional fluid flow. Ciliary dysfunction has been linked to an emerging class of multisystem disorders, collectively known as motile ciliopathies. Drug screening for ciliopathies is challenging due to the unavailability of high-throughput assays that can evaluate ciliary flow generation. Here, we describe the development of a unique assay that enables the direct and rapid evaluation of mucociliary flow, which simultaneously facilitates high-throughput screening of potential therapeutic agents for motile ciliopathies. The assay relies on the ability ofXenopustadpoles to promote mixing of a two-phase differential density aqueous mixture, through the robust flow generated by the mucociliary epithelium on their epidermis. We show that the rate of phase mixing is proportional to the rate of cilia-driven flow, therefore it directly represents the effectiveness of flow generation. We also demonstrate that the assay can detect changes in ciliary flow elicited by defects in cilia, CBF modulation and rotational polarity, providing an ideal assay for the identification of CBF-modulating compounds, as potential drugs for motile ciliopathies. Importantly we use the assay to show that CBF modulating drugs can improve flow generation and could thus be used as a potential therapeutic approach in PCD patients. The assay we have developed thus represents a powerful new tool for research, as well as drug development.
Monocyte-derived peritoneal macrophages protect C57BL/6 mice against surgery-induced adhesions
Authors: Sahputra Rinal , Dejyong Krittee , Woolf Adrian S , Mack Matthias , Allen Judi , Ruckerl Dominik , Herrick Sarah E
Published: July 2022

Peritoneal adhesions commonly occur after abdominal or pelvic surgery. These scars join internal organs to each other or to the cavity wall and can present with abdominal or pelvic pain, and bowel obstruction or female infertility. The mechanisms underlying adhesion formation remain unclear and thus, effective treatments are not forthcoming. Peritoneal macrophages accumulate after surgery and previous studies have attributed either pro- or anti-scarring properties to these cells. We propose that there are complex and nuanced responses after surgery with respect to both resident and also monocyte-derived peritoneal macrophage subpopulations. Moreover, we contend that differences in responses of specific macrophage subpopulations in part explain the risk of developing peritoneal scars. We characterised alterations in peritoneal macrophage subpopulations after surgery-induced injury using two strains of mice, BALB/c and C57BL/6, with known differences in macrophage response post-infection. At 14 days post-surgery, BALB/c mice displayed more adhesions compared with C57BL/6 mice. This increase in scarring correlated with a lower influx of monocyte-derived macrophages at day 3 post-surgery. Moreover, BALB/c mice showed distinct macrophage repopulation dynamics after surgery. To confirm a role for monocyte-derived macrophages, we used Ccr2-deficient mice as well as antibody-mediated depletion of CCR2 expressing cells during initial stages of adhesion formation. Both Ccr2-deficient and CCR2-depleted mice showed a significant increase in adhesion formation associated with the loss of peritoneal monocyte influx. These findings revealed an important protective role for monocyte-derived cells in reducing adhesion formation after surgery.
A CDKB/KRP/FB3 cell cycle core complex functions in rice gametes and zygotes
Authors: Xu Hengping , Bartley Laura , Libault Marc , Sundaresan Venkatesan , Fu Hong , Russell Scott
Published: July 2022

The cell cycle controls division and proliferation of all eukaryotic cells and is tightly regulated at multiple checkpoints by complexes of core cell cycle proteins. Due to the difficulty in accessing female gametes and zygotes of flowering plants, little is known about the molecular mechanisms underlying initiation embryogenesis despite the crucial importance of this process for seed crops. In this study, we reveal four levels of factors involved in rice zygotic cell cycle control and characterize their functions and regulation. Protein-protein interaction studies, including within zygote cells, and in vitro biochemical analyses delineate a model of the zygotic cell cycle core complex for rice. In this model, CDKB1, a major regulator of plant mitosis, is a cyclin (CYCD5)-dependent kinase; its activity is coordinately inhibited by two cell cycle inhibitors, KRP4 and KRP5; and both KRPs are regulated via F-box protein 3 (FB3)-mediated proteolysis. Supporting their critical role in controlling the rice zygotic cell cycle, mutations in KRP4, KRP5, and FB3 result in the compromised function of sperm cells and abnormal organization of female germ units, embryo and endosperm, thus significantly reducing seed-set rates. This work helps reveals regulatory mechanisms controlling the zygotic cell cycle toward seed formation in angiosperms.
Genomic and phenotypic trait variation of the opportunistic human pathogen Aspergillus flavus and its non-pathogenic close relatives
Authors: Hatmaker E. Anne , Rangel-Grimaldo Manuel , Raja Huzefa A. , Pourhadi Hadi , Knowles Sonja L. , Fuller Kevin , Adams Emily M. , Lightfoot Jorge D. , Bastos Rafael W. , Goldman Gustavo H. , Oberlies Nicholas H. , Rokas Antonis
Published: July 2022

Fungal diseases affect millions of humans annually, yet fungal pathogens remain understudied. The mold Aspergillus flavus is a causative agent of both aspergillosis and fungal keratitis infections, but species closely related to A. flavus are not considered clinically relevant. To study the evolution of A. flavus pathogenicity, we examined genomic and phenotypic traits of two strains of A. flavus and three closely related non- pathogenic species: Aspergillus arachidicola (two strains), Aspergillus parasiticus (two strains), and Aspergillus nomiae (one strain). We identified over 3,000 orthologous proteins unique to A. flavus, including seven biosynthetic gene clusters present in A. flavus strains and absent in the three non-pathogenic species. We chose to characterize secondary metabolite production for all seven strains under two clinically relevant conditions, temperature and salt concentration. Temperature impacted metabolite production in all species. Conversely, we found a lack of impact of salinity on secondary metabolite production. Strains of the same species produced different metabolites. Growth under stress conditions revealed additional heterogeneity within species. Using the invertebrate model of fungal disease Galleria mellonella, we found virulence of strains of the same species varied widely, and A. flavus strains were not more virulent than strains of the non-pathogenic species. In a murine model of fungal keratitis, we observed significantly lower disease severity and corneal thickness for A. arachidicola compared to other species at 48 hrs, but not at 72 hrs. Our work identifies key phenotypic, chemical, and genomic similarities and differences between the opportunistic human pathogen A. flavus and its non-pathogenic relatives.
Conserved Link between Catalytic Site Interactions and Global Conformation in P-loop Enzymes
Authors: Hajredini Fatlum , Ghose Ranajeet
Published: July 2022

P-loop enzymes, ubiquitous in all of life’s domains and viruses, comprise a monophyletic group with pre-LUCA origins that have differentiated into several three-layered α/β/α− sandwich domain families utilizing a basic β− loop−α−β structural module housing conserved nucleotide-binding Walker-A and Walker-B sequences. We have analyzed a large dataset of P-loop enzyme structures representing both their KG and ASCE branches as proxies for their sampled conformational landscapes. We developed a novel framework to correlate global conformations and local catalytic site geometry, specifically involving the Walker motifs, to identify conserved signatures despite substantial structural and functional diversity. Our results suggest that P-loop enzymes populate global states broadly classifiable as open or closed. In the closed states, that share similar overall geometries irrespective of family, key catalytic site residues are aligned to optimally engage the critical Mg2+ ion suggesting compatibility with the chemical step. These catalytic site interactions are disrupted in the open states resulting in the loss of the Mg2+- coordinating ability yielding conformations incapable of chemistry. In contrast to the closed states, open states are highly diverse, and this variability is facilitated by differential coupling of specific residues that are part of, or spatially proximal to, the Walker motifs with the clade-specific tertiary fold. We suggest that an essential feature in the activation and nucleotide exchange processes for all P-loop enzymes is the universal coupling between global closure and local reorganization of the catalytic site for efficient coordination of Mg2+ that carries a tightly associated cargo, the substrate NTP.
Maximizing CRISPRi efficacy and accessibility with dual-sgRNA libraries and optimal effectors
Authors: Replogle Joseph M. , Bonnar Jessica L. , Pogson Angela N. , Liem Christina R. , Maier Nolan K. , Ding Yufang , Russell Baylee J. , Wang Xingren , Leng Kun , Guna Alina , Norman Thomas M. , Pak Ryan A. , Ramos Daniel M. , Ward Michael E. , Gilbert Luke A. , Kampmann Martin , Weissman Jonathan S. , Jost Marco
Published: July 2022

CRISPR interference (CRISPRi) enables programmable, reversible, and titratable repression of gene expression (knockdown) in mammalian cells. Initial CRISPRi-mediated genetic screens have showcased the potential to address basic questions in cell biology, genetics, and biotechnology, but wider deployment of CRISPRi screening has been constrained by the large size of single guide RNA (sgRNA) libraries and challenges in generating cell models with consistent CRISPRi-mediated knockdown. Here, we present next-generation CRISPRi sgRNA libraries and effector expression constructs that enable strong and consistent knockdown across mammalian cell models. First, we combine empirical sgRNA selection with a dual-sgRNA library design to generate an ultra-compact (1-3 elements per gene), highly active CRISPRi sgRNA library. Next, we rigorously compare CRISPRi effectors to show that the recently published Zim3-dCas9 provides the best balance between strong on-target knockdown and minimal nonspecific effects on cell growth or the transcriptome. Finally, we engineer a suite of cell lines with stable expression of Zim3-dCas9 and robust on-target knockdown. Our results and publicly available reagents establish best practices for CRISPRi genetic screening.
Mutational spectra analysis reveals bacterial niche and transmission routes
Authors: Ruis Christopher , Weimann Aaron , Tonkin-Hill Gerry , Pandurangan Arun Prasad , Matuszewska Marta , Murray Gemma G. R. , Lévesque Roger C. , Blundell Tom L. , Floto R. Andres , Parkhill Julian
Published: July 2022

As observed in cancers, individual mutagens and defects in DNA repair create distinctive mutational signatures that combine to form context-specific spectra within cells. We reasoned that similar processes must occur in bacterial lineages, potentially allowing decomposition analysis to identify disrupted DNA repair processes and niche-specific mutagen exposure. Here we reconstructed mutational spectra for 84 clades from 31 diverse bacterial species, assigned signatures to specific DNA repair pathways using hypermutator lineages, and, by comparing mutational spectra of clades from different environmental and biological locations, extracted reproducible niche-associated mutational signatures. We show that mutational spectra can predict general and specific bacterial niches and therefore reveal the site of infection and types of transmission routes for established and emergent human bacterial pathogens.

One sentence summary

Variable mutagen exposure and DNA repair drive differential mutational spectra between bacteria and enable niche inference
Differences in single-motor and multi-motor motility properties across the kinesin-6 family
Authors: Poulos Andrew , Budaitis Breane G. , Verhey Kristen J.
Published: July 2022

Kinesin motor proteins are responsible for orchestrating a variety of microtubule-based processes including intracellular transport, cell division, cytoskeletal organization, and cilium function. During cell division, members of the kinesin-6 family play critical roles in anaphase and cytokinesis, however little is known about their motility properties. We find that truncated versions of MKLP1 (HsKIF23), MKLP2 (HsKIF20A), andHsKIF20B predominately display non-processive behavior as single molecules although slow, processive motility was occasionally observed, most prominently for MKLP2. Despite their non-processive nature, all kinesin-6 proteins were able to work in teams to drive microtubule gliding. MKLP1 and KIF20B were also able to work in teams to drive robust transport of both peroxisomes, a low-load cargo, and Golgi, a high-load cargo, in cells. In contrast, MKLP2 showed minimal transport of peroxisomes and was unable to drive Golgi dispersion. These results indicate that while all three mammalian kinesin-6 motor proteins are generally non-processive as single motors, they differ in their ability to work in teams and generate forces needed to drive cargo transport in cells.
Molecular Neurobiology of Loss
Authors: Smail Marissa A. , Smith Brittany L. , Shukla Rammohan , Alganem Khaled , Eby Hunter M. , Bollinger Justin L. , Parikh Ria K. , Chambers James B. , Reigle James K. , Moloney Rachel D. , Nawreen Nawshaba , Wohleb Eric S. , Pantazopoulos Harry , McCullumsmith Robert E. , Herman James P.
Published: July 2022

Psychological loss is a common experience that erodes well-being and negatively impacts quality of life. The molecular underpinnings of loss are poorly understood. Here, we investigate the mechanisms of loss using an enrichment removal (ER) paradigm in rats. A comprehensive multi-omics investigation of the basolateral amygdala (BLA) revealed alterations in microglia and extracellular matrix (ECM). Follow-up studies indicated that ER decreased microglia size, complexity, and phagocytosis, suggesting reduced immune surveillance. Loss also substantially increased ECM coverage, specifically targeting perineuronal nets surrounding parvalbumin interneurons, suggesting decreased plasticity and increased inhibition in the BLA following loss. Behavioral analyses suggest that these molecular effects are linked to impaired BLA salience evaluation, reflecting emotional blunting observed in human loss. These loss-like behaviors could be rescued by depleting BLA ECM during removal, helping us understand the mechanisms underlying loss and revealing novel molecular targets to ameliorate its impact.
Cortical patterns shift from sequence feature separation during planning to integration during motor execution
Authors: Yewbrey Rhys , Mantziara Myrto , Kornysheva Katja
Published: July 2022

Performing sequences of movements from memory and adapting them to changing task demands is a hallmark of skilled human behaviour, from handwriting to playing a musical instrument. Prior studies showed a fine-grained tuning of cortical primary motor, premotor, and parietal regions to motor sequences – from the low-level specification of individual movements to high-level sequence features like sequence order and timing. However, it is not known how tuning in these regions unfolds dynamically across planning and execution. To address this, we trained 24 healthy right-handed participants to produce four five-element finger press sequences with a particular finger order and timing structure in a delayed sequence production paradigm entirely from memory. Local cortical fMRI patterns during preparation and production phases were extracted from separate ‘No-Go’ and ‘Go’ trials, respectively, to tease out activity related to these peri-movement phases. During sequence planning, premotor and parietal areas increased tuning to movement order and timing, irrespective of their combinations. In contrast, patterns reflecting the unique integration of sequence features emerged in these regions during execution only, alongside timing-specific tuning in the ventral premotor, supplementary motor, and superior parietal areas. This was in line with the participants’ behavioural transfer of trained timing, but not of order to new sequence feature combinations. Our findings suggest a general neural state shift from high-level feature separation to low-level feature integration within cortical regions for movement execution. Recompiling sequence features trial-by-trial during planning may enable flexible last-minute adjustment before movement initiation.
Within-species differences in vocal production learning in a songbird are associated with differences in flexible rhythm pattern perception
Authors: Rouse Andrew A. , Patel Aniruddh D. , Wainapel Samantha , Kao Mimi H.
Published: July 2022

Humans readily recognize a familiar rhythmic pattern, such as isochrony (equal timing between events) across a wide range of rates. This ability reflects a facility with perceiving the relative timing of events, not just absolute interval durations. Several lines of evidence suggest that this ability is supported by precise temporal predictions that arise from forebrain auditory-motor interactions. We have shown previously that male zebra finches, which possess specialized auditory-motor networks and communicate with rhythmically patterned sequences, share our ability to recognize isochrony independent of rate. To test the hypothesis that flexible rhythm pattern perception is linked to vocal learning, we ask whether female zebra finches, which do not learn to sing, can also recognize global temporal patterns. We find that non-singing females can flexibly recognize isochrony but perform slightly worse than males on average. These findings are consistent with recent work showing that while females have reduced forebrain song regions, the overall network connectivity of vocal premotor regions is similar to that in males and supports predictions of upcoming events. Comparative studies of male and female songbirds thus offer an opportunity to study how individual differences in auditory-motor connectivity influence perception of relative timing, a hallmark of human music perception.
A synthesized retail brand personality framework: a cross-cultural study of Taiwan and the United States
Authors: Kuo Ya-Hui , Wu Pei-Chiang , Ahn Sun Young
Published: July 2022

Purpose

The purpose of this study was to develop a synthesized retail brand personality scale (RBPS) framework across retail formats. This research also addresses cultural differences by applying an emic-etic approach to scale development with United States (US) and Taiwanese samples.

Design/methodology/approach

After two focus group interviews and a pretest were conducted in both Taiwan and the US, a main test was conducted on consumer samples in Taiwan (N = 412) and in the US (N = 411). Confirmatory factor analysis was used to develop a valid, reliable RBPS.

Findings

The results revealed that sincerity and sophistication are comparable dimensions to those in the brand personality scale (BPS), and unpleasantness, traditionalism, enthusiasm, antagonism and innovativeness were found to be unique dimensions for retail brands. The findings also indicated that sincerity, unpleasantness and traditionalism are common dimensions across cultures, whereas innovativeness, sophistication and antagonism are culture-specific dimensions in the US, whereas enthusiasm is a specific dimension in Taiwan.

Originality/value

To the best of authors’ knowledge, this study is the first to develop a synthesized scale of retail brand personality that compares the identified dimensions to Aaker's (1997) BPS and includes an emic-etic approach. This research contributes to the branding literature and international marketing field, and has implications for retail practitioners.
The impact of COVID-19 lockdown on audit fees and audit delay: international evidence
Authors: Harjoto Maretno A. , Laksmana Indrarini
Published: July 2022

Purpose

The purpose of this study is to examine the impact of the 2020 COVID-19 lockdown on the audit fees and audit delay of audit client firms located in 52 countries and audit firm offices located in 40 countries.

Design/methodology/approach

Using archival audit data from Audit Analytics in the fiscal year 2020, this study examines the impact of the length of COVID-19 lockdown and other public health restrictions, measured by the stringency index (Hale et al., 2021), on audit fees and audit delay using a multivariate regression analysis.

Findings

Based on a sample of 2,726 US firms and 718 non-US firms from 51 different countries outside the USA and audit firm offices in 40 countries during the fiscal year 2020, the authors find that the COVID-19 lockdown and public health restrictions increase audit fees and audit delay. However, non-US firms experience longer audit delay because of the lockdown than their US counterparts. In addition, longer lockdown and greater restrictions increase the audit fees and audit delay of non-US firms with high audit risk at a greater rate than those of US firms with high audit risk.

Practical implications

The results of this study suggest that auditors increase audit fees and have longer audit delay when facing more COVID-19 restrictions. Increased audit fees and audit delay are likely to result from higher perceived audit risk and, consequently, additional audit effort to design new procedures, train staff to use the new procedures and implement them amid the pandemic restrictions. The impact of COVID lockdown and restrictions on audit fees and audit delay are more pronounced for non-US firms with greater audit risk. The results of this study suggest that audit firms should quickly adapt to the evolving audit, risk and financial landscape created by the pandemic.

Originality/value

Using archival audit data and large sample size, this study provides the first empirical evidence of the impact of lockdown and public health restrictions during the first wave of COVID-19 outbreak on audit processes as measured with audit fees and audit delay.
Public debt-investment nexus: the significance of investment-generation policy in West Africa
Authors: Fagbemi Fisayo , Adeosun Opeoluwa Adeniyi
Published: July 2022

Purpose

The main goal of the study is to explore the long run relationship between public debt and domestic investment in West Africa. Essentially, a study of this nature is to proffer major inroads into addressing low investment levels plaguing the region and securing critical fiscal policy measures.

Design/methodology/approach

The study examines the long-run relationship between public debt and domestic investment in 13 West African countries between 1986 and 2018 with the use of Panel Dynamic Least Squares (DOLS) and Panel Fully Modified Least Squares (FMOLS), and causality test based on Toda and Yamamoto.

Findings

Public debt (% of GDP) and external debt stocks have an insignificant effect on domestic investment in the long run, suggesting the negligible effect of public debt on the level of investments in the region. Further evidence shows that domestic investment Granger causes public debt indicators, implying that there is unidirectional causality. This suggests that any investment-generation policy could engender a rise in public borrowing, although such public loans might not be effective when there is pervasive mismanagement of public funds, as public debts need to be well managed for ensuring improved investment.

Research limitations/implications

The study suggests that maintaining a strong and effective debt-investment nexus requires fiscal consolidation efforts across countries, as such could lead to enhanced institutional capacity and sustainable investment-generation policy.

Originality/value

Since panel regression techniques used by the previous studies (Fixed and Random effects) could be susceptible to possible statistical errors due to endogeneity issue and might not be well suited for explaining long-run effect or capturing the part of investment sustainability, their conclusions could be misleading and remain untenable in West Africa' s context. Hence, the study adopts techniques (DOLS and FMOLS) which could account for endogeneity issue and provide better elucidations for long-term effects.
Service brand avoidance in business-to-business relationships
Authors: Otoo Dorothea Sekyiwa , Odoom Raphael , Braimah Stephen Mahama
Published: July 2022

Purpose

This paper aims to examine the drivers of service brand avoidance in business-to-business relationships within an emerging economy setting.

Design/methodology/approach

This study used an explanatory research design with a quantitative approach. Data was obtained through self-administered questionnaires and a uniform resource locator via Google Forms. The hypothesised relationships were analysed using the partial least squares structural equation modelling technique.

Findings

This research reveals that unmet expectations, symbolic incongruence and failed communications directly influence brand avoidance, while ideological incompatibility significantly impacts symbolic incongruence. In contrast, unacceptable trade-offs and ideological incompatibility do not directly influence brand avoidance in B2B relationships.

Research limitations/implications

Future studies may consider examining brand avoidance by business clients within other specific industries and its impact on co-branding agreements.

Originality/value

This study provides empirical evidence of drivers of service brand avoidance within business markets from an emerging economy perspective.
CCP committees, worker benefits and firm performance: empirical evidence from Chinese private firms
Authors: Long Cheryl , Yang Jin
Published: July 2022

Purpose

With an increasing number of Chinese private firms establishing primary level CPC Party committees, it is important to study the role of Party organizations in these firms. Using a nationwide survey of private firms in 2006, we empirically study the firm-level CCP committee's effect on workers' benefits and firm performance.

Design/methodology/approach

To overcome the potential endogeneity, we employ the regression discontinuity approach by utilizing the following rule from the Constitution of the CCP: Primary party committees should be established in any basic work unit with more than 3 full party members.

Findings

Our empirical results show that party committees in private firms have positive and statistically significant effects on many types of workers' benefits, including pension, unemployment insurance and workplace safety.

Originality/value

This paper highlights CCP committees as an important alternative mechanism in coordinating labor relationships in China when formal labor protecting institutions are weak.
Vertically versus horizontally differentiated information disclosure in travel live streams – the role of sensory imagery
Authors: Sun Jin , Yang Jingshu , Wang Yonggui
Published: July 2022

Purpose

This paper aims to investigate the differential effects of vertical attributes and horizontal attributes on visit intention under proximal and distal sensory imagery in travel live streams.

Design/methodology/approach

This research used a multimethod approach with four studies. Three designed experiments were first employed to prove casual relations of the hypothesized relations. Then, a structural model provided a new sample of the framework.

Findings

The results suggest that visit intention is higher when vertical (vs horizontal) attributes are associated with proximal (vs distal) sensory imagery. Physical presence mediates the interaction effects between attribute type and sensory imagery on visit intention.

Practical implications

The finding offers suggestions for multilateral information providers' capability of real-time advertising, seller-focused technology development and proactive relationship management with potential consumers.

Originality/value

Previous study is less sufficient to describe consumers' traveling interactivities in live-streaming media, where streamers are capable of modifying attribute-based messages and sensory modalities. Rather than focusing on imagery as a comprehensive modality or visual-dominated imagery, this study examines the interaction effects between attribute type and sensory imagery on visit intention. Drawing on reason-based choice and distance-on-distance theories, the finding enriches the evaluation of the effectiveness of live-streaming marketing across varying sensory interactions.
Fostering egalitarianism for team learning in professional service teams
Authors: Batt-Rawden Victoria H. , Traavik Laura E.M.
Published: July 2022

Purpose

The purpose of this study is to explore what contributes to egalitarian teams and facilitates for team learning in professional service teams.

Design/methodology/approach

A qualitative case study, including 41 in-depth interviews (n = 18) of professional service team members and managers in one of Nordics largest professional service companies was conducted.

Findings

This study reveals how acknowledgement of generational differences and humour can facilitate egalitarianism and psychological safety for members of professional service teams. This in turn relates to team learning processes and behaviours. Humour creates a “safe space” between team members representing different areas of the novice–expert continuum for idea generation and knowledge sharing.

Originality/value

To the best of the authors’ knowledge, this study is one of the first to contribute with insight on experiences and expectations of humour as an enabling mechanism for egalitarianism and team learning in professional service teams. The findings provide professional service firms with valuable and tangible insights, which could serve as a basis for designing learning and training practices.
Trait coordination in boreal mosses reveals a bryophyte economics spectrum
Authors: Grau‐Andrés Roger , Kardol Paul , Gundale Michael J.
Published: July 2022

The study of plant trait spectra and their association with trade‐offs in resource use strategy has greatly advanced our understanding of vascular plant function, yet trait spectra remain poorly studied in bryophytes, particularly outside of the Sphagnum genus. Here, we measured 25 traits related to carbon, nutrient and water conservation in 60 moss canopies (each dominated by one of 15 moss species) across diverse boreal forest habitats and used bi‐variate correlations and multi‐variate analyses to assess trait coordination and trait spectra.

We found substantial trait coordination along a main principal components axis driven by trade‐offs in carbon, nutrient and water conservation strategies. Along this trait spectrum, traits varied from resource‐acquisitive at one end (e.g. high maximum photosynthetic capacity, high tissue nitrogen content, low water‐holding capacity) to resource‐conservative at the other end, in line with resource economics theory.

Traits related to carbon turnover (photosynthesis and respiration rates, litter decomposability) were positively related to nitrogen content and to desiccation rates, in line with global trait spectra in vascular plants. However, architectural traits of the moss shoots and of the moss canopy were generally unrelated to the main axis of trait variation and formed a secondary axis of trait variation, contrary to what is observed for vascular plants.

Resource‐conservative trait spectra dominated in moss canopies from open and wet habitats (i.e. mires), indicating that high irradiance and possibly high moisture fluctuation induce a resource‐conservative trait strategy in mosses.

Synthesis. Our work suggests that trait relationships that are well established for vascular plants can be extended for bryophytes as well. Bryophyte trait spectra can be powerful tools to improve our understanding of ecosystem processes in moss‐dominated ecosystems, such as boreal or arctic environments, where bryophyte communities exert strong control on nutrient and carbon cycling.