bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphoproteomics highlights complex resource management upon inflammatory stimulation of fibroblasts
Authors: Janker-Bortel Patricia , Martinez-Val Ana , Hagn Gerhard , Skos Lukas , Olsen Jesper V. , Gerner Christopher
Published: October 2024

The stimulation of cells by inflammatory mediators gives rise to intricate signaling cascades, inducing specific biological functions. The role of kinase activation for the establishment of specific inflammatory functions has only scarcely been established. A time-course analysis of human fetal fibroblasts stimulated with Interleukin-1β (IL-1β) and/or Dexamethasone (Dex) was conducted using mass spectrometry-based proteomics and phosphoproteomics in conjunction with lysolipid and oxylipin profiling. The IL-1β induced proteome alterations indicated metabolic, transcriptional, and translational activation, including inflammatory marker proteins such as NOS1, THBS1, and STING1. The induction of mitochondrial proteins and the formation of numerous lysolipids indicated an increase in beta-oxidation. In addition to the NF-κB and STAT signaling pathways, which are characteristic of inflammatory activation, the MAP and AKT kinase signaling pathways were found to be strongly induced. Six hours after treatment, the observed signaling events exhibited a notable decline, nearly returning to their initial states after 24 hours. It is noteworthy that nearly all of these signaling activities were also observed in cells treated with Dex alone. Additionally, the proteome exhibited transient alterations, which included proteins otherwise characteristic of an inflammatory response, such as MMP3 and NFKB2. Activation of the kinase PIKFYVE was apparently specific for dexamethasone but constituted a minority of the total phosphorylation events. Only after 24 hours was the induction of proteins characteristic of glucocorticoids, such as TSC22D3 and MAOA, observed. The analysis of the effects of dexamethasone on the background of established inflammatory signaling verified the known inhibitory functions and resulted in the expression of anti-inflammatory proteins and oxylipins, but hardly affected the signaling events involving MAP and AKT kinases. In conclusion, this data demonstrates that a majority of inflammation-associated signaling events in fibroblasts needs to be attributed to resource and stress management rather than the establishment of specific inflammatory effector functions.
Inconsistencies in the published rabbit ribosomal rRNAs: a proposal for uniformity in sequence and site numbering
Authors: De Swastik , Zhou Michelle , Brown Zuben P , Burton-Smith Raymond N. , Hashem Yaser , Pestova Tatyana , Hellen Christopher U T , Frank Joachim
Published: October 2024

Examination of all publicly availableOryctolagus cuniculus(rabbit) ribosome cryo-EM structures reveals numerous confusing inconsistencies. First, there are a plethora of single nucleotide differences among the various rabbit 28S and 18S rRNA structures. Second, two nucleotides are absent from the NCBI Reference Sequence for the 18S rRNA gene. Moving forward, we propose using the Broad Institute’s rabbit whole genome shotgun sequence and numbering to reduce modeling ambiguity and improve consistency between ribosome models.
Population structure limits inferences from genomic prediction and genome-wide association studies in a forest tree
Authors: Slavov Gancho T. , Macaya-Sanz David , DiFazio Stephen P. , Howe Glenn T.
Published: October 2024

There is overwhelming evidence that forest trees are locally adapted to climate. Thus, genecological models based on population phenotypes have been used to measure local adaptation, assess risks of genetic maladaptation to climate, and guide assisted migration. However, instead of phenotypes, there is increasing interest in using genomic data for gene resource management. We used whole-genome resequencing and a replicated common- garden experiment to understand the genetic architecture of adaptive traits in black cottonwood. We studied the potential of using genome-wide association studies (GWAS) and genomic prediction to detect causal loci, identify climate-adapted phenotypes, and practice assisted migration. We analyzed hierarchical population structure by partitioning phenotypic and genomic (SNP) variation among 840 genotypes collected from 91 stands along 16 rivers. Most phenotypic variation (60-81%) occurred at the population level and was strongly associated with climate. Population phenotypes were predicted well using genomic data (e.g., predictive abilityr> 0.9) but almost as well using climate or geography (r> 0.8). In contrast, genomic prediction within populations was poor (r< 0.2). Similarly, we identified many GWAS associations among populations, but most appeared to be spurious based on pooled within-population analyses. Hierarchical partitioning of linkage disequilibrium and haplotype sharing suggested that within-population genomic prediction and GWAS were poor because allele frequencies of causal loci and linked markers differed among populations. Our results highlight the difficulty of using GWAS to identify causal loci when there is population structure, and the limitations of using genomic information alone to guide assisted migration.
An Adverse Outcome Pathway for Food Nanomaterial-induced Intestinal Barrier Disruption
Authors: Stanco Deborah , Lipsa Dorelia , Bogni Alessia , Bremer-Hoffmann Susanne , Clerbaux Laure-Alix
Published: October 2024

Introduction

Ingestion of nanomaterials (NMs) might impair intestinal barrier, but the underlying mechanisms remain evasive, and evidence is not systematically gathered or produced. A mechanistic-based approach would be instrumental to assess if relevant NMs disrupt intestinal barrier to support NM risk assessment in the food sector.

Methods

Here, we developed an adverse outcome pathway (AOP) based on biological plausibility and by leveraging existing information of an existing NM relevant AOP leading to hepatic outcomes. We then extracted the current evidence existing in the literature for a targeted selection of NMs with high food sector relevance, namely ZnO, CuO, FeO, SiO2, Ag NMs and nanocellulose.

Results

We propose a new AOP (AOP530) that starts with endocytic lysosomal uptake leading to lysosomal disruption inducing mitochondrial dysfunction. Mitochondrial impairments can lead to cell injury/death and disrupt the intestinal barrier. The evidence collected supports that those food NMs can be taken up by intestinal cells and indicates that intestinal barrier disruption by Ag, CuO, SiO2NMs might occur whilst only few studies support that outcome for FeO, ZnO. Lysosomal disruption and mitochondrial dysfunction are rarely evaluated. For nanocellulose, none of the studies report toxic-related events.

Conclusions

Collecting the existing scientific evidence supporting our AOP linking NM uptake to intestinal barrier impairments allowed us to highlight current evidence gaps but also data inconsistencies. Those latter could be associated with the variety of stressors, biological systems and KE-related assays used in the different studies, calling for further harmonized methodologies and production of mechanistic evidence in the safety regulatory assessment of NMs in the food sector.
GATA1-deficient human pluripotent stem cells generate neutrophils with improved antifungal immunity that is mediated by the integrin CD18
Authors: Wagner Andrew S. , Smith Frances M. , Bennin David A. , Votava James A. , Datta Rupsa , Giese Morgan A. , Zhao Wenxuan , Skala Melissa C. , Fan Jing , Keller Nancy P. , Huttenlocher Anna
Published: October 2024

Neutrophils are critical for host defense against fungi. However, the short life span and lack of genetic tractability of primary human neutrophils has limitedin vitroanalysis of neutrophil-fungal interactions. Human induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) are a genetically tractable alternative to primary human neutrophils. Here, we show that deletion of the transcription factor GATA1 from human iPSCs results in iNeutrophils with improved antifungal activity againstAspergillus fumigatus. GATA1 knockout (KO) iNeutrophils have increased maturation, antifungal pattern recognition receptor expression and more readily execute neutrophil effector functions compared to wild-type iNeutrophils. iNeutrophils also show a shift in their metabolism following stimulation with fungal β-glucan, including an upregulation of the pentose phosphate pathway (PPP), similar to primary human neutrophilsin vitro. Furthermore, we show that deletion of the integrin CD18 attenuates the ability of GATA1-KO iNeutrophils to killA. fumigatusbut is not necessary for the upregulation of PPP. Collectively, these findings support iNeutrophils as a robust system to study human neutrophil antifungal immunity and has identified specific roles for CD18 in the defense response.

Author Summary

Neutrophils are important first responders to fungal infections, and understanding their antifungal functions is essential to better elucidating disease dynamics. Primary human neutrophils are short lived and do not permit genetic manipulation, limiting their use to study neutrophil-fungal interactionsin vitro. Human induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) are a genetically tractable alternative to primary human neutrophils forin vitroanalyses. In this report we show that GATA1-deficient iPSCs generate neutrophils (iNeutrophils) that are more mature than wild-type iNeutrophils and display increased antifungal activity against the human fungal pathogenAspergillus fumigatus. We also show that GATA1-deficient iNeutrophils have increased expression of antifungal receptors than wild-type cells and shift their metabolism and execute neutrophil antifungal functions at levels comparable to primary human neutrophils. Deletion of the integrin CD18 blocks the ability of GATA1-deficient iNeutrophils to kill and control the growth ofA. fumigatus, demonstrating an important role for this integrin in iNeutrophil antifungal activity. Collectively, these findings support the use of iNeutrophils as a model to study neutrophil antifungal immunity.
Structural insights into the RNA binding inhibitors of the C-terminal domain of the SARS-CoV-2 nucleocapsid
Authors: Dhaka Preeti , Mahto Jai Krishna , Singh Ankur , Kumar Pravindra , Tomar Shailly
Published: October 2024

The SARS-CoV-2 nucleocapsid (N) protein is an essential structural element of the virion, playing a crucial role in enclosing the viral genome into a ribonucleoprotein (RNP) assembly, as well as viral replication and transmission. The C-terminal domain of the N-protein (N-CTD) is essential for encapsidation, contributing to the stabilization of the RNP complex. In a previous study, three inhibitors (ceftriaxone, cefuroxime, and ampicillin) were screened for their potential to disrupt the RNA packaging process by targeting the N-protein. However, the binding efficacy, mechanism of RNA binding inhibition, and molecular insights of binding with N-CTD remain unclear. In this study, we evaluated the binding efficacy of these inhibitors using isothermal titration calorimetry (ITC), revealing the affinity of ceftriaxone (18 ± 1.3 μM), cefuroxime (55 ± 4.2 μM), and ampicillin (28 ± 1.2 μM) with the N-CTD. Further inhibition assay and fluorescence polarisation assay demonstrated RNA binding inhibition, with IC50ranging from 10.4 to 12.4 μM and KDvalues between 24 and 32 μM for the inhibitors. Additionally, we also determined the inhibitor-bound complex crystal structures of N-CTD-Ceftriaxone (2.0 Å) and N-CTD-Ampicillin (2.2 Å), along with the structure of apo N-CTD (1.4 Å). These crystal structures revealed previously unobserved interaction sites involving residues K261, K266, R293, Q294, and W301 at the oligomerization interface and the predicted RNA-binding region of N-CTD. These findings provide valuable molecular insights into the inhibition of N-CTD, highlighting its potential as an underexplored but promising target for the development of novel antiviral agents against coronaviruses.

Highlights

The inhibitors ceftriaxone, cefuroxime, and ampicillin-demonstrated high-affinity binding to the C-terminal domain (N-CTD) of the SARS-CoV-2 nucleocapsid (N) protein, effectively disrupting the formation of the N-CTD-RNA complex.

Complex crystal structures of N-CTD with ceftriaxone and ampicillin revealed previously unobserved distinct binding sites.

Structures reveal how the selected inhibitors disrupt the oligomerization of N-CTD and hinder the RNA packaging process of the virus.
Mapping AAV capsid sequences to functions through function-guidedin silicoevolution
Authors: Zheng Hanyu , Guo Binjie , Mo Aisheng , Wei Hongyan , Wu Yile , Lin Xurong , Jiang Haohan , Li Hengguang , Zhang Yunshuo , Song Zhuoyuan , Ni Xuebin , Huang Yan , Gu Xiaosong , Yu Bin , Cheng Ningtao , Wang Xuhua
Published: October 2024

Artificial intelligence (AI) has been suggested to facilitate time- and cost-effective functional engineering of adeno-associated virus (AAV) capsid sequences. Nevertheless, an AI-empowered approach to identify AAV capsid sequence-to-multifunction relationships remains elusive. To overcome this challenge, we propose a machine-intelligent design method to map an AAV capsid sequence to multiple functions, thereby enabling directin silicoengineering of AAV capsids. To fuse multiple functions into a single capsid sequence, a heuristic algorithm coupled with contrastive learning and reinforcement learning, named function-guided evolution (FE), was introduced to steer further evolution of the high-performing capsid sequences generated by a naïve language model toward functions. We then illustrated the evolutionary mechanism of the FE approach for function-guided generation of capsid sequences. Further optimization steers the evolution toward desired functions within a function-guided landscape. Despite the constraint of datasets of only 129 entries, we successfully constructed a model to map AAV capsid sequences to multiple functions of improved viability coupled with central nervous system (CNS) tropism.In vivoexperiments confirmed that two of the top eight engineered variants exhibited enhanced viability and remarkable CNS tropism. This interpretable machine-intelligent design method represents a pioneering effort enabling directin silicoengineering of AAV capsids for effective gene delivery.

Graph Abstract

In Brief

This study introduces ALICE, a novel machine-intelligent design method that enables directin silicoengineering of adeno-associated virus (AAV) capsids with multiple functions.In vivoexperiments have validated the enhanced viability and central nervous system tropism of the variants engineered through ALICE.

Highlights

ALICE represents a pioneering machine-intelligent design method for directin silicoengineering of AAV capsids with multiple functions.

Utilizing a limited dataset of 129 entries, ALICE successfully maps AAV capsid sequences to multiple functions.

We elucidated the evolutionary mechanism of capsid sequences toward desired functions within the ALICE system.

We revealed that the AAV variants engineered by ALICE exhibit increased viability and about 372-fold increased central nervous system tropism.
Immersion in nature attenuates the development of mechanical secondary hyperalgesia: a role for insulo-thalamic effective connectivity
Authors: Medina Sonia , Hughes Sam
Published: October 2024

Nature-based social prescribing has been shown to improve physical and mental health and is increasingly used to manage chronic pain using immersive virtual reality (VR). However, the mechanisms of nature-based analgesia during immersive VR experiences remain unclear. In this study, we used experimentally induced sensitisation within central nociceptive pathways using high frequency stimulation (HFS) over the right forearm in 30 healthy participants and tracked the development of secondary hyperalgesia across three conditions: immersive VR nature, non-immersive 2D nature video, and no intervention. Immersive nature VR significantly reduced the development and spread of hyperalgesia, with sustained analgesic effects correlating with perceived presence. Bayesian modelling of neuroimaging endpoints collected separately revealed nature VR induced analgesic effects correlated with insulo-thalamic effective connectivity. We propose that the analgesic effects of nature are likely mediated via top-down endogenous analgesic systems which could be working to reduce the development and spread of heterotopic plasticity in the spinal cord.
Cortical alpha rhythms interpolate occluded motion from natural scene context
Authors: Yeh Lu-Chun , Bardelang Max , Kaiser Daniel
Published: October 2024

Tracking objects as they dynamically move in and out of sight is critical for parsing our ever-changing real-world surroundings. Here, we explored how the interpolation of occluded object motion in natural scenes is mediated by top-down information flows expressed in cortical alpha rhythms. We recorded EEG while participants viewed videos of a person walking across a scene. We then used multivariate decoding on alpha-band responses to decode the direction of movement across the scene. In trials where the person was temporarily occluded, alpha dynamics interpolated the person’s predicted movement. Critically, they did so in a context-dependent manner: When the scene context required the person to stop in front of an obstacle, alpha dynamics tracked the termination of motion during occlusion. As these effects were obtained with an orthogonal task at fixation, we conclude that alpha rhythms automatically interpolate occluded motion in a context-dependent way.
WITHDRAWN: Effect of inactivated conditioned media from DENV-2-infected endothelial cells on epithelial cell healing: live cell imaging analysis
Authors: Hincapie Victoria , Cardona-Gomez Juan Carlos , Gallego-Gomez Juan Carlos , Villarreal-Julio Rafael Guillermo , Blandon Jonny , Ordonez Brayan E. , Perez Gabriel A. , Cuartas-Lopez Alexandra Milena
Published: October 2024

Withdrawal Statement

The authors have withdrawn their manuscript because Several authors have expressed strong opposition to publishing in preprint, as they believe there are still important details, key experiments, and additional tests needed to complete the research. The authors argue that the study is not yet ready for publication as the investigation is still ongoing. Furthermore, some authors state that they did not grant their approval for preprint publication and therefore do not authorize its release at this stage. For these reasons, we kindly ask that our requests be respected. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Thank you very much for your understanding and cooperation.
Human tonsil organoids reveal innate pathways modulating humoral and cellular responses to ChAdOx1
Authors: Pudjohartono Maria Fransiska , Powell Kate , Barnes Eleanor , Klenerman Paul , Provine Nicholas M
Published: October 2024

The COVID-19 pandemic response demonstrated the effectiveness of adenovirus vector vaccines in inducing protective cellular and antibody responses. However, we still lack mechanistic understanding of the factors regulating immunity induced by this platform, especially innate pathways. We utilized a human tonsil organoid model to study the regulation of adaptive responses to ChAdOx1 nCoV-19.

Innate activation and cytokine release occurred within 24 hours and T and B cell activation and antigen-specific antibody secretion occurred during the ensuing 14-day culture. Among the immune cell populations, plasmacytoid dendritic cells (pDCs) exhibited the highest ChAdOx1 transduction levels. pDC-derived IFN-α was critical for humoral responses, but production of antigen in pDCs was dispensable. Furthermore, IL-6 enhanced humoral responses in both IFN-α-dependent and independent manners, indicating intricate signaling interplay. IFN-α and IL-6 also regulated the function of vaccine-activated CD4+T cells, including TFH. These data provide key insights into innate pathways regulating ChAdOx1-induced immunity and highlights the promise of this model for vaccine platform mechanistic studies.

Despite the success of adenovirus vector vaccines, we still lack understanding of the mechanisms regulating immunity induced by this platform. This study utilized human tonsil organoids to provide key insights into innate pathways regulating ChAdOx1-induced humoral and cellular immunity.
Using known births to account for delayed marking in population estimation of North Atlantic right whales
Authors: Linden Daniel W.
Published: October 2024

Population estimation using capture-recapture modeling typically requires that individuals are identifiable by unique marks. North Atlantic right whales (Eubalaena glacialis) can be identified by natural callosity patterns on their heads that are established nearly a year after birth, which has facilitated population monitoring using extensive aerial surveys. A well-maintained catalog of individual sightings has been used to annually estimate population size with a Jolly-Seber (J-S) model using a Bayesian state-space framework. Given that young animals cannot enter the catalog before an established callosity pattern, the terminal year population estimate never includes new calves despite breeding area surveys that provide a nearly complete census of births. Here, I illustrate a simple modification to the J-S likelihood whereby the number of expected entrants is a function of known births and a parameter representing initial offspring mortality. A simulation study was used as a proof of concept and indicated increased accuracy and precision of population estimates. The birth-integrated J-S model had more accurate terminal-year estimates of right whale population size that remained consistent during subsequent model fitting to additional years of sightings data. While the bias corrections were fairly small (5%) given low per capita calving rates, the demonstrated improvement in accuracy will be helpful to the conservation and management processes for this endangered species. Integrated modeling approaches make better use of available data and can improve inferences on population dynamics.
The ambiguity of “hybrid swarm”: inconsistent definitions and applications in existing research
Authors: Campbell Jillian N. , Mandeville Elizabeth G. , Lewis Nathan C. , Meuser Amanda V.
Published: October 2024

1

Hybridization is common in wild taxa and often increases in frequency following anthropogenic disturbance to an environment. Next-generation sequencing techniques make genomic analysis of a large number of individuals feasible, vastly improving the analysis for and promoting a greater frequency of studies on hybridization. However, terminology surrounding hybridization can be inconsistent; in particular, the term “hybrid swarm” has been used extensively in the literature but lacks a consistent definition. In this paper, we conducted a comprehensive review of the literature that uses the term “hybrid swarm” in reference to hybridization between taxa and challenged putative definitions of the term. We found that the term “hybrid swarm” is used in a variety of contexts, including some contradictory to other literature, and that there is little consensus on what constitutes a hybrid swarm in terms of hybrid outcomes, frequency relative to disturbances, or duration of existence. We dissuade researchers from use of the term “hybrid swarm” and instead suggest more specific and clear terminology to describe aspects of hybridization. Consequently, we hope that this paper promotes consensus surrounding hybridization terminology and improves the quality of future research on hybridization.
The Curated Cancer Cell Atlas: comprehensive characterisation of tumours at single-cell resolution
Authors: Tyler Michael , Gavish Avishai , Barbolin Chaya , Tschernichovsky Roi , Hoefflin Rouven , Mints Michael , Puram Sidharth V. , Tirosh Itay
Published: October 2024

Single-cell RNA-seq (scRNA-seq) has transformed the study of cancer biology. Recent years have seen a rapid expansion in the number of single-cell cancer studies, yet most of these studies profiled few tumours, such that individual datasets have limited statistical power. Combining the data and results across studies holds great promise but also involves various challenges. We recently began to address these challenges by curating a large collection of cancer scRNA-seq datasets, and leveraging it for systematic analyses of tumor heterogeneity. Here we significantly extend this repository to 124 datasets for over 40 cancer types, together comprising 2,822 samples, with improved data annotations, visualisations and exploration. Utilising this vast cohort, we systematically quantified context-dependent gene expression and proliferation patterns across cell types and cancer types. These data, annotations and analysis results are all freely available for exploration and download via the Curated Cancer Cell Atlas (3CA) website (https://www.weizmann.ac.il/sites/3CA/), a central source of data and analyses for the cancer research community that opens new avenues in cancer research.
Cefepime-Taniborbactam and Ceftibuten-Ledaborbactam Maintain Activity Against KPC Variants that Lead to Ceftazidime-Avibactam Resistance
Authors: Myers Cullen L. , Stevenson Annie , Miller Brittany , Daigle Denis M. , Uehara Tsuyoshi , Pevear Daniel C.
Published: October 2024

Klebsiella pneumoniaecarbapenemases (KPCs) are widespread β-lactamases that are a major cause of clinical non-susceptibility of Gram-negative bacteria to carbapenems and other β-lactam antibiotics. Ceftazidime combined with the β-lactamase inhibitor avibactam (CAZ-AVI) has been effective for treating infections by KPC-producing bacteria, but emergent KPC variants confer resistance to the combination. Taniborbactam and ledaborbactam are bicyclic boronate β-lactamase inhibitors under development with cefepime and ceftibuten, respectively, to treat carbapenem-resistant bacterial infections. Here, we assessed the effects of clinically important KPC-2 and KPC-3 variants (V240G, D179Y, D179Y T243M) on the antibacterial activity of cefepime-taniborbactam (FEP-TAN) and ceftibuten-ledaborbactam (CTB-LED) and examined catalytic activity and inhibition of these variants. FEP-TAN and CTB-LED were highly active against CAZ-AVI-resistant engineeredE. colistrains expressing these variants. Purified KPC variants catalyzed more efficient CAZ hydrolysis than wild-type enzymes, and D179Y-containing KPC-3 variants additionally catalyzed more efficient FEP hydrolysis than wild-type KPC-3. All KPC variants poorly hydrolyzed CTB, and D179Y-containing variants demonstrated significantly higher affinity for CAZ than FEP or CTB. Second-order rate constants (k2/K) for inhibition of D179Y-containing KPC-2 variants were significantly reduced relative to wild-type KPC-2, with AVI most impacted.K2/Kwas less affected for D179Y-containing KPC-3 variants, and reflected robust inhibition by TAN, LED and AVI. Together, the findings illustrate a biochemical basis for greater FEP-TAN and CTB-LED antibacterial activity in KPC variant expression backgrounds relative to CAZ-AVI, whereby the boronate inhibitors have sufficient inhibitory activity, whilst FEP and CTB are poorer substrates and bind to the variant enzymes with reduced affinity compared to CAZ.
Intranasal delivery of a broadly neutralizing single domain antibody targeting ACE2 protects against SARS-CoV-2 infection
Authors: Blachier Simon , Fernández Ignacio , Conquet Laurine , Giraud Emilie , Staropoli Isabelle , Michel Vincent , Szilagyi Fruzsina , Guez Salomé , Boucharlat Alix , Chiaravalli Jeanne , Tran-Rajau Jaouen , Dufour Evelyne , Petres Stéphane , Planas Delphine , Montagutelli Xavier , Agou Fabrice , Rey Felix , Lafaye Pierre , Enninga Jost , Ayme Gabriel , Schwartz Olivier , Brelot Anne
Published: October 2024

SARS-CoV-2 accumulates mutations over time leading to the emergence of variants, which become largely resistant to existing vaccines and spike protein-targeted antiviral treatment. Therefore, there is a need for other therapies with broad efficiency. Here, we targeted the angiotensin-converting enzyme 2 (ACE2), the major entry receptor for SARS-CoV-2. We purified three single domain heavy chain antibodies (VHHs) after immunization of an alpaca with the ectodomain of ACE2. These VHHs bound ACE2 with nanomolar affinity and specifically detected membrane-anchored ACE2. Two of them (B07 and B09) neutralized by a competitive mechanism multiple SARS-CoV-2 isolates, including Omicron variants (XBB.1.16.1; EG.5.1.3; BA.2.86.1), without impacting the proteolytic activity of the enzyme. Fusion of B07 with conventional Fc domain markedly improved its binding and neutralizing efficacy. This dimeric Fc-conjugated B07 (B07-Fc) recognized specific residues of the N-terminal helix 1 of ACE2. When administrated prophylactically and intranasally, B07-Fc induced a strong dose-dependent protection of mice expressing human ACE2 (K18-hACE2) from SARS-CoV-2 Omicron. Hamsters were weakly protected due to low binding of B07-Fc to hamster ACE2. These single domain antibodies targeting hACE2 represent potential broad-spectrum therapeutic candidates against any emerging viruses using ACE2 as a receptor. These inhalable neutralizing single domain antibodies also represent a non-invasive approach against respiratory viral infection.
High resolution deep mutational scanning of the melanocortin-4 receptor enables target characterization for drug discovery
Authors: Howard Conor J. , Abell Nathan S. , Osuna Beatriz A. , Jones Eric M. , Chan Leon Y. , Chan Henry , Artis Dean R. , Asfaha Jonathan B. , Bloom Joshua S. , Cooper Aaron R. , Liao Andrew , Mahdavi Eden , Mohammed Nabil , Su Alan L. , Uribe Giselle A. , Kosuri Sriram , Dickel Diane E. , Lubock Nathan B.
Published: October 2024

Deep Mutational Scanning (DMS) is an emerging method to systematically test the functional consequences of thousands of sequence changes to a protein target in a single experiment. Because of its utility in interpreting both human variant effects and protein structure-function relationships, it holds substantial promise to improve drug discovery and clinical development. However, applications in this domain require improved experimental and analytical methods. To address this need, we report novel DMS methods to precisely and quantitatively interrogate disease-relevant mechanisms, protein-ligand interactions, and assess predicted response to drug treatment. Using these methods, we performed a DMS of the melanocortin-4 receptor (MC4R), a G protein-coupled receptor (GPCR) implicated in obesity and an active target of drug development efforts. We assessed the effects of >6,600 single amino acid substitutions on MC4R's function across 18 distinct experimental conditions, resulting in >20 million unique measurements. From this, we identified variants that have unique effects on MC4R-mediated Gαs- and Gαq-signaling pathways, which could be used to design drugs that selectively bias MC4R's activity. We also identified pathogenic variants that are likely amenable to a corrector therapy. Finally, we functionally characterized structural relationships that distinguish the binding of peptide versus small molecule ligands, which could guide compound optimization. Collectively, these results demonstrate that DMS is a powerful method to empower drug discovery and development.
Public RNA-seq data are not representative of global human diversity
Authors: Romero Irene Gallego , Rodenberg Grace , Arner Audrey M. , Li Lani , Beasley Isobel J. , Rossow Ryan , Ryan Nicholas , Wang Selina , Lea Amanda J.
Published: October 2024

The field of human genetics has reached a consensus that it is important to work with diverse and globally representative participant groups. This diverse sampling is required to build a robust understanding of the genomic basis of complex traits and diseases as well as human evolution, and to ensure that all people benefit from downstream scientific discoveries. While previous work has characterized compositional biases and disparities for public genome-wide association (GWAS), microbiome, and epigenomic studies, we currently lack a comprehensive understanding of the degree of bias for transcriptomic studies. To address this gap, we analyzed the metadata for RNA-seq studies from two public databases—the Sequence Read Archive (SRA), representing 795,071 samples from 21,209 studies, and the Database of Genotypes and Phenotypes (dbGaP), representing 167,389 samples from 649 studies. We also randomly selected 620 studies from SRA for detailed, manual evaluation. We found that 3% of samples in SRA and 21% of individuals described in the literature had population descriptors (race, ethnicity, or ancestry); 28% of samples in dbGaP had paired genotype data that was used to empirically infer ancestry. In SRA, dbGaP, and the literature, race, ethnicity, and ancestry terms were frequently conflated and difficult to disambiguate. After standardizing population descriptors, we observed many clear biases: for example, among samples in SRA that were coded using US Census terms, 69.0% came from white donors, corresponding to an 1.2x overrepresentation of this group relative to the US population. Among samples in SRA coded using continental ancestry labels, 55.6% came from European ancestry donors—an 4.1x overrepresentation of this group relative to the global population. These biases were generally similar across datasets (SRA, dbGaP, literature review), and were comparable to previous reports for other ‘omics data types. However, we note that, relative to other ‘omics data subsets like GWAS, there is considerably less information, of arguably worse quality, about who is participating in RNA-seq studies. Together, these results demonstrate a critical need to improve our thoughtfulness, consistency, and effort around reporting population descriptors in RNA-seq studies, and to more generally strive for greater diversity in this important data type.
Tone at the top, corporate irresponsibility and the Enron emails
Authors: Taylor-Neu Kieran , Rahaman Abu S. , Saxton Gregory D. , Neu Dean
Published: October 2024

Purpose

This study aims to examine whether senior Enron executive emails celebrated, or at least left a space for, corporate irresponsibility. Engaging with prior organizational-focused research, we investigate how corporate emails sent by senior executives help constitute Enron by communicating to employees senior management’s stance about important topics and social characters.

Design/methodology/approach

The study analyzes the 527,356 sentences contained in 144,228 emails sent by Enron senior executives and other employees in the three-year period (1999–2001) before the company’s collapse. Sentences are used as the base-level speech unit because we are interested in identifying the tone and emotions expressed about specific topics and stakeholders. Tone is measured using Loughran and McDonald’s (2016) financial dictionary approach, and emotion is measured using Mohammad and Turney’s (2013) NRC word-emotion lexicon. Least Absolute Shrinkage and Selection Operator (LASSO) regressions are used to explore the determinants of senior management tone and emotions.

Findings

The analysis illustrates that while both senior executives and other employees utilized email to help accomplish task-related activities, they employed different evaluative tones to talk about key topics and stakeholders. Also important is what is left unsaid, with a “spiral of silence” emanating from senior management that created a space for corporate irresponsibility.

Originality/value

Combining advanced computerized textual analysis with qualitative techniques, we analyze a unique dataset to explore micro details involved in using email to communicate a tone at the top. The findings illustrate how what is said or not said by senior management contributes to the constitution of an organization.
Determinants of bank deposit in a small economy’s banking sector: a study of Fiji
Authors: Chand Shasnil Avinesh , Kumar Ronald Ravinesh , Stauvermann Peter Josef
Published: October 2024

Purpose

Deposits, a liability component of banks’ balance sheet, are an important source of funding for commercial and retail banks. In this study, the authors consider deposits as dependent variable and examine factors (bank-specific, macrofinance and structural) that could plausibly explain deposits. Subsequently, the findings are expected to support analysts, bank managers and regulators, especially in small economies such as Fiji, for asset–liability management.

Design/methodology/approach

This study uses a balanced panel of six commercial banks and two credit institutions over the period 2000–2022. To control for bank heterogeneity, a fixed-effect regression method is used.

Findings

Bank-specific variables such as bank size, profitability, loan-to-deposit ratio and bank stability are positively associated with bank deposits, whereas the capital adequacy ratio is negatively associated with bank deposits. Macroeconomic variables such as remittances and gross domestic product per capita are positively associated with bank deposits. Moreover, institutional variables such as control of corruption, political stability and regulatory quality are positively associated with bank deposits. However, tail events such as the global financial crisis of 2007–09 and the COVID-19 pandemic negatively influence bank deposits. Structural breaks for 2007 and 2011 of two banks (Bank of the Baroda and Bank of the South Pacific, respectively) are positively associated with bank deposits.

Originality/value

Previous studies have considered profitability, competition, nonperforming loans and stability of banks in Fiji. To the best of the authors’ knowledge, this study is the first to consider the determinants of bank deposits, an important source of funds for banks in many small countries including Fiji. In addition, this study examines the impact of structural breaks, tail events such as the recent pandemic (COVID-19) and institutional variables.
Design and kinematics of a novel rigid-flexible coupling hybrid robot for aeroengine blades in situ repair
Authors: Wu Mengli , Xu Yilong , Wang Xuhao , Liu Hao , Li Guanhao , Wang Chengfa , Cao Yiran , Guo Zhiyong
Published: October 2024

Purpose

This paper aims to present the mechanical design and kinematics of a novel rigid-flexible coupling hybrid robot to develop a promising aeroengine blades in situ repair technology.

Design/methodology/approach

According to requirements analysis, a novel rigid-flexible coupling hybrid robot is proposed by combining a three degrees of freedom (DOF) parallel mechanism with a flexible continuum section. Then the kinematics models of both parallel mechanism and flexible continuum section are derived respectively. Finally, based on equivalent joint method, a two-step numerical iterative inverse kinematics algorithm is proposed for the whole robot: (1) the flexible continuum section is equivalently transformed to a 2-DOF spherical joint, thus the approximate analytical inverse kinematic solution can be obtained; (2) the accurate solution is derived by an iterative derivation of both parallel mechanism and flexible continuum section.

Findings

To verify structure scheme and the proposed kinematics modeling method, numerical simulations and prototype experiments are implemented. The results show that the proposed kinematics algorithm has sufficient accuracy and computational efficiency in the whole available workspace, that is end-effector position error and orientation error are less than 0.2 mm and 0.01° respectively, and computation time is less than 0.22s.

Originality/value

A novel rigid-flexible coupling hybrid robot for aeroengine blades in situ repair is designed. A two-step numerical iterative inverse kinematics algorithm is proposed for this unique hybrid robots, which has good accuracy and computational efficiency.
Exploring workplace well-being strategies in Iranian public organizations: a mixed methods study
Authors: Ghanbary Vanani Raziyeh , Danaee Fard Hassan , Kazemi Seyed Hossein , Delkhah Jalil
Published: October 2024

Purpose

To ensure effective national governance, it is essential to enhance employees' well-being in the workplace. Employees with good mental and physical health are more likely to demonstrate a high level of commitment and engagement in advancing public policy objectives, which serve as instruments of public will. A comprehensive understanding of the various effective strategies to improve workplace well-being is indispensable to formulating human resource management policies within the public sector. Therefore, this study aims to uncover and prioritize the key strategies, programs and actions that contribute to enhancing the workplace well-being of public employees in Iran, drawing from their perspectives and experiences.

Design/methodology/approach

We conducted a mixed-method study incorporating both qualitative and quantitative phases to recognize and measure these strategies. In the first phase, a qualitative content analysis was carried out based on the perspectives of Iranian public sector employees. In the subsequent phase, a questionnaire derived from the qualitative findings was randomly distributed to 374 employees from 14 public organizations.

Findings

Workplace well-being strategies can be summarized according to the level of their importance as follows: employees' well-being through “inter-personal relationship,” “systems,” “technologies,” “structure,” “culture” and “environment” within the organization. These strategies as six themes divided into 13 categories and 60 subcategories of programs and actions to promote employee well-being in the work setting.

Originality/value

The importance of considering employees' perspectives on workplace well-being is highlighted as a crucial aspect, rather than depending exclusively on managerial viewpoints for the implementation of well-being initiatives. Adopting an integrated and holistic approach to workplace well-being through strategies, programs and actions is another significant contribution of this study.
Threats and forced displacement in Colombia: an analysis based on municipal data
Authors: Vargas Marlyn Vanessa
Published: October 2024

Purpose

This paper aims to examine the role of threats in the forced displacement of populations from their municipalities of origin in Colombia that is among the nations with the highest number of internally displaced people in the world with 6.7 million victims.

Design/methodology/approach

The data cover the period 2011–2017 and were obtained from the Unit for Attention and Integral Reparation to Victims. Using general panel data models and a difference-in-differences identification strategy, this paper finds that threats within the context of the armed conflict show a positive and significant contribution to forced displacement in municipalities.

Findings

Direct intimidations by illegal armed groups to the population seem to have an influence on the decision of the threatened person to leave the territory in general, although it is not a proportional reaction due to the fact that some victims of intimidations decide not to move to keep their assets and maintain territorial ties.

Research limitations/implications

The study highlights that the implementation of the Peace Agreements signed in 2016 and the negotiation with illegal armed groups is an effort that the Colombian State must strengthen to prevent the occurrence of threats.

Originality/value

This paper’s contribution to the literature is twofold: the paper reveals that rising threats encourage forced displacement in Colombia, by embracing a municipality panel data perspective and a difference-in-differences design that were not applied in previous studies; and the results offer suggestive evidence of the importance of decreasing threats for positive peace outcomes, especially in the most affected territories.
Organizational formalization neutralizes the effect of leader trait anger and vision on follower trust in the leader
Authors: Collins Michael , Li Yiqiong , Brienza Justin P. , Restubog Simon
Published: October 2024

Purpose

We integrate trait, individual differences and substitutes for leadership theories to examine how leader trait anger influences leader vision and follower trust in the leader across high versus low levels of organizational formalization.

Design/methodology/approach

We obtained data from two independent multi-source samples from different occupations and countries. Sample 1: leader–follower dyads (n = 179) collected over three measurement periods from the Philippines; Sample 2: cross-correlational sample of leaders (n = 166), their manager (n = 166) and their followers (n = 610) from Australia.

Findings

We tested our hypotheses using PROCESS (Hayes, 2018) and found that leader trait anger influenced follower trust in the leader both directly and indirectly through leader vision (Samples 1 & 2). We also found that organizational formalization neutralized the effect of leader vision on follower trust in the leader (Sample 2).

Research limitations/implications

While we used a time-lagged design in Sample 1, we cannot make strong causal claims as might be the case in an experimental study, for example.

Practical implications

Our results highlight the adverse effect of leader trait anger on perceptions of leader vision and follower trust in the leader, which we suggest should be considered in recruitment and promotion decisions. Our findings also suggest that high levels of organizational formalization may undermine the motivational effect of leader vision on followers, which should be considered in relation to organizational rules and procedures.

Originality/value

This research enhances our understanding of a previously unexplored boundary condition (i.e. organizational formalization) that appears to neutralize the motivational effect of leader vision. In addition, it highlights the ubiquitous effect of trait anger, in this case undermining the effectiveness of leader vision and trust in the leader, from two different observer perspectives (i.e. leaders’ followers and managers).
Chemical compositions and oxidative stabilities of cold‐pressed walnut oils (Juglans regia L.): Effects of chemical refining, water degumming, and molecular distillation
Authors: Liu Longfei , Cai Hongling , Zhang Youfeng , Jin Qingzhe , Wang Xingguo , Jin Jun
Published: October 2024

Walnut oils are of important academic and economic value, and are becoming one of the most important woody oils. Accurate and moderate refining techniques are required to produce high‐quality walnut oils. In this work, walnut oils obtained from cold processing were refined in three typical techniques, mainly chemical refining, water degumming, and molecular distillation. Physicochemical properties (acid value and peroxide value [POV]), minor components (tocopherol, polyphenols, and phytosterol), oxidative stability indices, and volatile compounds were analyzed to find out the appropriate refining method for the cold‐pressed walnut oils. Quality indices of all the refined oils from the three different refining methods met the requirements of the national standard, of which the POV of chemically refined oil (0.241 g/100 g) was higher than crude oil (0.058 g/100 g). Water degumming was most suitable for retaining of bioactive compounds, for example, the tocopherol was 259.40 mg/kg, the polyphenols was 44.54 mg GAE/kg, and the phytosterol was 987.32 mg/kg, but oxidation stability of the obtained oil (3.09 h) was lower than that of molecular distilled oil (4.18 h). Initial physicochemical properties especially the POV had a significant impact on oxidation stability. There is a trade‐off between the retention of nutrients and extending shelf life, indicating appropriate refining techniques should be developed; that is, water degumming is suggested to be involved in producing high‐quality cold‐pressed walnut oils.