bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidermal Growth Factor Receptor Signaling Governs the Host Inflammatory Response to Invasive Aspergillosis
Authors: Liu Hong , Lin Jianfeng , Phan Quynh T. , Bruno Vincent M. , Filler Scott G. 
Published: September 2024

AbstractThe epidermal growth factor receptor (EGFR) has been identified as an epithelial cell receptor for Mucorales fungi andCandida albicans. Blocking EGFR with small molecule inhibitors reduces disease severity in mouse models of mucormycosis and oropharyngeal candidiasis. In contrast, cases of invasive aspergillosis have been reported in cancer patients who were treated with EGFR inhibitors, suggesting that EGFR signaling may play a protective role in the host defense against this infection. Here, we analyzed transcriptomic data from the lungs of mice with invasive aspergillosis and found evidence thatAspergillus fumigatusinfection activates multiple genes that are predicted to function in the EGFR signaling pathway. We also found thatA. fumigatusinfection activates EGFR in both a human small airway epithelial (HSAE) cell line and in the lungs of immunosuppressed mice. EGFR signaling in HSAE cells is required for maximal endocytosis ofA. fumigatusand for fungal-induced proinflammatory cytokine and chemokine production. In a corticosteroid immunosuppressed mouse model of invasive pulmonary aspergillosis, inhibition of EGFR with gefitinib decreased whole lung chemokine levels and reduced accumulation of phagocytes in the lung, leading to a decrease in fungal killing, an increase in pulmonary fungal burden, and accelerated mortality. Thus, EGFR signaling is required for pulmonary epithelial cells to orchestrate the host innate immune defense against invasive aspergillosis in immunosuppressed hosts.ImportanceWhenA. fumigatusinfects the lungs, it invades epithelial cells that line the airways. During this process, the fungus interacts with epithelial cell receptors. This interaction stimulates epithelial cells to endocytose the fungus. It also induces these cells to secret proinflammatory cytokines and chemokines that recruit phagocytes to the site of infection where they can kill the fungus. Here, we show that in small airway epithelial cells, the epidermal growth factor receptor (EGFR) acts a sensor forA. fumigatusthat triggers the production of chemokines in response to fungal infection. In corticosteroid-immunosuppressed mice, blocking EGFR with the kinase inhibitor, gefitinib reduces chemokine production in the lungs. This leads to decreased accumulation of neutrophils and dendritic cell in the lungs, reducedA. fumigatuskilling, and increased mortality. These results provide a potential explanation as to why some cancer patients who are treated with EGFR inhibitors develop invasive aspergillosis.
The fission yeast SUMO-targeted Ubiquitin Ligase Slx8 functionally associates with clustered centromeres and the silent mating type region at the nuclear periphery
Authors: Chakraborty Shrena , Strachan Joanna , Schirmeisen Kamila , Besse Laetitia , Mercier Eve , Fréon Karine , Zhang Haidao , Zhao Ning , Bayne Elizabeth H , Lambert Sarah AE 
Published: September 2024

AbstractThe SUMO-targeted Ubiquitin ligase (STUbL) family is involved in multiple cellular processes via a wide range of mechanisms to maintain genome stability. One of the evolutionarily conserved functions of STUbL is to promote changes in the nuclear positioning of DNA lesions, targeting them to the nuclear periphery. InSchizossacharomyces pombe, the STUbL Slx8 is a regulator of SUMOylated proteins and promotes replication stress tolerance by counteracting the toxicity of SUMO conjugates. In order to study the dynamic dialectic between Ubiquitinylation and SUMOylation in the nuclear space of theS. pombegenome, we analyzed Slx8 localization. Unexpectedly, we did not detect replication stress-induced Slx8 foci. However, we discovered that Slx8 forms a single nuclear focus, enriched at the nuclear periphery, which marks both clustered centromeres at the spindle pole body and the silent mating type region. The formation of this single Slx8 focus requires the E3 SUMO ligase Pli1, poly-SUMOylation and the histone methyl transferase Clr4 that is responsible for the heterochromatin histone mark H3-K9 methylation. Finally, we established that Slx8 promotes centromere clustering and gene silencing at heterochromatin domains. Altogether, our data highlight evolutionarily conserved and functional relationships between STUbL and heterochromatin domains to promote gene silencing and nuclear organization.HighlightsTheS. pombeSTUbL Slx8 forms a single nuclear focus enriched at the nuclear periphery in a SUMO-chain-dependent manner.Slx8 foci mark clustered centromeres and the silenced mating type region but not telomeres.H3-K9 methylation by Crl4 promotes the single nuclear Slx8 focusSlx8 promotes centromere clustering and gene silencing.
Mutations Leading to Ceftolozane/Tazobactam and Imipenem/Cilastatin/Relebactam Resistance Duringin vivoexposure to Ceftazidime/Avibactam inPseudomonas aeruginosa
Authors: Rapsinski Glenn J. , Rokes Alecia B. , Van Tyne Daria , Cooper Vaughn S. 
Published: September 2024

ABSTRACTIdentifying resistance mechanisms to novel antimicrobials informs treatment and antimicrobial development, but frequently identifies multiple candidate resistance mutations without resolving the driver mutation. Using whole genome sequencing of longitudinalPseudomonas aeruginosathat developed imipenem/cilastatin/relebactam and ceftolozane/tazobactam resistance during ceftazidime/avibactam treatment, we determined mutations resulting in cross-resistance. Penicillin-binding proteinftsI, transcriptional repressorbepR, and virulence regulatorpvdSwere found in resistant isolates. We conclude that peptidoglycan synthesis gene mutations can alter the efficacy of multiple antimicrobials.
Transendothelial migration of the Lyme disease spirochete involves spirochete internalization as an intermediate step through a transcellular pathway that involves Cdc42 and Rac1
Authors: Alvarez-Olmedo Daiana , Kamaliddin Claire , Verhey Theodore B. , Ho May , DeVinney Rebekah , Chaconas George 
Published: September 2024

ABSTRACTDespite its importance in pathogenesis, the hematogenous dissemination pathway ofB. burgdorferiis still largely uncharacterized. To probe the molecular details of transendothelial migration more easily, we studied this process using cultured primary or telomerase-immortalized human microvascular endothelial cells in a medium that maintains both the human cells and the spirochetes. InB. burgdorferiinfected monolayers we observed ∼55% of wild-type spirochetes crossing the monolayer. Microscopic characterization revealed entrance points across the cellular surface rather than at cellular junctions, supporting a transcellular route. In support of this pathway, locking the endothelial junctions using a VE-PTP inhibitor did not reduce transendothelial migration. We also used inhibitors to block the most common endocytic pathways to elucidate effectors that might be involved inB. burgdorferiuptake and/or transmigration. Directly inhibiting Cdc42 reduced spirochete transmigration by impeding internalization. However, blocking Rac1 alone dramatically reduced transmigration and resulted in a concomitant increase in spirochete accumulation in the cell. Our combined results support thatB. burgdorferiinternalization is an intermediate step in the transendothelial migration process which requires both Cdc42 and Rac1; Cdc42 is needed for spirochete internalization while Rac1 is required for cellular egress. These are the first two host proteins implicated inB. burgdorferitransmigration across endothelial cells.IMPORTANCELyme borreliosis is caused byBorrelia burgdorferiand related bacteria. It is the most common tick-transmitted illness in the Northern Hemisphere. The ability of this pathogen to spread to a wide variety of locations results in a diverse set of clinical manisfestations, yet little is known regarding vascular escape of the spirochete, an important pathway for dissemination. Our current work has studied the traversal ofB. burgdorferiacross a monolayer of microvascular endothelial cells grown in culture. We show that this occurs by passage of the spirochetes directly through these cells rather than at cellular junctions and that internalization ofB. burgdorferiis an intermediate step in the transmigration process. We also identify the first two host proteins, Cdc42 and Rac1, that are used by the spirochetes to promote traversal of the cellular monolayer. Our new experimental system also provides a new avenue for further studies of this important process.
Mechanism of Actin Filament Severing and Capping by Gelsolin
Authors: Barrie Kyle R. , Rebowski Grzegorz , Dominguez Roberto 
Published: September 2024

AbstractGelsolin is the prototypical member of a family of Ca2+-dependent F-actin severing and capping proteins. A structure of Ca2+-bound full-length gelsolin at the barbed end shows domains G1G6 and the inter-domain linkers wrapping around F-actin. Another structure shows domains G1G3, a fragment produced during apoptosis, on both sides of F-actin. Conformational changes that trigger severing occur on one side of F-actin with G1G6 and on both sides with G1G3. Gelsolin remains bound after severing, blocking subunit exchange.
Anti-phase clustering of regulatory factors shapes gene transcription burst
Authors: Li Bitong , Wong Yew Yan , Flores-Rodriguez Neftali , Davidson Tara , Graus Matthew S , Smialkovska Valeriia , Ohishi Hiroaki , Feldmann Angelika , Ochiai Hiroshi , Francois Mathias 
Published: September 2024

AbstractThe ability of stem cells to divide and self-renew depends on a complex choreography of molecular events that maintain the transcriptional oscillation of pluripotency genes. Only a handful of transcription factors (TFs) are necessary to preserve pluripotency and reprogram differentiated cells into stem cells. Paradoxically, while the protein players are known, the challenge remains to decipher the series of steps that TFs undertake to modulate “on” and “off” fluctuations of gene transcription. In this study, we employ a trimodal imaging approach that integrates single-molecule tracking of SOX2 mobility,Nanoglocus diffusion, and real-timeNanogmRNA synthesis (STEAMING-tag reporter) to observe the coordinated activity of this molecular machinery. This combined system uncovered the temporal clustering dynamics of endogenous SOX2 occupancy at theNanoglocus and reveal how these dynamics relate to both transcriptional activity and the underlying chromatin behaviour in live embryonic stem cells. We link different types of SOX2 binding modes to roles in both transcriptional activation and termination or nucleosome repackaging. This redefines a dual function for SOX2 at the same gene locus during both gene expression and silencing processes. This work exposes a new layer of TF regulation, indicating a priming role rather than direct transcription initiation directly relevant to mammalian stem cell biology.
Autophagy across tissues of aging mice
Authors: Carosi Julian M. , Martin Alexis , Hein Leanne K. , Hassiotis Sofia , Hattersley Kathryn J. , Turner Bradley J , Fourrier Célia , Bensalem Julien , Sargeant Timothy J. 
Published: September 2024

AbstractAutophagy is a ‘waste-disposal’ pathway that protects against age-related pathology. It is widely accepted that autophagy declines with age, yet the role that sex and diet-related obesity play during aging remain unknown. Here, we present the most comprehensivein vivostudy of autophagic flux to date. We employed transgenic mice overexpressing tandem-florescent LC3B (RFP-GFP-LC3B) to measure autophagic flux in the blood (PBMCs), heart, and motor cortex neurons of aging mice that were fed regular chow or a high-fat diet for 6-, 12- or 18-months. In male mice, aging decreased autophagic flux in the heart, increased it in the blood, and had no effect in motor cortex neurons. Age-dependent changes autophagic flux were less pronounced in female mice. High-fat diet influenced autophagic flux in the blood and heart of male but not female mice. Overall, we uncovered sexual dimorphisms that underpin how autophagy changes with age across different tissues and in response to a high-fat diet.
A proteome-wide dependency map of protein interaction motifs
Authors: Marie Ambjørn Sara , Meeusen Bob , Kliche Johanna , Wang Juanjuan , Garvanska Dimitriya H. , Kruse Thomas , Lopez Mendez Blanca , Mann Matthias , Mailand Niels , Hertz Emil P.T. , Davey Norman E. , Nilsson Jakob 
Published: September 2024

AbstractShort linear motifs (SLiMs) are the most ubiquitous protein interaction modules in the unstructured regions of the human proteome. Despite their central role in protein function, our understanding of the contribution of SLiMs to cellular homeostasis remains limited. To address this, we designed base editor libraries to precisely mutate all curated SLiMs and a set of computationally predicted instances defined by SLiM-like evolutionary patterns. By targeting 7,293 SLiM containing regions with 80,473 mutations, we define a SLiM dependency map identifying 450 known and 264 predicted SLiMs required for normal cell proliferation. Notably, the vast majority of essential predicted SLiMs belong to novel classes of SLiMs. We also uncover the binding partners of several predicted SLiMs and provide mechanistic insight into disease causing mutations. Our study provides a proteome-wide resource on SLiM essentiality and highlights the presence of numerous uncharacterised essential SLiMs in the human proteome.
Single molecule Lipid Biosensors Mitigate Inhibition of Endogenous Effector Proteins
Authors: Holmes Victoria , Ricci Morgan M. C. , Weckerly Claire C. , Worcester Michael , Hammond Gerald R. V. 
Published: September 2024

Genetically encoded lipid biosensors uniquely provide real time, spatially resolved kinetic data for lipid dynamics in living cells. Despite clear strengths, these tools have significant drawbacks; most notably, lipid molecules bound to biosensors cannot engage with effectors, potentially inhibiting signaling. Here, we show that although PI 3-kinase (PI3K)-mediated activation of Akt is not significantly reduced in a cell population transfected with a PH-Akt1 PIP3/PI(3,4)P2biosensor, single cells expressing PH-Akt at visible levels have reduced activation. Tagging endogenous AKT1 with neonGreen reveals its EGF-mediated translocation to the plasma membrane. Co-transfection with the PH-Akt1 or other PIP3biosensors eliminates this translocation, despite robust recruitment of the biosensors. Inhibition is even observed with PI(3,4)P2-selective biosensor. However, expressing lipid biosensors at low levels, comparable with those of endogenous AKT, produced no such inhibition. Helpfully, these single-molecule biosensors revealed improved dynamic range and kinetic fidelity compared with over-expressed biosensor. This approach represents a non-invasive way to probe spatiotemporal dynamics of PI3K signaling in living cells.eTOC summaryHolmes and colleagues show that AKT activation is blocked by commonly used PIP3biosensors, but that this can be overcome by expressing biosensors at single molecule levels – which also improves kinetic fidelity and sensitivity.
Split Majoron model confronts the NANOGrav signal and cosmological tensions
Authors: Di Bari Pasquale , Rahat Moinul Hossain 
Published: September 2024

In the light of the evidence of a gravitational wave background from the NANOGrav 15 yr dataset, we reconsider the split Majoron model as a new physics extension of the standard model able to generate a needed contribution to solve the current tension between the data and the standard interpretation in terms of inspiraling supermassive black hole massive binaries. In the split Majoron model the seesaw right-handed neutrinos acquire Majorana masses from spontaneous symmetry breaking of global U(1)B−L in a strong first order phase transition of a complex scalar field occurring above the electroweak scale. The final vacuum expectation value couples to a second complex scalar field undergoing a low scale phase transition occurring after neutrino decoupling. Such a coupling enhances the strength of this second low scale first order phase transition and can generate a sizeable primordial gravitational wave background contributing to the NANOGrav 15 yr signal. Some amount of extraradiation is generated after neutron-to-proton ration freeze-out but prior to nucleosynthesis. This can be either made compatible with the current upper bound from primordial deuterium measurements or even be used to solve a potential deuterium problem. Moreover, the free streaming length of light neutrinos can be suppressed by their interactions with the resulting Majoron background, and this mildly ameliorates existing cosmological tensions. Thus cosmological observations nicely provide independent motivations for the model.

Published by the American Physical Society
2024
Managing supply chain disruptions in pharmaceutical distribution: the roles of disruption orientation and mitigation strategies
Authors: Abdallah Ayman Bahjat , Al Bourini Bara' Omar , Al-Shorman Hussam Mohd 
Published: September 2024

PurposeThe present study investigates the impact of supply chain disruption orientation (SCDO) on four supply chain disruption (SCD) mitigation strategies: supply chain integration (SCI), supply chain agility (SCA), supply chain visibility (SCV) and supply chain redundancy (SCR). It also examines the impact of the four mitigation strategies on SCD. The impact of the latter on business performance (BP) is also explored.Design/methodology/approachThis study employs an empirical approach through survey research methodology. It analyzes data collected from 304 managers from pharmaceutical distribution companies in Jordan. Appropriate validity and reliability tests were employed for the study constructs. Path analysis using AMOS software was performed to test the study hypotheses.FindingsSCDO was found to positively affect all SCD mitigation strategies. Furthermore, among the four mitigation strategies examined, SCV exhibited the highest significant impact in reducing SCD, followed by SCA and then SCR. However, the results revealed that SCI did not significantly impact SCD. Additionally, SCD proved to be negatively and significantly related to BP.Originality/valueThe present study fills a gap in the literature regarding the management of SCDs in pharmaceutical supply chains (SCs) generally and SCs of pharmaceutical distribution companies specifically. It also addresses an under-investigated area in the literature concerning the role of SCDO in promoting the adoption of SCD mitigation strategies.
Ownership structure characteristics and banks performance
Authors: Emengini Emeka Steve , Moguluwa Shedrach Chinwuba , Aernan Johnson Emberga , Anago Jude Chidiebere 
Published: September 2024

Purpose
This paper aims to examine the impact of ownership structure on the accounting-based performance of listed Nigerian deposit money banks (DMBs) on Nigerian Exchange Group (NGX) from 2011 to 2020.

Design/methodology/approach
The study adopts ex post facto research design, using initially “the panel fixed and random effects regression analysis and Hausman specification test and thereafter, the IV Generalised method of moments (GMM) to check for endogeneity issues and strengthen the robustness of the results.

Findings
The one lagged value result reveals that ownership structure of DMBs in Nigeria has cumulative significant impact to influence corporate financial performance of the banks in the future. Overall, CEO, board/managerial, family, government and foreign ownership structures in DMBs in Nigeria do not have significant influence on accounting-based corporate financial performance of the banks. However, the study reveals that board/managerial ownership could significantly improve market value/growth of DMBs in Nigeria.

Practical implications
Policy makers, investors (both local and foreign), academics, corporate governance administrators, and the government could apply the study's findings to the management of banking operations in Nigeria.

Originality/value
The paper highlights the impact of five ownership structures on the accounting-based performance of DMBs in Nigeria from 2011 to 2020, providing valuable insights into the influence of stockholding categories on corporate financial performance, which is a shift from extant literatures with limited insights.
An empirical study on the implications of social media for sustainable construction and productivity in Lagos State, Nigeria
Authors: Oke Ayodeji Emmanuel , Aliu John , Ukaha Onyeukwu Samuel , Jamir Singh Paramjit Singh , Azura Ramli Rosfaraliza , Shaharudin Samsurijan Mohamad 
Published: September 2024

PurposeDespite the growing use of Fourth Industrial Revolution (4IR) technologies in construction, the reasons behind adopting social media in this context and its real benefits for sustainable construction and productivity remain unclear. This study aims to examine how construction professionals perceive the impact of social media on sustainable construction and productivity in the industry.Design/methodology/approachThis research used a mixed-methods research approach (qualitative and quantitative), resulting in the formulation of a well-structured questionnaire which was distributed to construction professionals. Ordinal regression and multinomial logistic regression were carried out to assess the impact of social media use on sustainable construction and productivity enhancement, as well as the extent of social media utilization in construction projects.FindingsThrough exploratory factor analysis, five distinct clusters of social media consequences were identified, namely: information and knowledge sharing, community engagement and morale, environmental and resource management, disruptive and stressful effects and communication and collaboration. Furthermore, the extent of social media usage is closely related to three key factors: community engagement and morale, environmental and resource management and communication and collaboration.Originality/valueThis study represents one of the pioneering research efforts in Nigeria to investigate the implications of social media usage in the construction industry. Thus, future studies can build upon this research to further contribute to the multifaceted dimensions of social media’s impact on the construction industry.