bluuebunny/crossref_metadata_2025_split huggingface dataset:
Remodeling of perturbed chromatin can initiatede novotranscriptional and post-transcriptional silencing
Authors: Carlier Florian , Castro Ramirez Sebastian , Kilani Jaafar , Chehboub Sara , Loïodice Isabelle , Taddei Angela , Gladyshev Eugene 
Published: January 2024

ABSTRACTIn eukaryotes, repetitive DNA can become silencedde novo, either transcriptionally or post-transcriptionally, by processes independent of strong sequence-specific cues. The mechanistic nature of such processes remains poorly understood. We found that in the fungusNeurospora crassa,de novoinitiation of both transcriptional and post-transcriptional silencing was linked to perturbed chromatin, which was produced experimentally by the aberrant activity of transcription factors at thetetOoperator array. Transcriptional silencing was mediated by canonical constitutive heterochromatin. On the other hand, post-transcriptional silencing resembled repeat-induced quelling but occurred normally when homologous recombination was inactivated. All silencing of thetetOarray was dependent on SAD-6 (a fungal ortholog of the SWI/SNF chromatin remodeler ATRX), which was required to maintain nucleosome occupancy at the perturbed locus. In addition, we found that two other types of sequences (thelacOarray and native AT-rich DNA) could also undergo recombination-independent quelling associated with perturbed chromatin. These results suggested a model in which thede novoinitiation of transcriptional and post-transcriptional silencing is coupled to the remodeling of perturbed chromatin.SIGNIFICANCE STATEMENTThis study addresses an enigmatic question of how transcriptional and post-transcriptional gene silencing can be initiatedde novoin the absence of strong sequence-specific cues. Using the fungusNeurospora crassaas a model organism, we found that both types of silencing can be triggered in mitotic cells by the remodeling of a transiently perturbed (nucleosome-depleted) chromatin state. In this system, the initiation of silencing requires SAD-6, a conserved SWI/SNF chromatin remodeler orthologous to ATRX that has been already implicated in repetitive DNA silencing in fungi, plants, and animals. Thus, the model proposed in this study may underpin a range of gene-silencing phenomena observed in other eukaryotes.
Generation of natural killer and myeloid cells in a 3D artificial marrow organoid system
Authors: Schell Bérénice , Zhao Lin-Pierre , Kergaravat Camille , Lereclus Emilie , Kalogeraki Maria , Fenaux Pierre , Ades Lionel , Toubert Antoine , Espeli Marion , Balabanian Karl , Clave Emmanuel , Dulphy Nicolas , Bisio Valeria 
Published: January 2024

AbstractThe human bone marrow (BM) microenvironment involves hematopoietic and non-hematopoietic cell subsets organized in a complex architecture. Tremendous efforts have been made to model it in order to analyse normal or pathological hematopoiesis and its stromal counterpart. Herein, we report an original, fully-humanin vitro3D model of the BM microenvironment dedicated to study interactions taking place between mesenchymal stromal cells (MSC) and hematopoietic stem and progenitor cells (HSPC) during the hematopoietic differentiation. This artificial marrow organoid (AMO) model is highly efficient to support NK cell development from the CD34+ HSPC to the terminally differentiated NKG2A-KIR2D+CD57+ NK subset. In addition, myeloid differentiation can also be recapitulated in this model. Moreover, mature NK cell phenotype showed significant differences in the AMO compared to a conventional 2D coculture model for the expression of adhesion molecules and immune checkpoint receptors, thus better reflecting the NK cell behaviour in the BM microenvironment. Lastly, we proved that our model is suitable for evaluating anti-leukemic NK cell function in presence of treatments. Overall, the AMO is a versatile, low cost and simple model able to efficiently recapitulate hematopoiesis and granting better drug response taking into account both immune and non-immune BM microenvironment interactions.Graphical Abstract
MicroRNA-focused CRISPR/Cas9 Screen Identifies miR-142 as a Key Regulator of Epstein-Barr Virus Reactivation
Authors: Chen Yan , Kincaid Rodney P. , Bastin Kelley , Fachko Devin N. , Skalsky Rebecca L. 
Published: January 2024

AbstractReactivation from latency plays a significant role in maintaining persistent lifelong Epstein-Barr virus (EBV) infection. Mechanisms governing successful activation and progression of the EBV lytic phase are not fully understood. EBV expresses multiple viral microRNAs (miRNAs) and manipulates several cellular miRNAs to support viral infection. To gain insight into the host miRNAs regulating transitions from EBV latency into the lytic stage, we conducted a CRISPR/Cas9-based screen in EBV+ Burkitt lymphoma (BL) cells using anti-Ig antibodies to crosslink the B cell receptor (BCR) and induce reactivation. Using a gRNA library against >1500 annotated human miRNAs, we identified miR-142 as a key regulator of EBV reactivation. Genetic ablation of miR-142 enhanced levels of immediate early and early lytic gene products in infected BL cells. Ago2-PAR-CLIP experiments with reactivated cells revealed miR-142 targets related to Erk/MAPK signaling, including components directly downstream of the B cell receptor (BCR). Consistent with these findings, disruption of miR-142 enhanced SOS1 levels and Mek phosphorylation in response to surface Ig cross-linking. Effects could be rescued by inhibitors of Mek (cobimetinib) or Raf (dabrafenib). Taken together, these results show that miR-142 functionally regulates SOS1/Ras/Raf/Mek/Erk signaling initiated through the BCR and consequently, restricts EBV entry into the lytic cycle.
Translation initiation or elongation inhibition triggers contrasting effects onCaenorhabditis eleganssurvival during pathogen infection
Authors: Ghosh Annesha , Singh Jogender 
Published: January 2024

AbstractDiverse microbial pathogens are known to attenuate host protein synthesis. Consequently, the host mounts a defense response against protein translation inhibition, leading to increased transcript levels of immune genes. The seemingly paradoxical upregulation of immune gene transcripts in response to blocked protein synthesis suggests that the defense mechanism against translation inhibition may not universally benefit host survival. However, a comprehensive assessment of host survival on pathogens upon blockage of different stages of protein synthesis is currently lacking. Here, we investigate the impact of knockdown of various translation initiation and elongation factors on the survival ofCaenorhabditis elegansexposed toPseudomonas aeruginosa. Intriguingly, we observe opposing effects onC. eleganssurvival depending on whether translation initiation or elongation is inhibited. While translation initiation inhibition enhances survival, elongation inhibition decreases it. Transcriptomic studies reveal that translation initiation inhibition activates a bZIP transcription factor ZIP-2-dependent innate immune response that protectsC. elegansfromP. aeruginosainfection. In contrast, inhibiting translation elongation triggers both ZIP-2-dependent and ZIP-2-independent immune responses that, while effective in clearing the infection, are detrimental to the host. Thus, our findings reveal the opposing roles of translation initiation and elongation inhibition inC. eleganssurvival duringP. aeruginosainfection, highlighting distinct transcriptional reprogramming that may underlie these differences.
Inferring the selective history of CNVs using a maximum likelihood model
Authors: Malekpour Seyed Amir , Kalirad Ata , Majidian Sina 
Published: January 2024

AbstractCopy number variations (CNVs) – structural variations generated by deletion and/or duplication that result in change in DNA dosage – are prevalent in nature. CNVs can drastically affect the phenotype of an organism and have been shown to be both involved in genetic disorders and be used as raw material in adaptive evolution. Unlike single-nucleotide variations, the often large and varied effects of CNVs on phenotype hinders our ability to infer their selective advantage based on the population genetics data. Here, we present a likelihood-based approach, dubbed PoMoCNV, that estimates the evolutionary parameters of CNVs based on population genetics data. As a case study, we analyze the genomics data of 40 strains ofCaenorhabditis elegans, representing four different populations. We take advantage of the data on chromatin accessibility to interpret the evolutionary parameters of CNVs inferred by PoMoCNV. We further test the reliability of PoMoCNV by estimating the evolutionary parameters of CNVs for mutation-accumulation experiments inC. eleganswith varying levels of genetic drift.SignificanceInferring the evolutionary parameters of copy number variations (CNVs) based on population genetics data is crucial to understand their role in evolution. However, given the diversity in the size and effects of CNVs, such inference poses a challenge. We developed a likelihood-based approach called PoMoCNV to address this issue.
Auranofin induces disulfide bond-mimicking S-Au-S bonds in protein thiol pairs
Authors: Quadros Barsé Laísa , Düchting Petra , Lupilov Natalie , Bandow Julia E. , Krämer Ute , Leichert Lars I. 
Published: January 2024

ABSTRACTAuranofin is an inhibitor of human thioredoxin reductase, clinically used in the treatment of rheumatoid arthritis. More recently, it has been shown to possess strong antibacterial activity. Despite the structural dissimilarity and the independent evolutionary origins of human thioredoxin reductase and its bacterial counterpart (TrxB), inhibition of bacterial thioredoxin reductase is often suggested to be a major factor in auranofin’s antibacterial mode of action. To test this hypothesis, we attempted to determine the mechanism of inhibition of auranofin for bacterial TrxB in the presence of thioredoxin, TrxB’s natural substrate. However, the data obtained in these experiments was not consistent with a specific and exclusive interaction between TrxB and auranofin. Instead, it suggested that auranofin directly interacts with the cysteine thiols in thioredoxin, TrxB’s substrate. Using the fluorescent redox protein roGFP2, we showed that auranofin does indeed directly interact with cysteine pairs in proteins, forming a thiol modification that is similar to, but clearly distinct from a disulfide bond. The Au:S stoichiometries of auranofin-treated roGFP2 and thioredoxin strongly suggest the presence of an S-Au-S bridge between two cysteines in those proteins. These S-Au-S bonds form independent of thioredoxin reductase at a rate that indicates their pertinence in auranofin’s antibacterial mode of action.
Combining RASG12C(ON) inhibitor with SHP2 inhibition sensitises immune excluded lung tumours to immune checkpoint blockade: a strategy for turning cold tumours hot
Authors: Anastasiou Panayiotis , Moore Christopher , Rana Sareena , de Castro Andrea , Tomaschko Mona , Boumelha Jesse , Mugarza Edurne , Blaj Cristina , de Carné Sophie , Goldstone Robert , Smith Jacqueline A.M. , Quintana Elsa , Molina-Arcas Miriam , Downward Julian 
Published: January 2024

ABSTRACTMutant selective drugs targeting the inactive, GDP-bound form of KRASG12Chave been approved for use in lung cancer, but responses are short-lived due to rapid development of resistance. In this study we use a novel covalent tri-complex inhibitor, RMC-4998, that targets RASG12Cin its active, GTP-bound form to investigate treatment of KRAS mutant lung cancer in various immune competent mouse models. While this RASG12C(ON) inhibitor was more potent than the KRASG12C(OFF) inhibitor adagrasib, rapid pathway reactivation was still observed. This could be delayed using combined treatment with a SHP2 inhibitor, RMC-4550, which not only impacted RAS pathway signalling within the tumour cells but also remodelled the tumour microenvironment (TME) to be less immunosuppressive and promoted interferon responses. In an inflamed, “hot”, mouse model of lung cancer, RASG12C(ON) and SHP2 inhibitors in combination drive durable responses by suppressing tumour relapse and inducing development of immune memory, which can also be induced by combination of RASG12C(ON) and PD-1 inhibitors. In contrast, in an immune excluded, “cold”, mouse model of lung cancer, combined RASG12C(ON) and SHP2 inhibition does not cause durable responses, but does sensitise tumours to immune checkpoint blockade, enabling efficient tumour rejection, accompanied by significant TME reorganization, including depletion of immunosuppressive innate immune cells and recruitment and activation of T and NK cells. These preclinical results demonstrate the potential of the combination of RASG12C(ON) inhibitors with SHP2 inhibitors to sensitize anti-PD-1 refractory tumours to immune checkpoint blockade by stimulating anti-tumour immunity as well as by targeting KRAS-driven proliferation in tumour cells.
Griffiths phase in a facilitated Rydberg gas at low temperatures
Authors: Brady Daniel , Bender Jana , Mischke Patrick , Ohler Simon , Niederprüm Thomas , Ott Herwig , Fleischhauer Michael 
Published: January 2024

The spread of excitations by Rydberg facilitation bears many similarities to epidemics. Such systems can be modeled with Monte Carlo simulations of classical rate equations to great accuracy as a result of high dephasing. Motivated by experiments, we theoretically analyze the dynamics of a Rydberg many-body system in the facilitation regime in the limits of high and low temperatures. In the high-temperature limit, a homogeneous mean-field behavior is recovered, while characteristic effects of heterogeneity can be seen in a frozen gas. At high temperatures, the system displays an absorbing-state phase transition and, in the presence of an additional loss channel, self-organized criticality. In a frozen or low-temperature gas, excitations are constrained to a network resembling an Erdős-Rényi graph. We show that the absorbing-state phase transition is replaced with an extended Griffiths phase, which we accurately describe by a susceptible-infected-susceptible model on the Erdős-Rényi network taking into account Rydberg blockade.

Published by the American Physical Society
2024
The impact of legal systems on CEO compensation and bank stability: a cross-country study
Authors: Jardak Maha Khemakhem , Sallemi Marwa , Ben Hamad Salah 
Published: January 2024

Purpose
Remuneration policies may differ from country to country, and their effect on bank stability could be due to the legal framework. Therefore, this study aims to investigate how the legal system impacts the relationship between CEO compensation and bank stability across countries.

Design/methodology/approach
To test the study hypotheses, the authors use panel data of 74 banks operating in ten OECD countries during the period 2009–2016 and apply the generalized moments method regression model to better remediate the endogeneity problem.

Findings
The findings confirm that a country’s banking regulations significantly affect its bank stability. Common law countries have less bank stability than civil law countries. This result can be interpreted by the fact that, in common-law countries, banks’ CEO are strongly protected by the law, so they allocate a large part of bank assets to risky loans to improve their variable remuneration.

Practical implications
The research can help policymakers understand bank stability in one country. Any legal reform would require prior knowledge of how risk-taking may arise in executive compensation.

Originality/value
The contribution is to explain the controversial effect of executive compensation on bank stability in the framework of legal theory. The authors argue that regulators should monitor compensation structures and that the country’s legal origin of law shapes the CEO compensation structure and is a determinant of bank stability. To the best of the authors’ knowledge, there are no studies exploring this field. So, this study tries to shed more light on the dark side of CEOs’ behavior when undertaking risky projects to maximize their remuneration.
Perlmutter visited. Japanese international business strategic orientation transformation in India: progress made and forces against
Authors: Ashta Ashok 
Published: January 2024

PurposeAlthough Asia's rise in the global economy is increasingly recognized, international business (IB) interactions between Japan and India remain under-commented. These interactions are especially salient due to the United Nations Sustainable Development Goal 17 (UN SDG 17), which focuses on partnerships. This study updates and analyzes the strategic orientation of Japanese multinational enterprises (MNEs) in India.Design/methodology/approachFollowing a subjectivist approach, this study employs a constructivist epistemology. Utilizing mixed methods, it obtains primary data from interviews and informal conversations with senior personnel from Japan and India and secondary data from archives. These data then undergo manual organic thematic analysis.FindingsThe study reveals instances of Japanese MNEs diverging from traditional ethnocentric orientations, such as senior management's growing commitment to India. The findings also indicate that the transformation to a polycentric orientation remains incomplete.Practical implicationsThe study uncovers themes impeding a polycentric transformation, offering insights for strengthening international partnerships and emphasizing the necessity of prioritizing local demands and cultural expectations.Social implicationsClues to strengthening IB contribute to attain UN SDG 17, especially given the advanced-emerging characteristics of the Japan–India dyad.Originality/valueThis study’s research makes a novel contribution to the literature on international strategic orientations by providing insights into a rare dyad – namely, Japanese MNE expansion in India. It is also a valuable and timely addition consistent with current beyond-China business diversification trends.
Bi-objective optimization of a multi-mode, multi-site resource-constrained project scheduling problem
Authors: Hessami Shiba , Davari-Ardakani Hamed , Javid Youness , Ameli Mariam 
Published: January 2024

Purpose
This study aims to deal with the multi-mode resource-constrained project scheduling problem (MRCPSP) with the ability to transport resources among multiple sites, aiming to minimize the total completion time and the total cost of the project simultaneously.

Design/methodology/approach
To deal with the problem under consideration, a bi-objective optimization model is developed. All activities are interconnected by finish-start precedence relations, and pre-emption is not allowed. Then, the ɛ-constraint optimization method is used to solve 24 different-sized instances, ranging from 5 to 120 activities, and report the makespan, total cost and CPU time. A set of Pareto-optimal solutions are determined for some instances, and sensitivity analyses are performed to find the impact of changing parameters on objective values.

Findings
Results highlight the importance of resource transportability assumption on project completion time and cost, providing useful insights for decision makers and practitioners.

Originality/value
A novel bi-objective optimization model is proposed to deal with the multi-site MRCPSP, considering both the cost and time of resource transportation between multiple sites. To the best of the authors’ knowledge, none of the studies in the project scheduling area has yet addressed this problem.
Innovations, strategic organizational actions, and sailing-ship effect: illustrated with an IT product
Authors: Kompella Lakshminarayana 
Published: January 2024

Purpose
In socio-technical transition theory, resistance by existing technology and regime resistance plays a key role. The resistance is in the form of intentional improvements; eventually, the regime destabilizes and adopts the new technology, referred to as the sailing-ship effect. Researchers used a structural view and examined it as a strategic action and its relationship with new technology (competitive/symbiotic) in non-fast-changing sailing systems. This study uses a microlevel view and examines it in a fast-changing where products/services are developed by integrating existing technology with new product innovations; their success depends on addressing technical/market uncertainty. This study examines the sailing-ship effect in a fast-changing system and contributes to the socio-technical transition theory.

Design/methodology/approach
The authors need to examine the phenomena of the sailing-ship effect in its setting, and a case-study method is appropriate. The selected case provided diverse analytic and heuristic perspectives to examine the phenomena; therefore, it was a single case study.

Findings
In an IT scenario, the strategic actions decide and realize agility and competitive advantage by formulating appropriate goals with required budgets and coevolutionary changes to resources at product, process and organizational levels, addressing technical/market uncertainty. Moreover, the agility displayed by strategic actions determines the relationship with new technology, which is interspersed. Finally, it provided insights into struggle, navigation and negotiations, forming strategic actions to display the sailing-ship effect.

Research limitations/implications
The study selected a Banking Financial Services and Insurance product of an IT Services company. As start-ups exhibit inherent (emergent) agility, the authors can examine agility as a combination of emergent and strategic actions by selecting a start-up.

Practical implications
The study highlights the strategic actions specific to an IT services company. It developed its product and services by steering clear from IT innovations such as native cloud and continuous deployment. It improved its products/services with necessary organizational changes and achieved the desired agility and competitive advantage. Therefore, organizations devise appropriate strategic actions to combat the sailing-ship effect apart from setting goals and selecting IT innovations.

Originality/value
The study expands the socio-technical transition theory by selecting a fast-changing system. It provided insights into the relationship between existing and new technology and the strategic actions necessary to manage technical and market uncertainty and achieve the desired competitive advantage, or the sailing-ship effect.