bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early life stress-induced miR-708-5p regulates mood disorder-associated behavioural phenotypes in mice and is a potential diagnostic biomarker for bipolar disorder
Authors: Gilardi Carlotta , Martins Helena C. , Bianco Alessandra Lo , Bicker Silvia , Germain Pierre-Luc , Gross Fridolin , Sungur Ayse Özge , Kisko Theresa M. , Stein Frederike , Meinert Susanne , Schwarting Rainer K. W. , Wöhr Markus , Dannlowski Udo , Kircher Tilo , Schratt Gerhard 
Published: March 2024

AbstractMood-disorders (MDs) are caused by a complex interplay of genetic and environmental (GxE) risk factors. However, the molecular pathways engaged by GxE risk factors to trigger specific MD-associated endophenotypes are still poorly understood. Here, by using unbiased small RNA sequencing in peripheral blood mononuclear cells (PBMCs), we identified the BD-associated miR-708-5p as one of the most strongly upregulated microRNAs in peripheral blood of both healthy human subjects with a high genetic or environmental (early life stress) predisposition to develop MDs. miR-708 is also upregulated in the hippocampus of rats which underwent juvenile social isolation, a rodent model of early life stress. Furthermore, ectopic overexpression of miR-708-5p in the hippocampus of adult male mice is sufficient to elicit MD-associated behavioural endophenotypes, demonstrating a causal role for elevated miR-708-5p levels in MD development. We further show that miR-708-5p directly targets Neuronatin (Nnat), an endoplasmic reticulum (ER) resident protein involved in calcium homeostasis. Consequently, restoring Nnat expression in the hippocampus of miR-708-5p overexpressing mice rescues miR-708-5p dependent behavioural phenotypes. Finally, miR-708-5p is strongly upregulated in PBMCs derived from patients diagnosed with MD, in particular BD males. Peripheral expression of miR-708-5p, in conjunction with the previously identified miR-499-5p, allows to differentiate male BD patients from patients suffering from major depressive disorder (MDD) and healthy controls. In summary, we describe a functional role for the miR-708-5p/Nnat pathway in MD etiology and identify miR-708-5p as a potential biomarker for the differential diagnosis of MDs.
Slippery sequences stall the 26S proteasome at multiple points along the translocation pathway
Authors: Ragwan Edwin R. , Kisker Faith M. , Morning Amelia R. , Weiser Kaya R. , Lago Athena V. , Kraut Daniel A. 
Published: March 2024

AbstractIn eukaryotes, the ubiquitin-proteasome system is responsible for intracellular protein degradation. Proteins tagged with ubiquitin are recognized by ubiquitin receptors on the 19S regulatory particle (RP) of the 26S proteasome, unfolded, routed through the translocation channel of the RP, and are then degraded in the 20S core particle (CP). Aromatic paddles on the pore-1 loops of the RP’s Rpt subunits grip the substrate and pull folded domains into the channel, thereby unfolding them. The sequence that the aromatic paddles grip while unfolding a substrate is therefore expected to influence the extent of unfolding, and low complexity sequences have been shown to interfere with grip. However, the detailed spatial requirements for grip while unfolding proteins, particularly from the N-terminus, remain unknown. We determined how the location of glycine-rich tracts relative to a folded domain impairs unfolding. We find that, in contrast to a previous report, inserting glycine-rich sequences closer to the folded domain reduced unfolding ability more than positioning them further away. Locations that have the biggest effect on unfolding map onto the regions where the aromatic paddles are predicted to interact with the substrate. Effects on unfolding from locations up to 67 amino acids away from the folded domain suggest that there are additional interactions between the substrate and the proteasome beyond the aromatic paddles that facilitate translocation of the substrate. In sum, this study deepens understanding of the mechanical interactions within the substrate channel by mapping the spacing of interactions between the substrate and the proteasome during unfolding.ImportanceThe proteasome processively unfolds and degrades target proteins in eukaryotes. However, some substrates are prematurely released, and the resulting partially degraded proteins can cause problems for cells and can be linked to neurodegenerative diseases. In this paper, we use a series of substrates that can stall the proteasome during degradation to probe the translocation pathway substrates must traverse during unfolding. We find that multiple points along the translocation pathway are impacted by these slippery substrates.
Meiosis-specific functions of kinetochore protein SPC105R required for chromosome segregation inDrosophilaoocytes
Authors: Joshi Jay N. , Changela Neha , Mahal Lia , Defosse Tyler , Jang Janet , Wang Lin-Ing , Das Arunika , Shapiro Joanatta G. , McKim Kim 
Published: March 2024

AbstractThe reductional division of meiosis I requires the separation of chromosome pairs towards opposite poles. We have previously implicated the outer kinetochore protein SPC105R/KNL1 in driving meiosis I chromosome segregation through lateral attachments to microtubules and co-orientation of sister centromeres. To identify the domains of SPC105R that are critical for meiotic chromosome segregation, an RNAi-resistant gene expression system was developed. We found that SPC105R’s C-terminal domain (aa 1284-1960) is necessary and sufficient for recruiting NDC80 to the kinetochore and building the outer kinetochore. Furthermore, the C-terminal domain recruits BUBR1, which in turn recruits the cohesion protection proteins MEI-S332 and PP2A. Of the remaining 1283 amino acids, we found the first 473 are most important for meiosis. The first 123 amino acids of the N-terminal half of SPC105R contain the conserved SLRK and RISF motifs that are targets of PP1 and Aurora B kinase and are most important for regulating the stability of microtubule attachments and maintaining metaphase I arrest. The region between amino acids 124 and 473 are required for two activities that are critical for accurate chromosome segregation in meiosis I, lateral microtubule attachments and bi-orientation of homologs.Significance StatementKinetochore proteins regulate meiosis specific functions. SPC105R is a central regulator of kinetochore function but its role in meiosis is not well understood.We identified regions of SPC105R that regulate key meiosis I functions, including fusing sister centromeres and the way the kinetochore interacts with the microtubules.SPC105R is a hub that recruits several proteins to regulate kinetochore activity. Future work will involve identifying the proteins recruited by SPC105R that mediate these functions in meiosis.
Assessing Individual Sensitivity to the Thermal Grill Illusion: A Two-Dimensional Adaptive Psychophysical Approach
Authors: Sardeto Deolindo Camila , Ehmsen Jesper Fischer , Courtin Arthur S. , Mitchell Alexandra G. , Kraenge Camilla E. , Nikolova Niia , Allen Micah G. , Fardo Francesca 
Published: March 2024

AbstractIn the thermal grill illusion (TGI), the spatial alternation of non-noxious warm and cold temperatures elicits burning sensations that resemble the presence of noxious stimuli. Previous research has largely relied on the use of specific temperature values (i.e., 20°C and 40°C) to study this phenomenon in both healthy individuals and patient populations. However, this methodology fails to account for inter-individual differences in thermal sensitivity, limiting the precision with which TGI responses can be evaluated across diverse populations. To address this gap, we created a Two-Dimensional Thermal Grill Calibration (2D-TGC) protocol, enabling an efficient and precise estimation of the combinations of warm and cold temperatures needed to elicit burning sensations tailored to each individual. By applying the 2D-TGC protocol in 43 healthy participants, we demonstrated key findings: (1) The TGI can be thresholded using an adaptive psychophysical method. (2) Multiple combinations of warm and cold temperatures can elicit this phenomenon. (3) The protocol facilitated the identification of temperature combinations that elicit TGI with varying levels of probability, intensity, and perceived quality ranging from freezing cold to burning hot. (4) TGI responsivity can be quantified as a continuous variable, moving beyond the conventional classification of individuals as responders vs. non-responders based on arbitrary temperature values. The 2D-TGC offers a comprehensive approach to investigate the TGI across populations with altered thermal sensitivity, and can be integrated with other methods (e.g., neuroimaging) to elucidate the mechanisms responsible for perceptual illusions in the thermo-nociceptive system.
CAR T cell infiltration and cytotoxic killing within the core of 3D breast cancer spheroids under control of antigen sensing in microwell arrays
Authors: Cho Youngbin , Laird Matthew , Bishop Teddi , Li Ruxuan , Ruffo Elisa , Lohmueller Jason , Zervantonakis Ioannis K. 
Published: March 2024

AbstractThe success of chimeric antigen receptor (CAR) T cells in blood cancers has intensified efforts to develop CAR T therapies for solid cancers. In the solid tumor microenvironment, CAR T cell trafficking and suppression of cytotoxic killing represent limiting factors for therapeutic efficacy. Here, we present a microwell platform to study CAR T cell interactions with 3D tumor spheroids and determine predictors of anti-tumor CAR T cell function. To precisely control antigen sensing by CAR T cells, we utilized a switchable adaptor CAR system, that instead of directly binding to an antigen of interest, covalently attaches to co-administered antibody adaptors that mediate tumor antigen recognition. Following addition of an anti-HER2 adaptor antibody, primary human CAR T cells exhibited higher infiltration and clustering compared to the no adaptor control. By tracking CAR T cell killing at the individual spheroid level, we showed the suppressive effects of spheroid size and identified the initial CAR T cell : spheroid area ratio as a predictor of cytotoxicity. Spatiotemporal analysis revealed lower CAR T cell numbers and cytotoxicity in the spheroid core compared to the periphery. Finally, increasing CAR T cell seeding density, resulted in higher CAR T cell infiltration and cancer cell elimination in the spheroid core. Our findings provide new quantitative insights into CAR T cell-mediated killing of HER2+ breast tumor cells. Given the miniaturized nature and live imaging capabilities, our microfabricated system holds promise for discovering cell-cell interaction mechanisms that orchestrate antitumor CAR T cell functions and screening cellular immunotherapies in 3D tumor models.
Reduced GABA transmission onto ventral tegmental area dopamine neurons underlies vulnerability for hyperactivity in a mouse model of Anorexia Nervosa
Authors: Ducrocq Fabien , Brouwer Eileen , Kooij Karlijn L. , Wolterink-Donselaar Inge G. , Drost Lisa , Hak Jaimie , Veendijk Melissa , Luijendijk Mieneke C. M. , Meye Frank J. , Adan Roger A. H. 
Published: March 2024

ABSTRACTAnorexia nervosa (AN) has the highest mortality among psychiatric diseases. Hyperactivity is a persistent symptom, which is difficult to control for patients and a major barrier to recovery as it interferes with weight gain. Alteration of mesolimbic dopamine transmission has been hypothesized as a critical factor for the development and maintenance of the disease and for hyperactivity. At what level the changes in dopamine occur in anorexic states and whether local mesolimbic neurocircuit plasticity is causally involved remains unclear. Especially the role of local GABA control over dopamine neurons, a powerful regulator of the dopamine system, in an AN context is unknown. We hypothesize that combining caloric restriction with exercise, such as in the activity-based anorexia (ABA) model, alters dopamine transmission via GABA disinhibition that, in turn, facilitates the expression of maladaptive behaviors such as hyperactivity.Therefore, we characterized the impact of the ABA model on plasticity of the dopamine reward system. In ex-vivo brain slices of mice exposed to this model, ventral tegmental area dopamine (VTADA) neurons displayed a higher firing frequency compared to control mice supporting that the midbrain dopamine system undergoes plasticity. This coincided with reduced GABAergic transmission on VTADAneurons. This reduction was at least in part attributable to local VTA GABA (VTAGABA) neurons. Indeed, VTAGABAneurons were less excitable, displayed a lower firing frequency and a lower probability of release onto VTADAneurons. Restoring the excitability of VTAGABAneurons via chemogenetic activation rescued mice from starvation, by decreasing running wheel activity.In summary, we found that the anorexic state leads to dysregulation of VTAGABAtransmission on VTADAneurons that reinforces maladaptive behaviors such as excessive exercise. We uncovered a new mechanism linked to the disturbed dopamine system in ABA-exposed animals, identifying a hitherto unknown role of decreased local GABAergic control over VTA dopamine neuron output.
A small molecule inhibitor Mirin prevents TOP3A-dependent mtDNA breakage and segregation
Authors: Aasumets Koit , Hangas Anu , Bader Cyrielle P. J. , Erdinc Direnis , Wanrooij Sjoerd , Wanrooij Paulina H. , Goffart Steffi , Pohjoismäki Jaakko L.O. 
Published: March 2024

AbstractMirin, the chemical inhibitor of MRE11, has been recently reported to prevent immune response activation caused by mitochondrial DNA (mtDNA) breakage and release upon replication stalling. We show here that Mirin prevents mitochondrial replication fork breakage in mitochondrial 3’-exonuclease MGME1 deficient cells and the resulting innate immune response induction, but that this occurs independently of MRE11. Furthermore, Mirin also caused alteration of mtDNA supercoiling and accumulation of hemicatenated replication termination intermediates, hallmarks of topoisomerase dysfunction, as well as alleviated topological changes induced by the overexpression of mitochondrial TOP3A, including TOP3A-dependent strand breakage at the non-coding region of mtDNA, potentially explaining its protective effect in the MGME1-knockout cells. Although Mirin does not inhibit TOP3Ain vitro, our results demonstrate its MRE11-independent effects in cells and give insight into the mechanisms of mtDNA segregation, as well as the maintenance of genomic integrity in mitochondria.Significance StatementBroken mitochondrial DNA (mtDNA) inMGME1knockout cells activates innate immune response, which is prevented by Mirin, a small molecule inhibitor of MRE11.Mirin also interferes with mtDNA replication termination and segregation, suggesting that termination intermediates or paused forks are a major source of mtDNA breakage.We show that these effects are likely dependent on topoisomerase 3A (TOP3A) -related processes in mitochondria, questioning the Mirin target also in the nucleus.
A Toolbox forNeisseria meningitidis: Gene Editing, Complementation and Labelling
Authors: Wuckelt Morgane , Laurent Audrey , Mouville Clémence , Meyer Julie , Jamet Anne , Lecuyer Hervé , Nassif Xavier , Bille Emmanuelle , Pelicic Vladimir , Coureuil Mathieu 
Published: March 2024

ABSTRACTThe efficient transformation ofNeisseria meningitidisandNeisseria gonorrhoeaefacilitates the rapid construction of bacterial mutants with insertion of antibiotic resistance cassettes. However, this strategy limits the construction of strains with multiple mutations. Recent advances in markerless strategies forNeisseriaspecies have enabled the construction of mutants without antibiotic resistance markers. However, these innovative approaches have potential limitations related to the selection strategy or the possible occurrence of spontaneous mutations in the selection marker genes. In addition, complementation tools or labelling strategies forN. meningitidisare also lacking. In this study, we have introduced new tools for markerless mutation, genetic complementation and labelling inN. meningitidis, thus improving the research possibilities for understanding and tackling these pathogens.
Regulation of Versican Expression in Macrophages is Mediated by Canonical Type I Interferon Signaling via ISGF3
Authors: Chang Mary Y. , Chan Christina K. , Brune Jourdan E. , Manicone Anne M. , Bomsztyk Karol , Frevert Charles W. , Altemeier William A. 
Published: March 2024

ABSTRACTGrowing evidence supports a role for versican as an important component of the inflammatory response, with both pro- and anti-inflammatory roles depending on the specific context of the system or disease under investigation. Our goal is to understand the regulation of macrophage-derived versican and the role it plays in innate immunity. In previous work, we showed that LPS triggers a signaling cascade involving TLR4, the Trif adaptor, type I interferons, and the type I interferon receptor, leading to increased versican expression by macrophages. In the present study, we used a combination of chromatin immunoprecipitation, siRNA, chemical inhibitors, and mouse model approaches to investigate the regulatory events downstream of the type I interferon receptor to better define the mechanism controlling versican expression. Results indicate that transcriptional regulation by canonical type I interferon signaling via the heterotrimeric transcription factor, ISGF3, controls versican expression in macrophages exposed to LPS. This pathway is not dependent on MAPK signaling, which has been shown to regulate versican expression in other cell types. The stability of versican mRNA may also contribute to prolonged versican expression in macrophages. These findings strongly support a role for macrophage-derived versican as a type I interferon-stimulated gene and further our understanding of versican’s role in regulating inflammation.
Cross section measurements of neutron elastic and inelastic scattering on
Fe54
Authors: Gkatis G. , Diakaki M. , Noguere G. , Nyman M. , Oprea A. , Paradela C. , Pirovano E. , Plompen A. J. M. 
Published: March 2024

Scattering experiments were performed at the Geel Electron Linear Accelerator (GELINA) to determine the differential cross sections of neutron elastic and inelastic scattering on Fe54, using a highly enriched sample. Neutron energies were calculated via the time-of-flight technique. The scattered neutrons were detected using the ELastic and Inelastic Scattering Array (ELISA), a spectrometer consisting of 32 liquid organic scintillators, able to separate neutron and photon induced events via pulse-shape analysis. The detectors are mounted at eight specific angles with respect to the neutron beam direction to allow the concurrent calculation of both the differential and the integral cross section using the Gauss-Legendre quadrature rule. For elastic scattering, angular distributions and integral cross sections were produced in the energy range from 1 to 8 MeV, whereas for inelastic scattering, partial differential and angle integrated cross sections were estimated from the first excited state of Fe54 in the energy range from 2.5 to 5.5 MeV. The results are compared with the available experimental and evaluated nuclear data, as well as with theoretical calculations performed with the TALYS 1.9 and EMPIRE 3.2 codes.

Published by the American Physical Society
2024
Fuel consumption estimation for jet aircraft: a mathematical model development
Authors: Benkhaled Amar , Benkhedda Amina , Benaouda Zouaoui Braham , Ribouh Soheyb 
Published: March 2024

Purpose
Reducing aircraft fuel consumption has become a paramount research area, focusing on optimizing operational parameters like speed and altitude during the cruise phase. However, the existing methods for fuel reduction often rely on complex experimental calculations and data extraction from embedded systems, making practical implementation challenging. To address this, this study aims to devise a simple and accessible approach using available information.

Design/methodology/approach
In this paper, a novel analytic method to estimate and optimize fuel consumption for aircraft equipped with jet engines is proposed, with a particular emphasis on speed and altitude parameters. The dynamic variations in weight caused by fuel consumption during flight are also accounted for. The derived fuel consumption equation was rigorously validated by applying it to the Boeing 737–700 and comparing the results against the fuel consumption reference tables provided in the Boeing manual. Remarkably, the equation yielded closely aligned outcomes across various altitudes studied. In the second part of this paper, a pioneering approach is introduced by leveraging the particle swarm optimization algorithm (PSO). This novel application of PSO allows us to explore the equation’s potential in finding the optimal altitude and speed for an actual flight from Algiers to Brussels.

Findings
The results demonstrate that using the main findings of this study, including the innovative equation and the application of PSO, significantly simplifies and expedites the process of determining the ideal parameters, showcasing the practical applicability of the approach.

Research limitations/implications
The suggested methodology stands out for its simplicity and practicality, particularly when compared to alternative approaches, owing to the ready availability of data for utilization. Nevertheless, its applicability is limited in scenarios where zero wind effects are a prevailing factor.

Originality/value
The research opens up new possibilities for fuel-efficient aviation, with a particular focus on the development of a unique fuel consumption equation and the pioneering use of the PSO algorithm for optimizing flight parameters. This study’s accessible approach can pave the way for more environmentally conscious and economical flight operations.
Inverting the paradigm: digital transformation’s impact on firm performance and the counterintuitive role of gender
Authors: Shehadeh Maha , Alshurafat Hashem , Arabiat Omar 
Published: March 2024

Purpose
This study aims to analyze the impact of digital transformation on firm performance within the banking sector, specifically focusing on the Amman Stock Exchange (ASE)-listed banks from 2015 to 2022. Additionally, it explores the influence of gender dynamics on the implementation and outcomes of these digital transformation initiatives.

Design/methodology/approach
The study adopts a robust empirical approach, using manual content analysis of annual reports from ASE-listed banks. The Digital Transformation Disclosure Index (DTDI) is used to assess the extent and nature of digital transformation initiatives within these banks. The methodology is designed to provide a comprehensive evaluation of the correlation between digital transformation efforts, firm performance and gender dynamics.

Findings
The research reveals that digital transformation initiatives have a significant positive impact on the performance of ASE-listed banks. It also uncovers nuanced insights into the role of gender dynamics, indicating that gender diversity within firms influences the adoption and success of digital transformation strategies in complex ways.

Research limitations/implications
The findings of this study contribute to the understanding of digital transformation in the banking sector, offering empirical evidence on its benefits for firm performance. Additionally, the study illuminates the intricate role of gender dynamics in digital transformation, providing a new perspective on organizational diversity within the context of technological change.

Originality/value
This research pioneers in academically linking digital transformation and gender dynamics within the banking sector, addressing a notable gap and introducing a fresh academic perspective. Practically, it equips banking executives and policymakers with actionable insights for gender-inclusive digital strategies, crucial for enhanced firm performance. Methodologically, the study sets a benchmark in research innovation, using the DTDI to offer a replicable model for future investigations in this evolving field.