bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methodological Challenges using Routine Clinical Care Data for Real-World Evidence: a Rapid Review utilizing a systematic literature search and focus group discussion
Authors: Pfaffenlehner Michelle , Behrens Max , Zöller Daniela , Ungethüm Kathrin , Günther Kai , Rücker Viktoria , Reese Jens-Peter , Heuschmann Peter , Kesselmeier Miriam , Remo Flavia , Scherag André , Binder Harald , Binder Nadine ,   the EVA4MII project
Published: September 2024

AbstractBackgroundThe integration of real-world evidence (RWE) from real-world data (RWD) in clinical research is crucial for bridging the gap between clinical trial results and real-world outcomes. Analyzing routinely collected data to generate clinical evidence faces methodological concerns like confounding and bias, similar to prospectively documented observational studies. This study focuses on additional limitations frequently reported in the literature, providing an overview of the challenges and biases inherent to analyzing routine clinical care data, including health claims data (hereafter: routine data).MethodsWe conducted a literature search on routine data studies in four high-impact journals based on the Journal Citation Reports (JCR) category “Medicine, General & Internal” as of 2022 and three oncology journals, covering articles published from January 2018 to October 2023. Articles were screened and categorized into three scenarios based on their potential to provide meaningful RWE: (1) Burden of Disease, (2) Safety and Risk Group Analysis, and (3) Treatment Comparison. Limitations of this type of data cited in the discussion sections were extracted and classified according to different bias types: main bias categories in non-randomized studies (information bias, reporting bias, selection bias, confounding) and additional routine data-specific challenges (i.e., operationalization, coding, follow-up, missing data, validation, and data quality). These classifications were then ranked by relevance in a focus group meeting of methodological experts. The search was pre-specified and registered in PROSPERO (CRD42023477616).ResultsIn October 2023, 227 articles were identified, 69 were assessed for eligibility, and 39 were included in the review: 11 on the burden of disease, 17 on safety and risk group analysis, and 11 on treatment comparison. Besides typical biases in observational studies, we identified additional challenges specific to RWE frequently mentioned in the discussion sections. The focus group had varied opinions on the limitations of Safety and Risk Group Analysis and Treatment Comparison but agreed on the essential limitations for the Burden of Disease category.ConclusionThis review provides a comprehensive overview of potential limitations and biases in analyzing routine data reported in recent high-impact journals. We highlighted key challenges that have high potential to impact analysis results, emphasizing the need for thorough consideration and discussion for meaningful inferences.
Using TMS-EEG to study the intricate interplay between GABAergic inhibition and glutamatergic excitation during reactive and proactive motor inhibition
Authors: Zhu Tingting , Cao Chenglong , Coxon James , Sack Alexander T. , Leunissen Inge 
Published: September 2024

AbstractBackgroundCombining Transcranial magnetic stimulation (TMS) with electroencephalography (EEG) enables assess TMS-evoked potentials (TEP) and estimate γ-aminobutyric acid (GABA) and glutamatergic neurotransmission across the entire motor inhibition network. The N45 and N100 TEP peaks are associated with GABAa and GABAb signaling, respectively, whereas the N15, P30 and P60 TEPs reflect glutamatergic neurotransmission. This study applied TMS-EEG to investigate modulation of TEP components during reactive and proactive inhibition and whether individual differences in GABA and glutamate signaling predict inhibitory performance.MethodsTwenty-four healthy participants completed two TMS-EEG sessions, targeting either the left primary motor cortex (M1) or the pre-supplementary motor area (preSMA) at rest and during a stop-signal task. We compared TEP peak amplitudes across TMS (active/sham) and Trial Type (stop/go trials) and assessed their relationship with task performance.ResultsParticipants with a higher N45 amplitude at rest over M1, reflecting increased GABAa signaling, demonstrated a faster stop-signal reaction time. TMS during motor inhibition revealed higher N15 amplitudes over preSMA, reflecting increased glutamatergic neurotransmission, for successful stops versus go trials. Similarly, N15 was higher for uncertain than certain go trials suggesting that an early excitatory signal from preSMA is crucial for both reactive and proactive motor inhibition.ConclusionHigher GABAa inhibitory signaling in M1 at rest is linked to faster reactive inhibition. The preSMA likely plays a key role in both reactive and proactive motor inhibition. Here we provide novel direct empirical insights into the underlying neurophysiological mechanisms, highlighting a functional relevance of early glutamatergic excitatory signals for successful motor inhibition.
Deciphering the nanoscale architecture of presynaptic actin using a micropatterned presynapse-on-glass model
Authors: Tumminia Sofia , Mezache Louisa , Wiesner Theresa , Vianay Benoit , Théry Manuel , Papandréou Marie-Jeanne , Leterrier Christophe 
Published: September 2024

AbstractChemical synapses are fundamental units for the transmission of information throughout the nervous system. The cyto-skeleton allows to build, maintain and transform both pre- and postsynaptic contacts, yet its organization and the role of its unique synaptic nanostructures are still poorly understood. Here we present a presynapse-on-glass model where presynaptic specializations are robustly induced along the axons of cultured neurons by micropatterned dots of neuroligin, allowing the controlled orientation and easy optical visualization of functional induced presynapses. We demonstrate the relevance and usefulness of this presynapse-on-glass model for the study of presynaptic actin architecture, showing that a majority of induced presynapses are enriched in actin, with this enrichment being correlated to higher synaptic cycling activity. We confirm our previous results on bead-induced presynapses by identifying the same distinct actin nanostructures with-in presynapses: corrals, rails and mesh. Furthermore, we leverage the controlled orientation of the presynapse-on-glass model, visualizing the arrangement of these actin structures relative to the active zone nanoclusters using multicolor 3D Single Molecule Localization Microscopy (SMLM), and relative to the sub-diffractive localization exocytic events using a correlative live-cell and SMLM approach.
STRUCTURE-BASED DESIGN OF PROTACS FOR THE DEGRADATION OF SOLUBLE EPOXIDE HYDROLASE
Authors: Schönfeld J. , Brunst S. , Ciomirtan L. , Liebisch N. , Kumar A. , Ehrler J. H. M. , Wintermeier L. , Heering J. , Brüggerhoff A. , Weizel L. , Kaiser A. , Schubert-Zsilavecz M. , Knapp S. , Fürst R. , Proschak E. , Hiesinger K. 
Published: September 2024

AbstractSoluble epoxide hydrolase (sEH) represents a promising target for inflammation-related diseases as it hydrolyzes highly anti-inflammatory epoxy-fatty acids (EpFAs) to the less active corresponding diols.1sEH harbours two distinct catalytic domains, the C-terminal hydrolase domain and the N-terminal phosphatase domain which are connected by a proline-rich linker.2Although potent inhibitors of enzymatic activity are available for both domains, sEH-PROTACs offer the unique ability to simultaneously degrade both domains, mimicking the sEH knockout phenotype associated with beneficial effects as reducing inflammation, attenuating neuroinflammation, and delaying the progression of Alzheimer’s disease. Herein, we report the structure-based development of a potent sEH-PROTAC as a useful tool compound for the investigation of sEH. In order to facilitate a rapid testing of the synthesized compounds a cell-based sEH degradation assay was developed based on the HiBiT-technology. A structure-activity-relationship (SAR) investigation was performed, based on the crystal structure of previously published sEH inhibitor FL217 where we identified two possible exit vectors. We designed and synthesized a set of 24 PROTACs with varying linkers in a combinatorial manner. Furthermore, co-crystallization of sEH with two selected PROTACs allowed us to explore the binding mode and rationalize the appropriate linker length. After biological and physicochemical investigation, the most suitable PROTAC23was identified and applied to degrade sEH in primary human macrophages, marking the successful translation and applicability to non-artificial systems.
ADAR1 orchestrates the ZBP1-mediated PANoptosis and heart transplant rejection
Authors: Lu Haitao , Jiang Jifu , Huang Xuyan , Haig Aaron , Gunaratman Lakshman , Jevnikar Anthony M. , Zhang Zhu-Xu 
Published: September 2024

AbstractBackgroundPANoptosis is an integrated form of cell death that combines features of pyroptosis, apoptosis, and necroptosis and is regulated by a complex network of signaling proteins. The roles of ADAR1 (adenosine deaminase acting on RNA 1) and RIPK1 (receptor-interacting serine/threonine-protein kinase 1) in orchestrating the ZBP1 (Z-DNA binding protein 1)-RIPK3 complex to mediate PANoptosis is not fully understood, particularly in the context of heart transplantation.ObjectiveThis study investigated how ADAR1 and RIPK1 coordinate the activation of the ZBP1-RIPK3 complex to mediate PANoptosis and its implications in mouse heart transplantation.MethodsUsing both in vitro and in vivo models, we analyzed the interactions between ADAR1, RIPK1, ZBP1, and RIPK3. We employed western blotting, and siRNA to elucidate the dynamics of these interactions. Additionally, we assessed the impact of ZBP1 on mouse heart transplantation outcomes.ResultsOur studies revealed that ADAR1 regulates the activation of the ZBP1-RIPK3 complex for PANoptosis. The interaction of ADAR1 with ZBP1 protected against Z-DNA-induced cell death by limiting activations of ZBP1 and RIPK3. In mouse heart transplantation study, we found that ZBP1 and its ligand Z-DNA/Z-RNA were significantly increased in the graft post-transplantation. Furthermore, ZBP1 deficiency in the heart graft inhibited cardiac PANoptosis, attenuated acute graft injury, and induced long-term graft survival.ConclusionThis study elucidates the role of ADAR1 in ZBP1-mediated PANoptosis. Inhibition of ZBP1 can prevent heart graft injury and rejection. Understanding these mechanisms provides valuable insights into the regulation of cell death and may inform the development of novel therapeutic strategies to improve transplant outcomes.
Mitochondrial topoisomerase I (Top1MT) prevents the onset of metabolic dysfunction-associated steatohepatitis (MASH) in mice
Authors: Baechler SA , Saha LK , Factor VM , Chitnis C , Dhall A , Becker D , Marquardt JU , Pommier Y 
Published: September 2024

AbstractHigh fat (HF) diet is a major factor in the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatis (MASH), and mitochondria have been proposed to play a role in the pathogenesis of HF diet-induced MASH. Because Mitochondrial topoisomerase I (Top1MT) is exclusively present in mitochondria and Top1MT knock-out mice are viable, we were able to assess the role of Top1MT in the development of MASH. We show that after 16 weeks of HF diet, mice lacking Top1MT are prone to the development of severe MASH characterized by liver steatosis, lobular inflammation and hepatocyte damage. Mice lacking Top1MT also show prominent mitochondrial dysfunction, ROS production and mitochondrial DNA (mtDNA) release, accompanied by hepatic inflammation and fibrosis. In summary, our study demonstrates the importance of Top1MT in sustaining hepatocyte functions and suppressing MASH.
Honey bee egg composition changes seasonally and after acute maternal virus infection
Authors: Chapman Abigail , McAfee Alison , Kenzie L. C. C , Magaña Armando Alcazar , Tarpy David R. , Fine Julia D. , Rempel Zoe , Peters Kira , Currie Rob W. , Hoover Shelley E. R. , Foster Leonard J. 
Published: September 2024

AbstractHoney bee (Apis mellifera) colonies depend on the reproductive output of their queens, which in turn is contingent on the care provided by worker bees. Viral infections in queens can compromise reproductive output, while worker infections can inhibit the successful functioning of a colony and its ability to care for the queen. Transgenerational immune priming (TGIP) occurs when queens transfer immune-related compounds or immune elicitors to their offspring, enhancing the ability of subsequent generations to resist infections. These maternal effects on offspring could positively impact colony health and resilience to viral infections, but little is currently known about TGIP for viruses. In this study, we investigate how viral infections affect the proteomic composition of eggs laid by virus-challenged queens (injected with a mixture of black queen cell virus and deformed wing virus B), both in controlled experimental settings and natural field conditions. Our results showed that virus-challenged queens upregulated immune effectors in their eggs and ovaries. In contrast, naturally infected queens from field surveys did not; there were no significant differences in egg protein, lipid, or metabolite composition related to maternal viral load or ovary size. However, egg collection date strongly influenced egg composition, likely reflecting seasonal variations in pollen resources. These findings highlight that while viral infections can induce transgenerational effects on egg proteomes under short-term experimental conditions, such effects are less apparent in natural settings and can be overshadowed by seasonal and other ecological factors.
Unique Signatures of Highly Constrained Genes Across Publicly Available Genomic Databases
Authors: Schmitz-Abe Klaus , Li Qifei , Greene Sunny , Borrelli Michela , Luo Shiyu , Ramesh Madesh C. , Agrawal Pankaj B. 
Published: September 2024

AbstractPublicly available genomic databases and genetic constraint scores are crucial in understanding human population variation and the identification of variants that are likely to have a deleterious impact causing human disease. We utilized the one of largest publicly available databases, gnomAD, to determine genes that are highly constrained for only LoF, only missense, and both LoF/missense variants, identified their unique signatures, and explored their causal relationship with human conditions. Those genes were evaluated for unique patterns including their chromosomal location, tissue level expression, gene ontology analysis, and gene family categorization using multiple publicly available databases. Those highly constrained genes associated with human disease, we identified unique patterns of inheritance, protein size, and enrichment in distinct molecular pathways. In addition, we identified a cohort of highly constrained genes that are currently not known to cause human disease, that we suggest will be candidates to pursue as novel disease-associated genes. In summary, these insights not only elucidate biological pathways of highly constrained genes that expand our understanding of critical cellular proteins but also advance research in rare diseases.
Kinesin-8 motors dimerize by folding their proximal tail domain into a compact helical bundle
Authors: Trofimova Daria , Doubleday Caitlin , Hunter Byron , Arevalo Jesus Serrano , Davison Emma , Wen Eric , Munro Kim , Allingham John S. 
Published: September 2024

AbstractKinesin-8 motor proteins help align and segregate chromosomes during mitosis by regulating the dynamics of kinetochore-attached microtubules and the length and position of the mitotic spindle. Some kinesin-8 isoforms accomplish these roles by operating as multifunctional mechanoenzymes that can traverse microtubules, accumulate at the microtubule plus-ends, and then remove terminal αβ-tubulin subunits. While these activities are mainly powered by the motor domain, whose unique structure-function relationships have been recently reported, the non-motor tail domain contains integral functional elements that have not been structurally illuminated. Using theCandida albicansKip3 protein as a kinesin-8 model system, we present an X-ray crystal structure and hydrodynamic data showing how the motor domain-proximal segment of the tail directs the assembly of two kinesin-8 polypeptides into a homodimer that forms the stalk of this motor. Unlike the extended coiled coil-forming helices of most other motile kinesin stalks, the proximal tail ofCaKip3 folds into a compact 92 Å-long four-helix bundle that dimerizes. The first and third helices provide most of the surface area for the dimer interface, while the other two helices brace the folded stalk structure. The upper and lower lobules of the helical bundle are separated by a flexible hinge that gives the exterior faces of the stalk slightly different shapes when bent. We propose that these unique characteristics provide structural rigidity to the kinesin-8 stalk, as well as sites for transient interactions with kinesin-8-associated proteins or other regulatory regions of the motor.
Non-random segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in daughter cells
Authors: Segos Ioannis , Van Eeckhoven Jens , Berger Simon , Mishra Nikhil , Lambie Eric J. , Conradt Barbara 
Published: September 2024

AbstractThe non-random segregation of organelles has been proposed to be an intrinsic mechanism that contributes to cell fate divergence during asymmetric cell division; however,in vivoevidence is sparse. Using super-resolution microscopy, we analysed the segregation of organelles during the division of the neuroblast QL.p inC. eleganslarvae. QL.p divides to generate a daughter that survives, QL.pa, and a daughter that dies, QL.pp. We found that mitochondria segregate unequally by density and morphology and that this is dependent on mitochondrial fission and fusion. Furthermore, we found that mitochondrial density in QL.pp correlates with the time it takes QL.pp to die. We propose that low mitochondrial density in QL.pp promotes the cell death fate and ensures that QL.pp dies in a highly reproducible and timely manner. Our results provide the firstin vivoevidence that the non-random segregation of mitochondria can contribute to cell fate divergence during asymmetric cell division.
Design and test of an
X
-band constant gradient structure
Authors: Gao Qiang , Zha Hao , Shi Jiaru , Lin Xiancai , Du Yingchao , Feng Boyuan , Li Hongyu , Deng Heng , Hu Fangjun , Gao Jian , Li Qingzhu , Gu Weihang , Liu Jiayang , Huang Wenhui , Tang Chuanxiang , Chen Huaibi 
Published: September 2024

A light source project named very compact inverse Compton scattering gamma-ray source (VIGAS) is under development at Tsinghua University. VIGAS aims to generate monochromatic high-energy gamma rays by colliding 350-MeV electron beams with 400-nm laser photons within a 12-m beamline. To produce a high-energy electron beam in such a compact space, the system consists of an S-band high-brightness injector and six X-band high-gradient accelerating structures. The goal of the X-band structure is to operate at a high gradient of 80  MV/m. Therefore, we adopts the constant gradient traveling wave approach, where the iris from the first cell to the end cell is tapered. The structure has 72 cells, including 70 cells and 2 couplers, so we named it XT72. The frequency of XT72 is selected to 11.424 GHz, and the 2π/3 mode is adopted. In this paper, we present a comprehensive study covering the detailed design, fabrication, rf tuning, and high-power test results of the first XT72. Additionally, we compare the performance of this structure to that of the previous constant impedance structure. Our results demonstrate that the XT72 is capable of operating at an 80−MV/m gradient with a lower breakdown rate. This advancement paves the way for the development of VIGAS project and contributes to the wider application of X-band room-temperature high-gradient structures in compact accelerator facilities.

Published by the American Physical Society
2024
Top management team heterogeneity and peer effects in investment decision-making: based on the social learning perspective
Authors: Qian Shuai , Wen Yipeng 
Published: September 2024

PurposeThe purpose of this paper is to form propositions about the relationship between top management team (TMT) heterogeneity and peer effects in investment decision-making and explore the mediating role of social learning processes.Design/methodology/approachTo investigate the correlations between TMT heterogeneity and investment peer effects, we considered the TMT heterogeneity category, team process and contextual factors. With a sample of 8,467 firm-year observations from Chinese listed companies, we used the mean linear model and instrumental variable method to empirically examine their relationships. To identify the mediating role of social learning processes, we introduced a social learning model to find out the contextual factors influencing corporate social learning demands from three aspects and subsequently used comparative statics analysis to explore the variations in the main effect under these contextual factors.FindingsFor task-oriented heterogeneity (e.g. functional background, education and tenure heterogeneity), the opposite effects of information elaboration and social categorization processes make it a nonlinear multiplex correlation with investment peer effects. For relation-oriented heterogeneity (e.g. age and gender heterogeneity), the sole effect of social categorization processes leads to a negative linear correlation. Further, we identify the mediating role of social learning processes. In summary, we established a connection from the TMT heterogeneity, to information elaboration theory or social categorization theory, to social learning processes and ultimately to investment peer effects.Originality/valueThe results of this study provide a comprehensive perspective to predict the decision-making outcomes of team heterogeneity and contribute to heterogeneity research and practice.
Influence of coconut and castor oil coating on engine intake non-woven filter performance
Authors: Nallathambi Gobi , Akasaperumal Rajalekshmi , Robert Berly 
Published: September 2024

PurposeThis research focuses on the development and characterization of oil-wetted spun-bonded polypropylene (PP) non-woven filters for improved air intake systems in automobiles. The study aims to enhance engine performance, durability, fuel economy and emission reduction by addressing key aspects such as contaminants filtration efficiency, loading capacity, pressure drop, temperature performance and longevity.Design/methodology/approachThe research methodology involves the utilization of textile fabrics, particularly oil-wetted spun-bonded PP non-woven filters, renowned for their effective particle collection capability from intake air. Experiments were conducted using a Box–Behnken design with three variables – oil concentration, areal density and dust quantity – each at three different levels to establish correlations with the filter’s dust holding capacity (DHC) and pressure drop.FindingsThe findings indicate that immersing particles in oil-coated medium significantly enhances the filter’s DHC. Notably, castor oil as a coating demonstrates remarkable results, with a 97.53% increase in DHC and a high particulate matter filtration efficiency of 94.12%.Originality/valueThis study contributes to the originality of research by emphasizing the importance of oil density in determining the filter’s DHC and filtration efficiency. Furthermore, it highlights the superiority of castor oil over coconut oil-coated filter media, advancing air intake and/or filter systems for automotive engines.