bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of focused ultrasound blood-brain barrier disruption effect on inflammation as a function of treatment parameters
Authors: Angolano Cleide , Hansen Emily , Ajjawi Hala , Nowlin Paige , Zhang Yongzhi , Thunemann Natalie , Ferran Christiane , Todd Nick 
Published: July 2024

AbstractThe technology of focused ultrasound-mediated disruption of the blood-brain barrier (FUS- BBB opening) has now been used in over 20 Phase 1 clinical trials to validate the safety and feasibility of BBB opening for drug delivery in patients with brain tumors and neurodegenerative diseases. The primary treatment parameters, FUS intensity and microbubble dose, are chosen to balance sufficient BBB disruption to achieve drug delivery against potential acute vessel damage leading to microhemorrhage. This can largely be achieved based on both empirical results from animal studies and by monitoring the microbubble cavitation signal in real time during the treatment. However, other safety considerations due to second order effects caused by BBB disruption, such as inflammation and alteration of neurovascular function, are not as easily measurable, may take longer to manifest and are only beginning to be understood. This study builds on previous work that has investigated the inflammatory response following FUS-BBB opening. In this study, we characterize the effect of FUS intensity and microbubble dose on the extent of BBB disruption, observed level of microhemorrhage, and degree of inflammatory response at three acute post-treatment time points in the wild-type mouse brain. Additionally, we evaluate differences related to biological sex, presence and degree of the anti- inflammatory response that develops to restore homeostasis in the brain environment, and the impact of multiple FUS-BBB opening treatments on this inflammatory response.
BATF2 is a regulator of interferon-γ signaling in astrocytes during neuroinflammation
Authors: Tinkey Rachel A. , Smith Brandon C. , Habean Maria L. , Williams Jessica L. 
Published: July 2024

SummaryAstrocytic interferon (IFN)γ signaling is associated with a reduction in neuroinflammation. We have previously shown that the benefits of astrocytic IFNγ arise from a variety of mechanisms; however, downstream effectors responsible for regulating this protection are unknown. We address this by identifying a specific transcription factor that may play a key role in modulating the consequences of IFNγ signaling. RNA-sequencing of primary human astrocytes treated with IFNγ revealed basic leucine zipper ATF-like transcription factor (BATF)2 as a highly expressed interferon-specific gene. Primarily studied in the periphery, BATF2 has been shown to exert both inflammatory and protective functions; however, its function in the central nervous system (CNS) is unknown. Here, we demonstrate that human spinal cord astrocytes upregulate BATF2 transcript and protein in an IFNγ-specific manner. Additionally, we found that BATF2 prevents overexpression of interferon regulatory factor (IRF)1 and IRF1 targets such as Caspase-1, which are known downstream pro-inflammatory mediators. We also show thatBatf2−/−mice exhibit exacerbated clinical disease severity in a murine model of CNS autoimmunity, characterized by an increase in both CNS immune cell infiltration and demyelination.Batf2−/−mice also exhibit increased astrocyte-specific expression of IRF1 and Caspase-1, suggesting an amplified interferon responsein vivo. Further, we demonstrate that BATF2 is expressed primarily in astrocytes in MS lesions and that this expression is co-localized with IRF1. Collectively, our results further support a protective role for IFNγ and implicate BATF2 as a key suppressor of overactive immune signaling in astrocytes during neuroinflammation.
Distinct spatially organized striatum-wide acetylcholine dynamics for the learning and extinction of Pavlovian associations
Authors: Bouabid Safa , Zhang Liangzhu , Vu Mai-Anh T. , Tang Kylie , Graham Benjamin M. , Noggle Christian A. , Howe Mark W. 
Published: July 2024

ABSTRACTStriatal acetylcholine (ACh) signaling has been proposed to counteract reinforcement signals to promote extinction and behavioral flexibility. ACh dips to cues and rewards may open a temporal window for associative plasticity to occur, while elevations may promote extinction. Changes in multi-phasic striatal ACh signals have been widely reported during learning, but how and where signals are distributed to enable region-specific plasticity for the learning and degradation of cue-reward associations is poorly understood. We used array fiber photometry in mice to investigate how ACh release across the striatum evolves during learning and extinction of Pavlovian associations. We report a topographic organization of opposing changes in ACh release to cues, rewards, and consummatory actions across distinct striatum regions. We localized reward prediction error encoding in particular phases of the ACh dynamics to a specific region of the anterior dorsal striatum (aDS). Positive prediction errors in the aDS were expressed in ACh dips, and negative prediction errors in long latency ACh elevations. Silencing aDS ACh release impaired behavioral extinction, suggesting a role for ACh elevations in down-regulating cue-reward associations. Dopamine release in aDS dipped for cues during extinction, but glutamate input onto cholinergic interneurons did not change, suggesting an intrastriatal mechanism for the emergence of ACh elevations. Our large scale measurements indicate how and where ACh dynamics can shape region-specific plasticity to gate learning and promote extinction of Pavlovian associations.
Rate variation and recurrent sequence errors in pandemic-scale phylogenetics
Authors: De Maio Nicola , Willemsen Myrthe , Guo Zihao , Saha Abhratanu , Hunt Martin , Ly-Trong Nhan , Minh Bui Quang , Iqbal Zamin , Goldman Nick 
Published: July 2024

AbstractPhylogenetic analyses of genome sequences from infectious pathogens reveal essential information regarding their evolution and transmission, as seen during the COVID-19 pandemic.Recently developed pandemic-scale phylogenetic inference methods reduce the computational demand of phylogenetic reconstruction from genomic epidemiological datasets, allowing the analysis of millions of closely related genomes. However, widespread homoplasies, due to recurrent mutations and sequence errors, cause phylogenetic uncertainty and biases.We present new algorithms and models to substantially improve the computational performance and accuracy of pandemic-scale phylogenetics. In particular, we account for, and identify, mutation rate variation and recurrent sequence errors. We reconstruct reliable and public sequence alignment and phylogenetic tree of>2 million SARS-CoV-2 genomes encapsulating the evolutionary history and global spread of the virus up to February 2023.
Small molecule FICD inhibitors suppress endogenous and pathologic FICD-mediated protein AMPylation
Authors: Chatterjee Bhaskar K. , Alam Maroof , Chakravorty Arghya , Lacy Shannon M. , Rech Jason , Brooks Charles L. , Arvan Peter D. , Truttmann Matthias C. 
Published: July 2024

SummaryThe AMP transferase, FICD, is an emerging drug target finetuning stress signaling in the endoplasmic reticulum (ER). FICD is a bi-functional enzyme, catalyzing both AMP addition (AMPylation) and removal (deAMPylation) from the ER resident chaperone BiP/GRP78. Despite increasing evidence linking excessive BiP/GRP78 AMPylation to human diseases, small molecules to inhibit pathogenic FICD variants are lacking. Using anin-vitrohigh-throughput screen, we identify two small-molecule FICD inhibitors, C22 and C73. Both molecules significantly inhibit FICD-mediated BiP/GRP78 AMPylation in intact cells while only weakly inhibiting BiP/GRP78 deAMPylation. C22 and C73 also efficiently inhibit pathogenic FICD variants and improve proinsulin processing in β cells. Our study identifies and validates FICD inhibitors, highlighting a novel therapeutic avenue against pathologic protein AMPylation.
Diagnostic accuracy of fractional exhaled nitric oxide (FeNO) with or without blood eosinophils in childhood, adolescent, and adult asthma: protocol for a systematic review and meta-analysis
Authors: Roy Marc-André , Gronnier Morgane , Ramphul Manisha , Divall Pip , Lemaire-Paquette Samuel , Côté Andréanne , Ducharme Francine M , Gaillard Erol A , Couillard Simon 
Published: July 2024

ABSTRACTIntroductionAsthma poses a diagnostic challenge due to its intermittent symptoms and variable airflow obstruction. Diagnostic assessments such as spirometry and bronchodilator response are frequently non-diagnostic, necessitating confirmatory bronchial provocation testing. Biomarkers of type-2 inflammation —exhaled nitric oxide (FeNO) and blood eosinophil counts (BEC)— are useful in asthma, but their diagnostic values in children and in combination (FeNO+BEC) are unclear. This systematic review will evaluate the diagnostic accuracy of FeNO alone or in combination with BEC in paediatric and adult asthma.Methods and AnalysisThis protocol is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. The review will include studies of any design on the diagnostic accuracy of FeNO with or without BEC in asthma compared to the reference standards bronchodilator response and provocation testing in patients ≥ 5 years old selected from MEDLINE, Embase, and Cochrane CENTRAL databases. Screening, study selection, and data extraction will be independently performed by two reviewers. Risk of bias will be assessed using QUADAS-2 and QUADAS-C. Meta-analysis will be carried out by pooling the sensitivity and specificity of FeNO alone or in combination with BEC in a bivariate random effects model allowing the generation of summarised operating characteristic curves and summary points. Further analysis utilising a multiple thresholds model will enable the computation of diagnostic thresholds for FeNO.Ethics and DisseminationNo patient data will be stored without prior approval from ethics committee. The findings will be submitted in a peer-reviewed publication.RegistrationPROSPERO CRD42023489738SOCIAL MEDIA MESSAGEDiagnosing asthma is challenging. Spirometry and bronchodilator reversibility are often non-diagnostic, calling for provocation testing. Our systematic review will explore complementary approaches using FeNO with and without the blood eosinophil count.
The initiation and early development of apical-basal polarity inToxoplasma gondii
Authors: Arias Padilla Luisa F. , Lopez Jonathan Munera , Shibata Aika , Murray John M. , Hu Ke 
Published: July 2024

ABSTRACTThe human parasiteToxoplasma gondiihas a distinctive body plan with a well-defined polarity. In the apical complex, the minus ends of the 22 cortical microtubules are anchored to the apical polar ring, a putative microtubule-organizing center. The basal complex caps and constricts the parasite posterior end, and is critical for cytokinesis. How this apical-basal polarity axis is initiated was unknown. Here we examined the development of the apical polar ring and the basal complex in nascent daughters using expansion microscopy. We found that different substructures in the apical polar ring have different sensitivity to stress. In addition, apical-basal differentiation is already established upon nucleation of the cortical microtubule array: arc forms of the apical polar ring and basal complex associate with opposite ends of the microtubules. As the construction of the daughter framework progresses towards the centrioles, the apical and the basal arcs co-develop in striking synchrony ahead of the microtubule array, and close into a ring-form before all the microtubules are nucleated. We also found that two apical polar ring components, APR2 and KinesinA, act synergistically. The removal of each protein individually has modest to no impact on the lytic cycle. However, the loss of both results in abnormalities in the microtubule array and highly reduced plaquing and invasion efficiency.
Identifying Metabolomic and Proteomic Biomarkers for Age-Related Morbidity in a Population-Based Cohort - the Cooperative Health Research in South Tyrol (CHRIS) study
Authors: Hantikainen Essi , Weichenberger Christian X. , Dordevic Nikola , Hernandes Vinicius Verri , Foco Luisa , Gögele Martin , Melotti Roberto , Pattaro Cristian , Ralser Markus , Amari Fatma , Farztdinov Vadim , Mülleder Michael , Pramstaller Peter P. , Rainer Johannes , Domingues Francisco S. 
Published: July 2024

AbstractIdentifying biomarkers able to discriminate individuals on different health trajectories is crucial to understand the molecular basis of age-related morbidity. We investigated multi-omics signatures of general health and organ-specific morbidity, as well as their interconnectivity. We examined cross-sectional metabolome and proteome data from 3,142 adults of the Cooperative Health Research in South Tyrol (CHRIS) study, an Alpine population study designed to investigate how human biology, environment, and lifestyle factors contribute to people’s health over time. We had 174 metabolites and 148 proteins quantified from fasting serum and plasma samples. We used the Cumulative Illness Rating Scale (CIRS) Comorbidity Index (CMI), which considers morbidity in 14 organ systems, to assess health status (any morbidity vs. healthy). Omics-signatures for health status were identified using random forest (RF) classifiers. Linear regression models were fitted to assess directionality of omics markers and health status associations, as well as to identify omics markers related to organ-specific morbidity.Next to age, we identified 21 metabolites and 10 proteins as relevant predictors of health status and results confirmed associations for serotonin and glutamate to be age-independent. Considering organ-specific morbidity, several metabolites and proteins were jointly related to endocrine, cardiovascular, and renal morbidity. To conclude, circulating serotonin was identified as a potential novel predictor for overall morbidity.
Genetic-Driven Rapid and Precise Mimicry of Cardiovascular Fluctuations
Authors: Liao Minghao , Li Zhongyou , Jiang Wentao , Bai Taoping , Liu Lingjun , Yan Fei 
Published: July 2024

AbstractBackgroundPhysics-based reduced-order models have gained significant attention for capturing cardiovascular fluctuations. However, achieving quick and precise mimicry of these fluctuations has been a persistent issue for decades.MethodsInspired by the principle of natural selection, we used a complex whole-body circulation model as an example and utilized genetic algorithms to automate the coordination of model parameters. Additionally, we introduced a “pseudo-distance” metric to evaluate the similarity between the simulated fluctuation curves and the target curves.ResultsThrough rapid iterations (40 times), this strategy achieved a complete match with the target in both blood pressure and flow fluctuation amplitude and time domains, resulting in highly realistic fluctuation mimicry.ConclusionThis study addresses the major challenge of reduced-order models in the mimicry of blood circulation, ending the history of manual parameter coordination that took months or even years.Clinical PerspectiveWhat Is New?Physics-based reduced-order models are essential for analyzing whole-body hemodynamic status, but they have struggled with complex parameter coordination for decades. This study completely addressed this challenge by employing “genetic algorithms” and an updated “pseudo-distance” criterion, achieving precise mimicry of waveforms both spatially and temporally. Additionally, this work eliminates the dependency on large datasets, making personalized modeling more accessible and practical.What Are the Clinical Implications?This study lowers the barrier for researchers utilizing these models, significantly advancing the modeling of blood circulation and potentially benefitting physiological analysis, clinical diagnostics, and treatment planning in various cardiovascular events.
Actin dynamics sustains spatial gradients of membrane tension in adherent cells
Authors: García-Arcos Juan Manuel , Mehidi Amine , Velázquez Julissa Sánchez , Guillamat Pau , Tomba Caterina , Houzet Laura , Capolupo Laura , D’Angelo Giovanni , Colom Adai , Hinde Elizabeth , Aumeier Charlotte , Roux Aurélien 
Published: July 2024

AbstractTension propagates in lipid bilayers over hundreds of microns within milliseconds, precluding the formation of tension gradients. Nevertheless, plasma membrane tension gradients have been evidenced in migrating cells and along axons. Here, using a fluorescent membrane tension probe, we show that membrane tension gradients exist in all adherent cells, whether they migrate or not. Non-adhering cells do not display tension gradients. We further show that branched actin increases tension, while membrane-to-cortex attachments facilitate its propagation. Tension is the lowest at the edge of adhesion sites and highest at protrusions, setting the boundaries of the tension gradients. By providing a quantitative and mechanistic basis behind the organization of membrane tension gradients, our work explains how they are actively sustained in adherent cells.
Supervised Deep Learning with Gene Annotation for Cell Classification
Authors: Lin Zhexiao , Sun Wei 
Published: July 2024

AbstractGene-by-gene differential expression analysis is a popular supervised learning method for analyzing single-cell RNA sequencing (scRNA-seq) data. However, the large number of cells in scRNA-seq studies often results in numerous differentially expressed genes with extremely small p-values but minimal effect sizes, complicating interpretation. To address this challenge, we developed a method called Supervised Deep Learning with gene ANnotation (SDAN). SDAN integrates gene annotation and gene expression data using a graph neural network to identify gene sets to classify cells, and then the corresponding individuals. We demonstrated the usage of SDAN by identifying gene sets associated with severe COVID-19, dementia, and cancer patients’ responses to immunotherapy.
EPHA1 and EPHB4 tyrosine kinase receptors regulate epithelial morphogenesis
Authors: Lavoie Noémie , Scribe Anaëlle , Chartier François J.M. , Ghani Karim , Jetté Alexandra , Banerjee Sara L. , Caruso Manuel , Laurin Mélanie , Freywald Andrew , Elowe Sabine , Laprise Patrick , Bisson Nicolas 
Published: July 2024

SUMMARYOrgan formation and homeostasis require the coordination of cell-cell adhesion, epithelial cell polarity and orientation of cell division to organize epithelial tissue architecture. We have previously identified proximity protein networks acting downstream of members of the EPH family of tyrosine kinase receptors and found within these networks an enrichment of components associated with cell morphogenesis and cell-cell junctions. Here, we show that two EPH receptors, EPHA1 and EPHB4, are localized to the basolateral domain of Caco-2 cells in spheroidal cultures. Depletion of either EPHA1 or EPHB4 disrupts spheroid morphogenesis, without affecting cell polarity, but via randomizing mitotic spindle orientation during cell division. Strikingly, EPHA1 and EPHB4 exert this function independently of their catalytic activity but still requiring EFN ligand binding. Consistent with this, the most abundantly expressed EPHB4 ligand in Caco-2 cells, EFNB2, is also compartmentalized at the basolateral domain in spheroids, and is required for epithelial morphogenesis. Taken together, our data reveal a new role for EPHRs in epithelial morphogenesis.
Genetic manipulation of Bacteriophage T4 utilizing the CRISPR-Cas13b system
Authors: Bhoobalan-Chitty Yuvaraj , Stouf Mathieu , De Paepe Marianne 
Published: July 2024

ABSTRACTCRISPR-Cas type II and type V systems are inefficient in modifying bacteriophage T4 genome, due to the hypermodification of its DNA. Here, we present a genome editing technique for bacteriophage T4 using the type VI CRISPR-Cas system. Using BzCas13b targeting of T4 phage, we were able to individually delete both T4 glucosyl transferase genes,α-gtandβ-gt. Furthermore, we employed this method to mutate two conserved residues within the T4 DNA polymerase and to introduce the yellow fluorescent protein (YFP) coding sequence into T4 phage genome, enabling us to visualize phage infections. The T4 genome editing protocol was optimized to obtain recombinant phages within a 6-hour timescale. Finally, spacers homologous to a variety of T4 genes were used to study the generality of Cas13b targeting, revealing important variability in targeting efficiency. Overall, this study presents a detailed description of the rapid and easy production of T4 phage specific mutants.IMPORTANCEThe use of phages for therapeutic purposes requires a complete understanding of their life cycle. For this purpose, it’s very useful to have a wide range of phage genome engineering tools at our disposal, each adapted to a particular phage or situation. Although T4 phage has been studied extensively over the past seven decades, a complete understanding of its lytic cycle is still lacking. Cas9- and Cpf1-dependent genome editing techniques for T4 have proven to be inconsistent due to the glucosyl-hydroxymethyl modification of the cytosine residues in its genome. The RNA targeting of the Cas13 system presents an ideal alternative, as demonstrated here, to overcome interference from DNA hypermodification. Apart from demonstrating a new genome editing technique in T4, we have generated a range of T4 variants demonstrating the efficacy of our technique in obtaining meaningful and difficult to construct phage mutants.
Higgs boson precision analysis of the full LHC run 1 and run 2 data
Authors: Heo Yongtae , Jung Dong-Won , Lee Jae Sik 
Published: July 2024

We perform global fits of the Higgs boson couplings to the full Higgs datasets collected at the LHC with the integrated luminosities per experiment of approximately 5/fb at 7 TeV, 20/fb at 8 TeV, and up to 139/fb at 13 TeV. Our combined analysis based on the experimental signal strengths used in this work and the theoretical ones elaborated for our analysis reliably reproduce the results in the literature. We reveal that the LHC Higgs precision data are no longer best described by the Standard Model (SM) Higgs boson taking account of extensive and comprehensive CP-conserving and CP-violating scenarios found in several well-motivated models beyond the SM. Especially, in most of the fits considered in this work, we observe that the best-fitted values of the normalized Yukawa couplings are about 2σ below the corresponding SM ones with the 1σ errors of 3%–5%. On the other hand, the gauge-Higgs couplings are consistent with the SM with the 1σ errors of 2%–3%. Incidentally, the reduced Yukawa couplings help to explain the excess of the H→Zγ signal strength of 2.2±0.7 recently reported by the ATLAS and CMS collaborations.

Published by the American Physical Society
2024
Investigating
Ξ
resonances from a pentaquark perspective
Authors: Yan Ye , Huang Qi , Zhu Xinmei , Huang Hongxia , Ping Jialun 
Published: July 2024

We have investigated the qssq¯q (q=u or d) system to find possible pentaquark explanations for the Ξ resonances. The bound state calculation is carried out within the framework of the quark delocalization color screening model. The scattering processes are also studied to examine the possible resonance states. The current results indicate that the Ξ(1950) state can be interpreted as a ΛK¯* state with JP=1/2−. Three states are identified that match the Ξ(2250), which are a Σ*K¯* state with JP=3/2−, a Σ*K¯* state with JP=5/2−, and a Ξ*ρ state with JP=5/2−. This may explain the conflicting experimental values for the width of the Ξ(2250) state. A new Ξ resonance is predicted, whose mass and width are 2066–2079 MeV and 186–189 MeV, respectively. These results contribute to understanding the nature of the Ξ resonances and to the future search for new Ξ resonances. Moreover, it is meaningful to further investigate the Ξ resonances from an unquenched picture on the basis of pentaquark investigation.

Published by the American Physical Society
2024