bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ibudilast Protects Retinal Bipolar Cells from Excitotoxic Retinal Damage and Activates the mTOR Pathway
Authors: Hamadmad Sumaya , Heisler-Taylor Tyler , Goswami Sandeep , Hawthorn Evan , Chaurasia Sameer , Martini Dena , Summitt Diana , Zaatari Ali , Urbanski Elizabeth G , Bernstein Kayla , Racine Julie , Satoskar Abhay , El-Hodiri Heithem M. , Fischer Andy J. , Cebulla Colleen M. 
Published: March 2024

AbstractIbudilast, an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE), has been recently shown to have neuroprotective effects in a variety of neurologic diseases. We utilize a chick excitotoxic retinal damage model to investigate ibudilast’s potential to protect retinal neurons. Using single cell RNA-sequencing (scRNA-seq), we find that MIF, putative MIF receptors CD74 and CD44, and several PDEs are upregulated in different retinal cells during damage. Intravitreal ibudilast is well tolerated in the eye and causes no evidence of toxicity. Ibudilast effectively protects neurons in the inner nuclear layer from NMDA-induced cell death, restores retinal layer thickness on spectral domain optical coherence tomography, and preserves retinal neuron function, particularly for the ON bipolar cells, as assessed by electroretinography. PDE inhibition seems essential for ibudilast’s neuroprotection, as AV1013, the analogue that lacks PDE inhibitor activity, is ineffective. scRNA-seq analysis reveals upregulation of multiple signaling pathways, including mTOR, in damaged Müller glia (MG) with ibudilast treatment compared to AV1013. Components of mTORC1 and mTORC2 are upregulated in both bipolar cells and MG with ibudilast. The mTOR inhibitor rapamycin blocked accumulation of pS6 but did not reduce TUNEL positive dying cells. Additionally, through ligand-receptor interaction analysis, crosstalk between bipolar cells and MG may be important for neuroprotection. We have identified several paracrine signaling pathways that are known to contribute to cell survival and neuroprotection and might play essential roles in ibudilast function. These findings highlight ibudilast’s potential to protect inner retinal neurons during damage and show promise for future clinical translation.Graphical AbstractMain Points- Ibudilast, a MIF and PDE inhibitor, preserves the form and function of the retina, especially bipolar cells, during excitotoxic damage- Ibudilast upregulates multiple signaling pathways, including mTOR, in damaged Müller glia and bipolar cells
Stable and robust Xi and Y transcriptomes drive cell-type-specific autosomal and Xa responsesin vivoandin vitroin four human cell types
Authors: Blanton Laura V. , San Roman Adrianna K. , Wood Geryl , Buscetta Ashley , Banks Nicole , Skaletsky Helen , Godfrey Alexander K. , Pham Thao T. , Hughes Jennifer F. , Brown Laura G. , Kruszka Paul , Lin Angela E. , Kastner Daniel L. , Muenke Maximilian , Page David C. 
Published: March 2024

SummaryRecentin vitrostudies of human sex chromosome aneuploidy showed that the Xi (“inactive” X) and Y chromosomes broadly modulate autosomal and Xa (“active” X) gene expression in two cell types. We tested these findingsin vivoin two additional cell types. Using linear modeling in CD4+ T cells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes, we identified 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosagein vivo. Changes in sex-chromosomal expression were remarkably constantin vivoandin vitroacross all four cell types examined. In contrast, autosomal responses to Xi and/or Y dosage were largely cell-type-specific, with up to 2.6-fold more variation than sex-chromosomal responses. Targets of the X- and Y-encoded transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses bothin vivoandin vitro. We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable across the four cell types examined, yet they modulate autosomal and Xa genes – and cell function – in a cell-type-specific fashion. These emerging principles offer a foundation for exploring the wide-ranging regulatory roles of the sex chromosomes across the human body.
Cluster-free annotation of single cells using Earth mover’s distance-based classification
Authors: Forlin Rikard , Tajvar Pouria , Wang Nana , Dimarogonas Dimos , Brodin Petter 
Published: March 2024

AbstractGrouping individual cells in clusters and annotating these based on feature expression is a common procedure in single-cell analysis pipelines. Multiple methods have been reported for single-cell mRNA sequencing and cytometry datasets where the vast majority rely on sequential 2-step procedures involving I) cell clustering based on notions of similarity and II) cluster annotation via manual or semi-automated methods. However, as arbitrary borders are drawn between more or less similar groups of cells, one cannot guarantee that all cells within a cluster are of the same type. Further, dimensionality reduction has been shown to cause considerable distortion in high-dimensional datasets and is prone to variable annotations of the same cell when relative changes occur in data composition. Another limitation of existing methods is that simultaneous analyses of large sets of cells are computationally expensive and difficult to scale for growing datasets or metanalyses across multiple datasets. Here we present an alternative method based on calculation of Earth Mover’s Distance and a Bayesian classifier coupled to Random Forest, which annotates one cell at a time removing the need for prior clustering and resulting in improved accuracy, better scaling with increasing cell numbers and less computational resources needed.
Estrogen regulation and functional role of FGFR4 in estrogen receptor positive breast cancer
Authors: Ding Kai , Chen Lyuqin , Levine Kevin , Sikora Matthew , Tasdemir Nilgun , Dabbs David , Jankowitz Rachel , Hazan Rachel , Shah Osama S , Atkinson Jennifer M , Lee Adrian V , Oesterreich Steffi 
Published: March 2024

AbstractBackgroundResistance to endocrine therapy is a major challenge of managing estrogen receptor positive (ER+) breast cancer. We previously reported frequent overexpression of FGFR4 in endocrine resistant cell lines and breast cancers that recurred and metastasized following endocrine therapy, suggesting FGFR4 as a potential driver of endocrine resistance. In this study, we investigated the role of FGFR4 in mediating endocrine resistance and explored the therapeutic potential of targeting FGFR4 in advanced breast cancer.MethodsA gene expression signature of FGFR4 activity was examined in ER+ breast cancer pre- and post-neoadjuvant endocrine therapy and the association between FGFR4 expression and patient survival was examined. A correlation analysis was used to uncover potential regulators of FGFR4 overexpression. To investigate if FGFR4 is necessary to drive endocrine resistance, we tested response to FGFR4 inhibition in long term estrogen deprived (LTED) cells and their paired parental cells. Doxycycline inducible FGFR4 overexpression and knockdown cell models were generated to examine if FGFR4 was sufficient to confer endocrine resistance. Finally, we examined response to FGFR4 monotherapy or combination therapy with fulvestrant in breast cancer cell lines to explore the potential of FGFR4 targeted therapy for advanced breast cancer and assessed the importance of PAM50 subtype in response to FGFR4 inhibition.ResultsA FGFR4 activity gene signature was significantly upregulated post neoadjuvant aromatase inhibitor treatment, and high FGFR4 expression predicted poorer survival in patients with ER+ breast cancer. Gene expression association analysis using TCGA, METABRIC and SCAN-B datasets uncovered ER as the most significant gene negatively correlated with FGFR4 expression. ER negatively regulates FGFR4 expression at both the mRNA and protein level across multiple ER+ breast cancer cell lines. Despite robust overexpression of FGFR4, LTED cells did not show enhanced responses to FGFR4 inhibition compared to parental cells. Similarly, FGFR4 overexpression, knockdown or hotspot mutations did not significantly alter response to endocrine treatment in ER+ cell lines, nor did FGFR4 and fulvestrant combination treatment show synergistic effects. The HER2-like subtype of breast cancer showed elevated expression of FGFR4 and an increased response to FGFR4 inhibition relative to other breast cancer subtypes.ConclusionsDespite ER-mediated upregulation of FGFR4 post endocrine therapy, our study does not support a general role of FGFR4 in mediating endocrine resistance in ER+ breast cancer. Our data suggests that specific genomic backgrounds such as HER2 expression may be required for FGFR4 function in breast cancer and should be further explored.
Ventral hippocampus mediates inter-trial responding in signaled active avoidance
Authors: Oleksiak Cecily R. , Plas Samantha L. , Carriaga Denise , Vasudevan Krithika , Maren Stephen , Moscarello Justin M. 
Published: March 2024

AbstractThe hippocampus has a central role in regulating contextual processes in memory. We have shown that pharmacological inactivation of ventral hippocampus (VH) attenuates the context-dependence of signaled active avoidance (SAA) in rats. Here, we explore whether the VH mediates intertrial responses (ITRs), which are putative unreinforced avoidance responses that occur between trials. First, we examined whether VH inactivation would affect ITRs. Male rats underwent SAA training and subsequently received intra-VH infusions of saline or muscimol before retrieval tests in the training context. Rats that received muscimol performed significantly fewer ITRs, but equivalent avoidance responses, compared to controls. Next, we asked whether chemogenetic VH activation would increase ITR vigor. In male and female rats expressing excitatory (hM3Dq) DREADDs, systemic CNO administration produced a robust ITR increase that was not due to nonspecific locomotor effects. Then, we examined whether chemogenetic VH activation potentiated ITRs in an alternate (non-training) test context and found it did. Finally, to determine if context-US associations mediate ITRs, we exposed rats to the training context for three days after SAA training to extinguish the context. Rats submitted to context extinction did not show a reliable decrease in ITRs during a retrieval test, suggesting that context-US associations are not responsible for ITRs. Collectively, these results reveal an important role for the VH in context-dependent ITRs during SAA. Further work is required to explore the neural circuits and associative basis for these responses, which may be underlie pathological avoidance that occurs in humans after threat has passed.
Health activism, vaccine, and mpox discourse: BERTopic based mixed-method analyses of tweets from sexual minority men and gender diverse (SMMGD) individuals in the U.S.
Authors: Wang Yunwen , O’Connor Karen , Flores Ivan , Berdahl Carl T. , Urbanowicz Ryan J. , Stevens Robin , Bauermeister José A. , Gonzalez-Hernandez Graciela 
Published: March 2024

AbstractObjectivesTo synthesize discussions among sexual minority men and gender diverse (SMMGD) individuals on mpox, given limited representation of SMMGD voices in existing mpox literature.MethodsBERTopic (a topic modeling technique) was employed with human validations to analyze mpox-related tweets (n= 8,688; October 2020—September 2022) from 2,326 self-identified SMMGD individuals in the U.S.; followed by content analysis and geographic analysis.ResultsBERTopic identified 11 topics: health activism (29.81%); mpox vaccination (25.81%) and adverse events (0.98%); sarcasm, jokes, emotional expressions (14.04%); COVID-19 and mpox (7.32%); government/public health response (6.12%); mpox symptoms (2.74%); case reports (2.21%); puns on the virus’ naming (i.e., monkeypox; 0.86%); media publicity (0.68%); mpox in children (0.67%). Mpox health activism negatively correlated with LGB social climate index at U.S. state level,ρ= -0.322,p= 0.031.ConclusionsSMMGD discussions on mpox encompassed utilitarian (e.g., vaccine access, case reports, mpox symptoms) and emotionally-charged themes—advocating against homophobia, misinformation, and stigma. Mpox health activism was more prevalent in states with lower LGB social acceptance.Public Health ImplicationsFindings illuminate SMMGD engagement with mpox discourse, underscoring the need for more inclusive health communication strategies in infectious disease outbreaks to control associated stigma.
Beveled shaped axial oxygenator with improved hemodynamics
Authors: Franke B. , Goubergrits L. 
Published: March 2024

AbstractOxygenators are a lifesaving technology used for blood oxygenation and decarboxylation in case of acute respiratory failure, chronic lung disease, and during open-heart surgery. Devices typically consist of a bundle of thousands of fiber membranes in a housing, with gas flowing inside the fibers and blood flowing in the opposite direction outside the fibers. Both ends of the fiber membranes are attached with an adhesive to prevent direct contact between gas and blood. The shape of the volume through which the blood flows is determined by the housing of the oxygenator and the internal end surfaces of the bonded parts of the fiber-membrane bundle. The traditional potting process results in a volume shape that is associated with stagnation zones, which are known to promote thrombus formation. In this study, an adapted potting process is proposed which results in a blood compartment with beveled end faces of the glued bundle parts. Using a numerical study, we have demonstrated that the novel oxygenator design results in optimized flow conditions.
Three Prime Repair Exonuclease 1 preferentially degrades the integration-incompetent HIV-1 DNA through favorable kinetics, thermodynamic, structural and conformational properties
Authors: Prakash Prem , Khodke Purva , Balasubramaniam Muthukumar , Davids Benem-Orom , Hollis Thomas , Davis Jamaine , Pandhare Jui , Kumbhar Bajarang , Dash Chandravanu 
Published: March 2024

AbstractHIV-1 integration into the human genome is dependent on 3’-processing of the reverse transcribed viral DNA. Recently, we reported that the cellular Three Prime Repair Exonuclease 1 (TREX1) enhances HIV-1 integration by degrading the unprocessed viral DNA, while the integration-competent 3’-processed DNA remained resistant. Here, we describe the mechanism by which the 3’-processed HIV-1 DNA resists TREX1-mediated degradation. Our kinetic studies revealed that the rate of cleavage (kcat) of the 3’-processed DNA was significantly lower than the unprocessed HIV-1 DNA by TREX1. The efficiency of degradation (kcat/KM) of the 3’-processed DNA was also significantly lower than the unprocessed DNA. Furthermore, the binding affinity (Kd) of TREX1 was markedly lower to the 3’-processed DNA compared to the unprocessed DNA. Molecular docking and dynamics studies revealed distinct conformational binding modes of TREX1 with the 3’-processed and unprocessed HIV-1 DNA. Particularly, the unprocessed DNA was favorably positioned in the active site with polar interactions with the catalytic residues of TREX1. Additionally, a stable complex was formed between TREX1 and the unprocessed DNA compared the 3’-processed DNA. These results pinpoint the biochemical mechanism by which TREX1 preferentially degrades the integration-incompetent HIV-1 DNA and reveal the unique structural and conformational properties of the integration-competent 3’-processed HIV-1 DNA.
The impact of DNA extraction on the quantification ofLegionella, with implications for ecological studies
Authors: Cavallaro Alessio , Gabrielli Marco , Hammes Frederik , Rhoads William J. 
Published: March 2024

AbstractMonitoring the levels of opportunistic pathogens in drinking water is important to plan interventions and understand the ecological niches that allow them to proliferate. Quantitative PCR is an established alternative to culture methods that can provide a faster, higher throughput, and more precise enumeration of the bacteria in water samples. However, PCR-based methods are still not routinely applied forLegionellamonitoring, and techniques such as DNA extraction differ notably between laboratories. Here, we quantify the impact that DNA extraction methods had on downstream PCR quantification and community sequencing. Through a community science campaign, we collected 50 water samples and corresponding shower hoses, and compared two commonly used DNA extraction methodologies to the same biofilm and water phase samples. The two methods showed clearly different extraction efficacies, which was reflected in both the quantity of DNA extracted and the concentrations ofLegionellaenumerated in both the matrices. Notably, one method resulted in higher enumeration in nearly all samples by about one order of magnitude and detectedLegionellain 21 samples that remained undetected by the other method. 16S rRNA amplicon sequencing revealed that the relative abundance of individual taxa, including sequence variants ofLegionella, significantly varied depending on the extraction method employed. Given the implications of these findings, we advocate for improvement in documentation of the performance of DNA extraction methods used in drinking water to detect and quantifyLegionella, and characterise the associated microbial community.
Medication Use is Associated with Distinct Microbial Features in Anxiety and Depression
Authors: Dilmore Amanda Hazel , Kuplicki Rayus , McDonald Daniel , Kumar Megha , Estaki Mehrbod , Youngblut Nicholas , Tyakht Alexander , Ackermann Gail , Blach Colette , MahmoudianDehkordi Siamak , Dunlop Boadie W. , Bhattacharyya Sudeepa , Guinjoan Salvador , Mandaviya Pooja , Ley Ruth E. , Kaddaruh-Dauok Rima , Paulus Martin P. , Knight Rob ,   Alzheimer Gut Microbiome Project Consortium
Published: March 2024

AbstractThis study investigated the relationship between gut microbiota and neuropsychiatric disorders (NPDs), specifically anxiety disorder (ANXD) and/or major depressive disorder (MDD), as defined by DSM-IV or V criteria. The study also examined the influence of medication use, particularly antidepressants and/or anxiolytics, classified through the Anatomical Therapeutic Chemical (ATC) Classification System, on the gut microbiota. Both 16S rRNA gene amplicon sequencing and shallow shotgun sequencing were performed on DNA extracted from 666 fecal samples from the Tulsa-1000 and NeuroMAP CoBRE cohorts. The results highlight the significant influence of medication use; antidepressant use is associated with significant differences in gut microbiota beta diversity and has a larger effect size than NPD diagnosis. Next, specific microbes were associated with ANXD and MDD, highlighting their potential for non-pharmacological intervention. Finally, the study demonstrated the capability of Random Forest classifiers to predict diagnoses of NPD and medication use from microbial profiles, suggesting a promising direction for the use of gut microbiota as biomarkers for NPD. The findings suggest that future research on the gut microbiota’s role in NPD and its interactions with pharmacological treatments are needed.
A genetic exploration of the relationship between Posttraumatic Stress Disorder and cardiovascular diseases
Authors: Lukas Eva , Veeneman Rada R , Smit Dirk JA ,   CHARGE Inflammation Working Group, Vermeulen Jentien M , Pathak Gita A , Polimanti Renato , Verweij Karin JH , Treur Jorien L 
Published: March 2024

ABSTRACTBackground and AimsExperiencing a traumatic event may lead to Posttraumatic Stress Disorder (PTSD), including symptoms such as flashbacks and hyperarousal. Individuals suffering from PTSD are at increased risk of cardiovascu-lar disease (CVD), but it is unclear why. This study assesses shared genetic liability and potential causal pathways between PTSD and CVD.MethodsWe leveraged summary-level data of genome-wide association studies (PTSD: N= 1,222,882; atrial fibril-lation (AF): N=482,409; coronary artery disease (CAD): N=1,165,690; hypertension: N=458,554; heart failure (HF): N=977,323). First, we estimated genetic correlations and utilized genomic structural equation modeling to identify a common genetic factor for PTSD and CVD. Next, we assessed biological, behavioural, and psychosocial factors as potential mediators. Finally, we employed multivariable Mendelian randomiza-tion to examine causal pathways between PTSD and CVD, incorporating the same potential mediators.ResultsSignificant genetic correlations were found between PTSD and CAD, HT, and HF (rg=0.21-0.32, p≤3.08·10*16), but not between PTSD and AF. Insomnia, smoking, alcohol dependence, waist-to-hip ratio, and inflammation (IL6, C-reactive protein) partly mediated these associations. Mendelian randomization indicated that PTSD causally increases CAD (IVW OR=1.53, 95% CIs=1.19-1.96, p=0.001), HF (OR=1.44, CIs=1.08-1.92, p=0.012), and to a lesser degree hypertension (OR=1.25, CIs=1.05-1.49, p=0.012). While insomnia, smoking, alcohol, and inflammation were important mediators, independent causal effects also remained.ConclusionsIn addition to shared genetic liability between PTSD and CVD, we present strong evidence for causal effects of PTSD on CVD. Crucially, we implicate specific lifestyle and biological mediators (insomnia, substance use, inflammation) which has important implications for interventions to prevent CVD in PTSD patients.Translational perspectiveThe significant mental and physical strain experienced by patients suffering from Post-traumatic Stress Disorder (PTSD) remains a domain necessitating further insight for the development of effective intervention strategies. Our study elucidates the complex genetic architecture that underlies the relationship between PTSD and cardiovascular disease. We present evidence supporting a causal link from PTSD to coronary artery disease and heart failure. Further, we identify various mediators of this causality, including inflammatory markers, substance use, waist-to-hip ratio and sleep deprivation. Our work calls for tar-geted preventive and therapeutic approaches to reduce the dual burden of mental and physical disease in PTSD patients.
Color congruence on Instagram: the role of flow and aesthetic experience
Authors: Luarn Pin , Chen Chiao-Chieh , Chiu Yu-Ping 
Published: March 2024

PurposeSocial media has emerged as a prominent platform for marketers and brands to disseminate brand-related information. This study aims to investigate the impact of color congruence between themes and background on marketing effectiveness, focusing specifically on Instagram.Design/methodology/approachA laboratory experiment was conducted to investigate how color congruence between themes and background in brand posts influences flow and aesthetic experience, subsequently affecting marketing communication parameters such as brand attitude, visit intention, and eWOM on Instagram. Moreover, Adidas Originals was selected as the focal brand, and blue and white color was chosen as the primary color palette for the experimental material.FindingsThis study demonstrates that color congruence, regardless of brand layout or post, significantly influences flow and aesthetic experience, subsequently affecting marketing effectiveness.Originality/valueThis study contributes to the theoretical understanding of congruence theory and social media marketing, providing valuable insights for brands to enhance their communication through photographs and effectively manage their official Instagram accounts.