bluuebunny/crossref_metadata_2025_split huggingface dataset:
The nuclear receptor Nurr1 is preferentially expressed in human pro-inflammatory macrophages and limits their inflammatory profile
Authors: Solís-Barbosa Miguel A , Santana Eduardo , Muñoz-Torres José R , Segovia-Gamboa Norma C , Patiño-Martínez Eduardo , Meraz-Ríos Marco A , Samaniego Rafael , Sánchez-Mateos Paloma , Sánchez-Torres Carmen 
Published: December 2023

Abstract
Nurr1 is a member of the orphan nuclear receptor family NR4A (nuclear receptor subfamily 4 group A) that modulates inflammation in several cell lineages, both positively and negatively. Macrophages are key regulators of inflammatory responses, yet information about the role of Nurr1 in human macrophages is scarce. Here we examined Nurr1 expression and activity in steady state and activated human macrophages. Pro- and anti-inflammatory macrophages were generated in vitro by culture of blood monocytes with granulocyte/macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), respectively. Nurr1 expression was predominant in macrophages with the pro-inflammatory phenotype. Nurr1 activation with the agonists 1,1-bis(3ʹ-indolyl)-1-(p-chlorophenyl) methane (C-DIM12) or isoxazolo-pyridinone 7e (IP7e) did not globally modify the polarization status of pro-inflammatory macrophages, but they decreased their production of TNF, IL-1β, IL-6, IL-8, IL-12 p40, CCL2, IFN-β, and reactive oxygen species, with variable potencies. Conversely, Nurr1 deficient macrophages increased the expression of transcripts encoding inflammatory mediators, particularly that of IL6, IFNB1, and CCL2. Mechanistically, endogenous Nurr1 interacted with NF-κB p65 in basal conditions and upon lipopolysaccharide (LPS)-mediated activation. C-DIM12 stabilized those complexes in cells exposed to LPS and concurrently decreased NF-κB transcriptional activity and p65 nuclear translocation. Expression of high levels of Nurr1 was associated with a subset of dermal macrophages that display enhanced levels of TNF and lower expression of the anti-inflammatory marker CD163L1 in skin lesions from patients with bullous pemphigoid (BP), a chronic inflammatory autoimmune blistering disorder. These results suggest that Nurr1 expression is linked with the pro-inflammatory phenotype of human macrophages, both in vivo and in vitro, where it may constitute a brake to attenuate the synthesis of inflammatory mediators.
Effect of albumin substitution on pharmacokinetics of piperacillin/tazobactam in patients with severe burn injury admitted to the ICU
Authors: Wulkersdorfer Beatrix , Bergmann Felix , Amann Lisa , Fochtmann-Frana Alexandra , Al Jalali Valentin , Kurdina Elizaveta , Lackner Edith , Wicha Sebastian G , Dorn Christoph , Schäfer Bruno , Ihra Gerald , Rath Thomas , Radtke Christine , Zeitlinger Markus 
Published: December 2023

Abstract

Background
Pathophysiological changes in severely burned patients alter the pharmacokinetics (PK) of anti-infective agents, potentially leading to subtherapeutic concentrations at the target site. Albumin supplementation, to support fluid resuscitation, may affect pharmacokinetic properties by binding drugs. This study aimed to investigate the PK of piperacillin/tazobactam in burn patients admitted to the ICU before and after albumin substitution as total and unbound concentrations in plasma.

Patients and methods
Patients admitted to the ICU and scheduled for 4.5 g piperacillin/tazobactam administration and 200 mL of 20% albumin substitution as part of clinical routine were included. Patients underwent IV microdialysis, and simultaneous arterial plasma sampling, at baseline and multiple timepoints after drug administration. PK analysis of total and unbound drug concentrations under steady-state conditions was performed before and after albumin supplementation.

Results
A total of seven patients with second- to third-degree burns involving 20%–60% of the total body surface were enrolled. Mean (SD) AUC0–8 (h·mg/L) of total piperacillin/tazobactam before and after albumin substitution were 402.1 (242)/53.2 (27) and 521.8 (363)/59.7 (32), respectively. Unbound mean AUC0–8 before and after albumin supplementation were 398.9 (204)/54.5 (25) and 456.4 (439)/64.5 (82), respectively.

Conclusions
Albumin supplementation had little impact on the PK of piperacillin/tazobactam. After albumin supplementation, there was a numerical increase in mean AUC0–8 of total and unbound piperacillin/tazobactam, whereas similar Cmax values were observed. Future studies may investigate the effect of albumin supplementation on drugs with a higher plasma protein binding.
Evaluation framework for conversational agents with artificial intelligence in health interventions: a systematic scoping review
Authors: Ding Hang , Simmich Joshua , Vaezipour Atiyeh , Andrews Nicole , Russell Trevor 
Published: December 2023

AbstractObjectivesConversational agents (CAs) with emerging artificial intelligence present new opportunities to assist in health interventions but are difficult to evaluate, deterring their applications in the real world. We aimed to synthesize existing evidence and knowledge and outline an evaluation framework for CA interventions.Materials and MethodsWe conducted a systematic scoping review to investigate designs and outcome measures used in the studies that evaluated CAs for health interventions. We then nested the results into an overarching digital health framework proposed by the World Health Organization (WHO).ResultsThe review included 81 studies evaluating CAs in experimental (n = 59), observational (n = 15) trials, and other research designs (n = 7). Most studies (n = 72, 89%) were published in the past 5 years. The proposed CA-evaluation framework includes 4 evaluation stages: (1) feasibility/usability, (2) efficacy, (3) effectiveness, and (4) implementation, aligning with WHO’s stepwise evaluation strategy. Across these stages, this article presents the essential evidence of different study designs (n = 8), sample sizes, and main evaluation categories (n = 7) with subcategories (n = 40). The main evaluation categories included (1) functionality, (2) safety and information quality, (3) user experience, (4) clinical and health outcomes, (5) costs and cost benefits, (6) usage, adherence, and uptake, and (7) user characteristics for implementation research. Furthermore, the framework highlighted the essential evaluation areas (potential primary outcomes) and gaps across the evaluation stages.Discussion and ConclusionThis review presents a new framework with practical design details to support the evaluation of CA interventions in healthcare research.Protocol registrationThe Open Science Framework (https://osf.io/9hq2v) on March 22, 2021.
Phase I/IIa trial of 18F-prostate specific membrane antigen (PSMA) 1007 PET/CT in healthy volunteers and prostate cancer patients
Authors: Tateishi Ukihide , Kimura Koichiro , Tsuchiya Junichi , Kano Daisuke , Watabe Tadashi , Nonomura Norio , Saito Katsuhiko , Yokoyama Kota , Yamagiwa Ken , Adachi Takuya , Kojima Yuji , Yoshida Soichiro , Fujii Yasuhisa 
Published: December 2023

Abstract

Objective
18F-PSMA 1007 is a promising PET tracer for prostate cancer. We aimed to examine the safety, biodistribution, radiation dosimetry, and clinical effectiveness in Japanese healthy volunteers and patients with prostate cancer.

Methods
Part A evaluated the pharmacokinetics and exposure doses in three healthy volunteers. Part B evaluated the diagnostic accuracy in patients with untreated preoperative prostate cancer (Cohort 1, n = 7) and patients with biochemical recurrence (Cohort 2, n = 3). All subjects received a single dose of 3.7 MBq/kg 18F-PSMA 1007. Results: 18F-PSMA 1007 was found to be safe and well tolerated in all subjects. No serous AEs or drug-related AEs were identified during the present study. The average blood radioactivity concentration reached a maximum of 47.87 ± 1.05 (percentage of injected dose [%ID]/ml) at 5 min and then decreased to 1.60 ± 0.78 in 6 h. The systemic radioactivity reached a maximum of 211.05 ± 6.77 (%ID$\times$103) at 5 min and decreased to 7.18 ± 3.91 in 6 h. The sensitivity and positive predictive value were 100% and 100% based on both pathologic and imaging confirmation as gold standard. In Cohort 1, 15 primary foci (11.9%) were &gt;5 mm in the largest diameter and identified in 39 of 126 segments (30.1%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for 60 min uptake time acquisition were 80.0, 96.5, 91.4, 91.2 and 91.3%, respectively.

Conclusions
Our study revealed that 18F-PSMA 1007 was safe, well tolerated and showed high accuracy in the diagnosis of prostate cancer.
Effect of ethanol exposure on innate immune response in sepsis
Authors: Roychowdhury Sanjoy , Pant Bishnu , Cross Emily , Scheraga Rachel , Vachharajani Vidula 
Published: December 2023

Abstract
Alcohol use disorder, reported by 1 in 8 critically ill patients, is a risk factor for death in sepsis patients. Sepsis, the leading cause of death, kills over 270,000 patients in the United States alone and remains without targeted therapy. Immune response in sepsis transitions from an early hyperinflammation to persistent inflammation and immunosuppression and multiple organ dysfunction during late sepsis. Innate immunity is the first line of defense against pathogen invasion. Ethanol exposure is known to impair innate and adaptive immune response and bacterial clearance in sepsis patients. Specifically, ethanol exposure is known to modulate every aspect of innate immune response with and without sepsis. Multiple molecular mechanisms are implicated in causing dysregulated immune response in ethanol exposure with sepsis, but targeted treatments have remained elusive. In this article, we outline the effects of ethanol exposure on various innate immune cell types in general and during sepsis.
Health-related quality of life with pembrolizumab plus chemotherapy vs placebo plus chemotherapy for advanced triple-negative breast cancer: KEYNOTE-355
Authors: Cescon David W , Schmid Peter , Rugo Hope S , Im Seock-Ah , Md. Yusof Mastura , Gallardo Carlos , Lipatov Oleg , Barrios Carlos H , Perez-Garcia Jose , Iwata Hiroji , Masuda Norikazu , Otero Marco Torregroza , Gokmen Erhan , Loi Sherene , Haiderali Amin , Zhou Xuan , Guo Zifang , Nguyen Allison Martin , Cortes Javier 
Published: December 2023

Abstract

Background
In KEYNOTE-355 (NCT02819518), the addition of pembrolizumab to chemotherapy led to statistically significant improvements in progression-free survival and overall survival in patients with advanced triple-negative breast cancer with tumor programmed cell death ligand 1 (PD-L1) combined positive score of at least 10. We report patient-reported outcomes from KEYNOTE-355.

Methods
Patients were randomly assigned 2:1 to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus investigator’s choice chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30), Breast Cancer–Specific Quality of Life Questionnaire, and EuroQol 5-Dimension questionnaire visual analog scale were prespecified. Patient-reported outcomes were analyzed for patients who received at least 1 dose of study treatment and completed at least 1 patient-reported outcome assessment. Changes in patient-reported outcome scores from baseline were assessed at week 15 (latest time point at which completion and compliance rates were at least 60% and at least 80%, respectively). Time to deterioration in patient-reported outcomes was defined as time to first onset of at least a 10-point worsening in score from baseline.

Results
Patient-reported outcome analyses included 317 patients with tumor PD-L1 combined positive score of at least 10 (pembrolizumab plus chemotherapy: n = 217; placebo plus chemotherapy: n = 100). There were no between-group differences in change from baseline to week 15 in QLQ-C30 global health status/quality of life (QOL; least-squares mean difference = −1.81, 95% confidence interval [CI] = −6.92 to 3.30), emotional functioning (least-squares mean difference = −1.43, 95% CI = −7.03 to 4.16), physical functioning (least-squares mean difference = −1.05, 95% CI = −6.59 to 4.50), or EuroQol 5-Dimension questionnaire visual analog scale (least-squares mean difference = 0.18, 95% CI = −5.04 to 5.39) and no between-group difference in time to deterioration in QLQ-C30 global health status/QOL, emotional functioning, or physical functioning.

Conclusions
Together with the efficacy and safety findings, patient-reported outcome results from KEYNOTE-355 support pembrolizumab plus chemotherapy as a standard of care for patients with advanced triple-negative breast cancer with tumor PD-L1 expression (combined positive score ≥10).
The journalistic preference for extreme exemplars: educational socialization, psychological biases, or editorial policy?
Authors: Aarøe Lene , Andersen Kim , Skovsgaard Morten , Svith Flemming , Schmøkel Rasmus 
Published: December 2023

Abstract
Exemplars are central in news reporting. However, extreme negative exemplars can bias citizens’ factual perceptions and attributions of political responsibility. Nonetheless, our knowledge of the factors shaping journalistic preferences for including exemplars in news stories is limited. We investigate the extent to which educational socialization, psychological biases, and editorial policy shape journalistic preferences for extreme negative exemplars. We field large-scale survey experiments to a population sample of journalism students, a nationally representative sample of citizens, and a representative sample of “young people” and obtain evaluations of news value, newsworthiness, and behavioral measures of the actual write-up of news articles. We find significant support for the role of editorial policy and limited support for the role of educational socialization and psychological biases. In a time where economic pressures and the proliferation of digital media potentially lead editors to prioritize clickbait, these findings suggest that structural biases in news coverage may be aggravated.
Interstitial fluid transport in a multi-compartment model of cerebral blood flow
Authors: Payne Stephen 
Published: December 2023

Abstract
Whole brain models are a valuable tool to gain a better understanding of cerebral blood flow and metabolism. Recent work has developed multi-compartment models of blood flow and oxygen transport that can be used in a finite element framework to simulate whole brain behaviour with low computational expense, helping to move such tools towards clinical application. However, the transport of fluid between the vascular space and the interstitial space has not yet been considered in detail in this context, despite this playing an important role in several cerebrovascular diseases. In this study, an extended framework is proposed to include this transport, coupled with a linear elastic model of tissue displacement to simulate the movement of fluid and the resulting displacement of brain tissue. This framework is compared in detail with previous models. The resulting equations are found to exhibit multiple time scales, and a separation of scales is performed to analyse the behaviour at different time scales. Finally, a simplified model is proposed that can be easily implemented within existing computational frameworks, providing a valuable extension of the pathological conditions that can be simulated.
Aberrant accumulation of ceramides in mitochondria triggers cell death by inducing autophagy in Arabidopsis
Authors: Bao He-Nan , Yin Jian , Wang Ling-Yan , Wang Rui-Hua , Huang Li-Qun , Chen Yi-Li , Wu Jian-Xin , Sun Jia-Qi , Liu Wei-Wei , Yao Nan , Li Jian 
Published: December 2023

Abstract
Sphingolipids are membrane lipids and play critical roles in signal transduction. Ceramides are central components of sphingolipid metabolism that are involved in cell death. However, the mechanism of ceramides regulating cell death in plants remains unclear. Here, we found that ceramides accumulated in mitochondria of accelerated cell death 5 mutant (acd5), and expression of mitochondrion-localized ceramide kinase (ACD5) suppressed mitochondrial ceramide accumulation and the acd5 cell death phenotype. Using immuno-electron microscopy, we observed hyperaccumulation of ceramides in acer acd5 double mutants, which are characterized by mutations in both ACER (alkaline ceramidase) and ACD5 genes. The results confirmed that plants with specific ceramide accumulation exhibited localization of ceramides to mitochondria, resulting in an increase in mitochondrial reactive oxygen species production. Interestingly, when compared with the wild type, autophagy-deficient mutants showed stronger resistance to ceramide-induced cell death. Lipid profiling analysis demonstrated that plants with ceramide accumulation exhibited a significant increase in phosphatidylethanolamine levels. Furthermore, exogenous ceramide treatment or endogenous ceramide accumulation induces autophagy. When exposed to exogenous ceramides, an increase in the level of the autophagy-specific ubiquitin-like protein, ATG8e, associated with mitochondria, where it directly bound to ceramides. Taken together, we propose that the accumulation of ceramides in mitochondria can induce cell death by regulating autophagy.
Identification of promoter targets by Aureochrome 1a in the diatom Phaeodactylum tricornutum
Authors: Im Soo Hyun , Lepetit Bernard , Mosesso Niccolò , Shrestha Sandeep , Weiss Laura , Nymark Marianne , Roellig Robert , Wilhelm Christian , Isono Erika , Kroth Peter G 
Published: December 2023

Abstract
Aureochromes (AUREOs) are unique blue light receptors and transcription factors found only in stramenopile algae. While each of the four AUREOs identified in the diatom Phaeodactylum tricornutum may have a specific function, PtAUREO1a has been shown to have a strong impact on overall gene regulation, when light changes from red to blue light conditions. Despite its significance, the molecular mechanism of PtAUREO1a is largely unexplored. To comprehend the overall process of gene regulation by PtAUREO1a, we conducted a series of in vitro and in vivo experiments, including pull-down assays, yeast one-hybrid experiments, and phenotypical characterization using recombinant PtAUREOs and diatom mutant lines expressing a modified PtAureo1a gene. We describe the distinct light absorption properties of four PtAUREOs and the formation of all combinations of their potential dimers. We demonstrate the capability of PtAUREO1a and 1b to activate the genes, diatom-specific cyclin 2, PtAureo1a, and PtAureo1c under both light and dark conditions. Using mutant lines expressing a modified PtAUREO1a protein with a considerably reduced light absorption, we found novel evidence that PtAUREO1a regulates the expression of PtLHCF15, which is essential for red light acclimation. Based on current knowledge, we present a working model of PtAUREO1a gene regulation properties.
Environmental regulation of male fertility is mediated through Arabidopsis transcription factors bHLH89, 91, and 10
Authors: Robson Jordan K , Tidy Alison C , Thomas Stephen G , Wilson Zoe A 
Published: December 2023

Abstract
Formation of functional pollen and successful fertilization rely on the spatial and temporal regulation of anther and pollen development. This process responds to environmental cues to maintain optimal fertility despite climatic changes. Arabidopsis transcription factors basic helix–loop–helix (bHLH) 10, 89, and 91 were previously thought to be functionally redundant in their control of male reproductive development, however here we show that they play distinct roles in the integration of light signals to maintain pollen development under different environmental conditions. Combinations of the double and triple bHLH10,89,91 mutants were analysed under normal (200 μmol m–2 s–1) and low (50 μmol m–2 s–1) light conditions to determine the impact on fertility. Transcriptomic analysis of a new conditionally sterile bhlh89,91 double mutant shows differential regulation of genes related to sexual reproduction, hormone signal transduction, and lipid storage and metabolism under low light. Here we have shown that bHLH89 and bHLH91 play a role in regulating fertility in response to light, suggesting that they function in mitigating environmental variation to ensure fertility is maintained under environmental stress.
Low sucrose availability reduces basal spikelet fertility by inducing abscisic acid and jasmonic acid synthesis in wheat
Authors: Sun Wan , Lu Chongjing , Wen Liangyun , Liu Yaqun , Zhou Xiaohan , Xiao Xuechen , Guo Xiaolei , Wang Zhimin , Sun Zhencai , Zhang Zhen , Zhang Yinghua 
Published: December 2023

Abstract
Within a spike of wheat, the central spikelets usually generate three to four fertile florets, while the basal spikelets generate zero to one fertile floret. The physiological and transcriptional mechanism behind the difference in fertility between the basal and central spikelets is unclear. This study reports a high temporal resolution investigation of transcriptomes, number and morphology of floret primordia, and physiological traits. The W6.5–W7.5 stage was regarded as the boundary to distinguish between fertile and abortive floret primordia; those floret primordia reaching the W6.5–W7.5 stage during the differentiation phase (3–9 d after terminal spikelet stage) usually developed into fertile florets in the next dimorphism phase (12–27 d after terminal spikelet stage), whereas the others aborted. The central spikelets had a greater number of fertile florets than the basal spikelets, which was associated with more floret primordia reaching the W6.5–W7.5 stage. Physiological and transcriptional results demonstrated that the central spikelets had a higher sucrose content and lower abscisic acid (ABA) and jasmonic acid (JA) accumulation than the basal spikelets due to down-regulation of genes involved in ABA and JA synthesis. Collectively, we propose a model in which ABA and JA accumulation is induced under limiting sucrose availability (basal spikelet) through the up-regulation of genes involved in ABA and JA synthesis; this leads to floret primordia in the basal spikelets failing to reach their fertile potential (W6.5–W7.5 stage) during the differentiation phase and then aborting. This fertility repression model may also regulate spikelet fertility in other cereal crops and potentially provides genetic resources to improve spikelet fertility.
Phosphoregulation in the N-terminus of NRT2.1 affects nitrate uptake by controlling the interaction of NRT2.1 with NAR2.1 and kinase HPCAL1 in Arabidopsis
Authors: Li Zhi , Na Wu Xu , Jacquot Aurore , Chaput Valentin , Adamo Mattia , Neuhäuser Benjamin , Straub Tatsiana , Lejay Laurence , Schulze Waltraud X 
Published: December 2023

Abstract
NRT2.1, the major high affinity nitrate transporter in roots, can be phosphorylated at five different sites within the N- and the C-terminus. Here, we characterized the functional relationship of two N-terminal phosphorylation sites, S21 and S28, in Arabidopsis. Based on a site-specific correlation network, we identified a receptor kinase (HPCAL1, AT5G49770), phosphorylating NRT2.1 at S21 and resulting in active nitrate uptake. HPCAL1 itself was regulated by phosphorylation at S839 and S870 within its kinase domain. In the active state, when S839 was dephosphorylated and S870 was phosphorylated, HPCAL1 was found to interact with the N-terminus of NRT2.1, mainly when S28 was dephosphorylated. Phosphorylation of NRT2.1 at S21 resulted in a reduced interaction of NRT2.1 with its activator NAR2.1, but nitrate transport activity remained. By contrast, phosphorylated NRT2.1 at S28 enhanced the interaction with NAR2.1, but reduced the interaction with HPCAL1. Here we identified HPCAL1 as the kinase affecting this phospho-switch through phosphorylation of NRT2.1 at S21.