bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peli1 Deficiency in Macrophages Attenuates Pulmonary Hypertension by Enhancing Foxp1-Mediated Transcriptional Inhibition of IL-6
Authors: Lin Donghai , Hu Li , Wei Dong , Li Yan , Yu Yanfang , Wang Qiang , Sun Xiaoxuan , Shen Yueyao , Yu Youjia , Li Kai , Zhang Zhiwei , Cao Yue , Li Jiantao , Li Yuehua , Fulton David , Chen Jingyu , Wang Jie , Huang Huijie , Chen Feng 
Published: December 2024

BACKGROUND:
The infiltration of macrophages into the lungs is a common characteristic of perivascular inflammation, contributing to vascular remodeling in pulmonary hypertension (PH). Peli1 (pellino E3 ubiquitin-protein ligase 1) plays a critical role in regulating the production of proinflammatory cytokines and the polarization of macrophages in various diseases. However, the role of Peli1 in PH remains to be investigated.

METHODS:
The expression and biological function of Peli1 were investigated in both human and experimental models of PH. Peli1-deficient mice and bone marrow transplant mice were utilized to explore the roles of Peli1 in macrophages in vivo. Proteomic analysis and molecular biology techniques were used to uncover the underlying mechanisms.

RESULTS:

The upregulation of Peli1 in the lungs and alveolar macrophages was observed in hypoxia-treated mice. Peli1 knockout mice and myeloid Peli1-deficient mice significantly ameliorated hypoxia-induced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling. Mechanistically, Peli1 facilitated the ubiquitination and subsequent proteasomal degradation of Foxp1 (forkhead box p1), thereby alleviating its suppression of
IL
(
interleukin
)
-6
transcription and contributing to macrophage activation. Furthermore, myeloid Foxp1 deficiency partially eliminates the protective effect of myeloid Peli1 deficiency in hypoxia-induced PH mice.

CONCLUSIONS:
Our findings demonstrate that the Peli1-Foxp1-IL-6 pathway plays a crucial role in macrophage activation and recruitment during the development of PH, underscoring the potential of Peli1 as a therapeutic target for PH.
Analyzing the brain’s dynamic response to targeted stimulation using generative modeling
Authors: Maran Rishikesan , Müller Eli J. , Fulcher Ben D. 
Published: December 2024

Abstract
Generative models of brain activity have been instrumental in testing hypothesized mechanisms underlying brain dynamics against experimental datasets. Beyond capturing the key mechanisms underlying spontaneous brain dynamics, these models hold an exciting potential for understanding the mechanisms underlying the dynamics evoked by targeted brain stimulation techniques. This paper delves into this emerging application, using concepts from dynamical systems theory to argue that the stimulus-evoked dynamics in such experiments may be shaped by new types of mechanisms distinct from those that dominate spontaneous dynamics. We review and discuss (a) the targeted experimental techniques across spatial scales that can both perturb the brain to novel states and resolve its relaxation trajectory back to spontaneous dynamics and (b) how we can understand these dynamics in terms of mechanisms using physiological, phenomenological, and data-driven models. A tight integration of targeted stimulation experiments with generative quantitative modeling provides an important opportunity to uncover novel mechanisms of brain dynamics that are difficult to detect in spontaneous settings.
Rescue Conversations from Dead-ends: Efficient Exploration for Task-oriented Dialogue Policy Optimization
Authors: Zhao Yangyang , Dastani Mehdi , Long Jinchuan , Wang Zhenyu , Wang Shihan 
Published: December 2024

Abstract
Training a task-oriented dialogue policy using deep reinforcement learning is promising but requires extensive environment exploration. The amount of wasted invalid exploration makes policy learning inefficient. In this paper, we define and argue that dead-end states are important reasons for invalid exploration. When a conversation enters a dead-end state, regardless of the actions taken afterward, it will continue in a dead-end trajectory until the agent reaches a termination state or maximum turn. We propose a Dead-end Detection and Resurrection (DDR) method that detects dead-end states in an efficient manner and provides a rescue action to guide and correct the exploration direction. To prevent dialogue policies from repeating errors, DDR also performs dialogue data augmentation by adding relevant experiences that include dead-end states and penalties into the experience pool. We first validate the dead-end detection reliability and then demonstrate the effectiveness and generality of the method across various domains through experiments on four public dialogue datasets.
Filtered Corpus Training (FiCT) Shows that Language Models Can Generalize from Indirect Evidence
Authors: Patil Abhinav , Jumelet Jaap , Chiu Yu Ying , Lapastora Andy , Shen Peter , Wang Lexie , Willrich Clevis , Steinert-Threlkeld Shane 
Published: December 2024

Abstract
This paper introduces Filtered Corpus Training, a method that trains language models (LMs) on corpora with certain linguistic constructions filtered out from the training data, and uses it to measure the ability of LMs to perform linguistic generalization on the basis of indirect evidence. We apply the method to both LSTM and Transformer LMs (of roughly comparable size), developing filtered corpora that target a wide range of linguistic phenomena. Our results show that while transformers are better qua LMs (as measured by perplexity), both models perform equally and surprisingly well on linguistic generalization measures, suggesting that they are capable of generalizing from indirect evidence.
The Docking and Dynamics Simulation  of Natural Compounds from Abrus  precatorius L. for Investigating the Possibility  of GluR3 Inhibition to Treat Depression
Authors: Rezgui R. , Alharazi T. , Alshaghdali K. , Elnaem I. , Salih M. A. I. , Aldakheel F. , Saeed M. , Tasleem M. , Ginawi I. , Saeed A. 
Published: December 2024

Background The rising incidence of Major Depressive Disorder (MDD), in conjunction with the inadequate effectiveness and resistance observed in existing therapeutic approaches, emphasizes the urgent need to investigate novel therapeutics that provide enhanced efficacy with reduced adverse effects. Abrus precatorius L., an herb that is readily available and frequently utilized in traditional medicine, is frequently prescribed to patients suffering from neurological disorders. Purpose The goal of this study is to discover novel active compounds from the A. precatorius plant that can specifically target the GluR3 receptor using in silico techniques, to develop a safe and efficient treatment for MDD. Methods Homology modeling, molecular docking, molecular dynamics simulation, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis were employed in this investigation to screen compounds derived from A. precatorius. Their potential to inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activity, specifically glutamate receptor 3 (GluR3), which is associated with MDD, was the objective of this study. Results Among 31 compounds derived from A. precatorius, 15 successfully cleared the ADMET filter criteria. Subsequently, the best homology model of GluR3 was constructed using Phyre2. This facilitated an investigation into the intramolecular interactions exhibited by the filtered compounds. Notably, the four compounds with the most pronounced binding affinities are identified by their PubChem compound IDs (CIDs): 160511, 44257585, 1983, and 145857. The binding affinity and internal molecular interactions of the top-ranking compound, PubChem CID 160511, were subjected to further validation through MD simulations, affirming its sustained stability in binding. Conclusion CIDs: The compound 160511 cleared ADMET analysis with no notable side effects and high binding affinity and stability, making it a potential drug candidate for MDD. To ascertain the precise efficacy of medications, additional in vitro, in vivo, and clinical studies are required.
Cardiac Function Decline After General Anesthesia and Cardiac Catheterization in Pediatric Cardiac Transplant Recipients
Authors: Thimmarayan Gokul , Schmitz Michael , Spray Beverly J. , Knecht Kenneth , Garcia Xiomara , Guerrero Jorge , Dossey Amy , Reemtsen Brian , Greiten Lawrence , Heye Thomas , Chau Destiny F. 
Published: December 2024

Background Pediatric cardiac transplant recipients undergo elective cardiac catheterization and endomyocardial biopsy (CC/EMB) for graft dysfunction surveillance often facilitated by general anesthesia (GA). GA and positive pressure ventilation (PPV) also depress cardiac function confounding the graft’s functional assessment. We aimed to evaluate the frequency of cardiac function decline, going from the awake to the anesthetized state, and determine its association with anesthetic and patient-related factors. Methods Electronic medical records of pediatric heart transplant recipients undergoing CC/EMB under GA/PPV were retrospectively reviewed. Patients with awake normal cardiac function, assessed by same-day preoperative echocardiographic left ventricular shortening fraction (LVSF) ≥28% were included. A priori, groups were: (1) cardiac function decline (post- catheterization under GA, LVSF< 28%), and (2) no cardiac function decline. Univariate and logistic regression analysis accounting for repeated encounters per patient were performed. Results 225 eligible encounters occurred in 102 patients. Cardiac function declined in 17.3% (39/225) encounters, and in 25% (26/102) of patients. Logistic regression identified independent predictors as: older age (OR 1.4, 95% CI: 1.1–1.7, P = 0.002), angiotensin-converting enzyme inhibitor (ACEI) use (OR 2.5, 95% CI: 1.2–4.3, P = 0.018), and elevated right ventricular end diastolic pressure (RVEDP) (OR 2.4, 95% CI: 1.1–5.4, P = 0.039), with AUC 0.75. Older age and ACEI use ( P = 0.001) and, older age and elevated RVEDP ( P = 0.037) were correlated. Conclusions One in 4 patients demonstrated cardiac function decline from the awake to the anesthetized state, occurring most commonly in older children with elevated RVEDP using ACEI. Most cardiac function declines are unrelated to rejection.
Design of an international, phase IV, open-label study of simoctocog alfa in women/girls with hemophilia A undergoing surgery (NuDIMENSION)
Authors: Marquardt Natascha , Langer Florian , Holstein Katharina , Álvarez Román María Teresa , Núñez Vázquez Ramiro , Miljić Predrag , Drillaud Nicolas , Ardillon Laurent , Lehtinen Anna-Elina , Santoro Rita Carlotta , Napolitano Mariasanta , Siragusa Sergio , Gidley Gillian , Jansen Martina , Knaub Sigurd , Oldenburg Johannes 
Published: December 2024

Background: Although hemophilia A mainly affects males, carriers (defined as females with hemophilia A, as well as symptomatic or asymptomatic hemophilia A carriers) are at risk of excessive bleeding, particularly during trauma or during surgical procedures. Clinical trials have focused on male patients with severe disease, and data for females are limited. Improved, evidence-based treatment guidelines for management of hemophilia A carriers are required. Objectives and design: The NuDIMENSION study is a phase IV, prospective, open-label, single-arm study that will evaluate the perioperative efficacy and safety of simoctocog alfa (Nuwiq®), a recombinant factor VIII (FVIII), in women/girls with hemophilia A undergoing major surgery. The study will be conducted at approximately 15 centers worldwide. Women/girls aged ⩾12 years, with mild or moderate hemophilia A (residual FVIII activity (FVIII:C) ⩾1% to <40%) and with no current/past FVIII inhibitors are eligible. All patients must be scheduled to undergo a major surgical procedure during which simoctocog alfa will be administered. Methods and analysis: The primary endpoint is overall perioperative hemostatic efficacy (“success” or “failure”) of simoctocog alfa. Hemostatic efficacy will be assessed at the end of surgery and at the end of the postoperative period (i.e., completion of wound healing), with overall adjudication by an Independent Data Monitoring Committee. Safety endpoints will include the incidences of thrombotic events and FVIII inhibitor development. The aim is to recruit 28 patients to achieve 26 evaluable surgeries. Ethics: Ethical approval will be received from institutional review boards/independent ethics committees, and the study will be conducted in compliance with the Declaration of Helsinki. Discussion: Data from NuDIMENSION will generate much-needed evidence on surgical management of women/girls with hemophilia A, which will help to enable the development of treatment guidelines specific for such patients. Trial Registration: CT EU 2022-502061-17-00; NCT05936580
Esomeprazole’s Antifibrotic Effects on Rats With Epidural Fibrosis
Authors: Borekci Ali , Kuru Bektasoglu Pinar , Somay Adnan , Hazneci Jülide , Gürer Bora 
Published: December 2024

Study Design Rat subjects were randomly assigned to control, local, and systemic esomeprazole groups (n = 4-6 per group). Objective Excessive scar formation after laminectomy can cause nerve entrapment and postoperative pain and discomfort. A rat laminectomy model determined whether topical application and systemic administration of esomeprazole can prevent epidural fibrosis. Methods Laminectomy alone was performed in the control group. Topical esomeprazole was introduced to the laminectomy area in the local esomeprazole group. Intraperitoneal esomeprazole was introduced in the systemic esomeprazole group following laminectomy. Macroscopic and histopathologic examinations were performed four weeks after laminectomy. Results In the systemic esomeprazole group, the macroscopic epidural fibrosis score was less than the control group ( P < 0.001). Microscopic epidural fibrosis score and fibroblast cell density classification scores in local and systemic esomeprazole groups did not significantly differ. Fibrosis thickness was significantly lower in the local and systemic esomeprazole groups compared to the control group ( P < 0.01, P < 0.001, respectively). Conclusions Esomeprazole reduced the formation of epidural fibrosis in the rat laminectomy model.
RAPID-CRISPR: highly sensitive diagnostic assay for detection of PML::RARA isoforms in acute promyelocytic leukemia
Authors: Maity Akash , Sathyanarayanan Amritha , Kumar Rohit , Vora Jesal , Gawde Jitendra , Jain Hasmukh , Bagal Bhausaheb , Subramanian P. G. , Sengar Manju , Khattry Navin , Patkar Nikhil , Hasan Syed K. 
Published: December 2024

Abstract
Acute promyelocytic leukemia (APL), distinguished by the presence of PML::RARA fusion transcript, is a medical emergency because of its high early death rate, which is preventable when diagnosed early. Current diagnostic methods are precise and reliable but are time intensive, require sophisticated instruments, and analytical expertise. This study has redefined APL identification by CRISPR system (RAPID-CRISPR) to rapidly (&lt;3 hours) detect PML::RARA. APL cell lines (NB4 and UF-1) and bone marrow/peripheral blood samples from 74 patients with APL (66/8, retrospective/prospective) and 48 controls were included in the study. We used a DETECTR (DNA endonuclease-targeted CRISPR transreporter) assay to identify the bcr1, bcr2, and bcr3 PML::RARA isoforms. To ensure high specificity, we used PML::RARA–specific loop-mediated isothermal amplification (LAMP) primers, synthetic protospacer-adjacent motif sites, and isoform-specific CRISPR RNAs. RAPID-CRISPR recognized APL with 100% sensitivity and 100% specificity in an ambispective cohort of patient samples. Furthermore, our blinded validation approach to detect PML::RARA in an unbiased manner provides an additional layer in the diagnostic precision of APL. RAPID-CRISPR demonstrated superior sensitivity, detecting as few as 1 copy of PML::RARA compared with 10 copies by the gold-standard reverse transcriptase qualitative and quantitative polymerase chain reaction. The nucleic acid extraction–free protocol combined with the 1-step reverse transcriptase LAMP–based DETECTR followed by lateral flow readout makes the RAPID-CRISPR assay suitable for diagnosing APL in point-of-care settings. This simple, cost-effective tool, with its easy-to-read format, is particularly valuable in underresourced regions. The assay facilitates timely diagnosis and prompt administration of lifesaving therapies such as all-trans retinoic acid and arsenic trioxide in APL.
SENP3 mediates deSUMOylation of SIX1 to promote prostate cancer proliferation and migration
Authors: Shao Zhenlong , Liu Shutong , Sun Wenshuang , Zhuang Xuefen , Yin Shusha , Cheng Ji , Xia Xiaohong , Liao Yuning , Liu Jinbao , Huang Hongbiao 
Published: December 2024

Abstract
Background
Sentrin/SUMO-specific protease 3 (SENP3) is essential to regulate protein stability and function in normal and cancer cells. Nevertheless, its role and action mechanisms in prostate cancer (PCa) remain elusive. Thus, clarification of SENP3’s involvement and the SUMOylation process in PCa is pivotal for discovering potential targets and understanding SUMOylation dynamics.

Methods
Cell viability, EdU staining, live cell imaging, and cell cycle assays were used to determine proliferation of PCa cells. Transwell and wound-healing assays were used to detect migration of PCa cells. The interaction between SENP3 and SIX1 was determined by co-immunoprecipitation, western blotting, and immunofluorescence assays. Xenograft models established on NOD-SCID mice were used to evaluate in vivo effects post SENP3 knockdown. Immunohistochemistry was performed to investigate the expression of SENP3 in PCa tissues.

Results
This study found that SENP3 is highly expressed in PCa cell lines and tissues from PCa patients. Overexpressed SENP3 is associated with metastatic malignancy in PCa. Various in vivo and in vitro experiments confirmed that SENP3 promotes the proliferation and migration of PCa. In addition, SENP3 interacts with the SD domain of SIX1 and mediates its deSUMOylation and protein stability. Lys154 (K154) is required for the SUMOylation of SIX1. More importantly, SENP3 promotes the malignancy of PCa through the regulation of SIX1.

Conclusions
We unravel the significant role of SENP3 in regulating protein stability of SIX1 and progression of PCa, which may deepen our understanding of the SUMOylation modification and provide a promising target for management of metastatic PCa.
Salivary gland protective and antiinflammatory effects of genistein in Sjögren’s syndrome by inhibiting Xist/ACSL4-mediated ferroptosis following binding to estrogen receptor-alpha
Authors: Mao Tianjiao , Wei Wei , Chen Bo , Chen Yixin , Liang Shuqi , Chen Guiping , Liu Zhuoyuan , Wu Xiaodan , Wu Lihong , Li Xiaomeng , Watanabe Nobumoto , Mayo Kevin H. , Pathak Janak L. , Li Jiang 
Published: December 2024

Abstract
Background
Sjögren’s syndrome (SS) is an autoimmune disease with limited effective treatment options. This study aimed to explore the underlying mechanism by which genistein–estrogen receptor alpha (ERα) complex targets X-inactive specific transcript (Xist) then leads to the inhibition of ferroptosis by regulating acyl-CoA synthetase long-chain family member 4 (ACSL4) expression in salivary gland epithelial cells (SGECs) to attenuate SS.

Methods
The effects of genistein treatment on the progression and underlying mechanism of SS were investigated using nondiabetic obese (NOD)/LtJ mice in vivo and Interferon-γ (IFNγ)-treated SGECs in vitro. Water intake and saliva flow rate were measured to evaluate the severity of xerostomia. Hematoxylin–eosin staining, real-time quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay were conducted to examine the pathological lesions. Western blotting and immunohistochemistry analysis were used to evaluate the protein expression. RNA sequencing and RNA fluorescence in situ hybridization were employed to verify the relationship between Xist and ACSL4. Surface plasmon resonance, molecular docking, and molecular dynamics were used to investigate the binding between genistein and ERα. Furthermore, a chromatin immunoprecipitation assay was used to analyze ERα–XIST promoter interactions. The levels of malondialdehyde, glutathione, Fe2+, and mitochondrial changes were measured to evaluate ferroptosis of SGECs.

Results
In NOD/LtJ mice, a ferroptosis phenotype was observed in salivary glands, characterized by downregulated Xist and upregulated X chromosome inactivation gene Acsl4. Genistein significantly alleviated SS symptoms, upregulated the Xist gene, and downregulated Acsl4 expression. Genistein upregulated Xist expression in the salivary gland of NOD/LtJ mice via the ERα signaling pathway. It downregulated Acsl4 and ferroptosis in the salivary glands of NOD/LtJ mice. IFNγ-treatment induced inflammation and ferroptosis in SGECs. Genistein binding to ERα upregulated XIST, and aquaporin 5 expression, downregulated ACSL4, and SS antigen B expression, and reversed ferroptosis in SGECs. Genistein mitigated inflammation and ferroptosis in SGECs by upregulated-XIST-mediated ACSL4 gene silencing.

Conclusions
Genistein binding to ERα targets Xist, leading to inhibiting ferroptosis by regulating ACSL4 expression in SGECs. This finding provides evidence for genistein as a treatment for SS and identifies Xist as a novel drug target for SS drug development, offering great promise for improving SS outcomes.

Graphical Abstract