bluuebunny/crossref_metadata_2025_split huggingface dataset:
K27-linked RORγt ubiquitination by Nedd4 potentiates Th17-mediated autoimmunity
Authors: Zeng Qiuming , Guo Hui , Tang Na , Renavikar Pranav S. , Karandikar Nitin J. , Lovett-Racke Amy E. , Racke Michael K. , Yan Chengkai , Tang Rong , Sinha Sushmita , Ghosh Krishnendu , Ryal Jeremy P. , Ouyang Song , Chen Min , Amari Foued , Vincenzo Coppola , Pope R. Marshall , Li Yalan , Yang Huan , Langdon Wallace Y. , Zhang Jian 
Published: February 2025

Abstract

Background
The HECT E3 ubiquitin ligase Nedd4 has been shown to positively regulate T cell responses, but its role in T helper (Th) cell differentiation and autoimmunity is unknown. Th17 cells are believed to play a pivotal role in the development and pathogenesis of autoimmune diseases. Nevertheless, the regulation of RORγt activation during Th17 cell differentiation by TCR signaling is yet to be elucidated. These uncharted aspects inspire us to explore the potential role of Nedd4 in Th17-mediated autoimmunity.

Methods
We evaluated the impact of Nedd4 deficiency on mouse T cell development and differentiation using flow cytometry and siRNA transfection, and subsequently validated these findings in T cells from patients with multiple sclerosis (MS). Furthermore, we investigated the influence of Nedd4 deficiency on Th17-mediated autoimmunity through experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Subsequently, we elucidated the molecular mechanism underlying the interaction between Nedd4 and RORgt through immunoprecipitation, mass spectrometry analysis, and lentiviral transduction. Additionally, we identified Nedd4 as an E3 ubiquitin ligase for RORγt. Moreover, we characterized the tyrosine residue sites and polyubiquitination patterns involved in RORγt ubiquitination.

Results
In this study, we report that loss of Nedd4 in T cells specifically impairs pathogenic and non-pathogenic Th17 responses, and Th17-mediated EAE development. At the molecular level, Nedd4 binds to the PPLY motif within the ligand binding domain of RORγt, and targets RORγt at K112 for K27-linked polyubiquitination, thus augmenting its activity.

Conclusion
Nedd4 is a crucial E3 ubiquitin ligase for RORγt in the regulating Th17 cell development and offers potential therapeutic benefits for treating Th17-mediated autoimmune diseases.
The integrated stress response in neurodegenerative diseases
Authors: Bravo-Jimenez Maria Astrid , Sharma Shivangi , Karimi-Abdolrezaee Soheila 
Published: February 2025

Abstract
The integrated stress response (ISR) is a conserved network in eukaryotic cells that mediates adaptive responses to diverse stressors. The ISR pathway ensures cell survival and homeostasis by regulating protein synthesis in response to internal or external stresses. In recent years, the ISR has emerged as an important regulator of the central nervous system (CNS) development, homeostasis and pathology. Dysregulation of ISR signaling has been linked to several neurodegenerative diseases. Intriguingly, while acute ISR provide neuroprotection through the activation of cell survival mechanisms, prolonged ISR can promote neurodegeneration through protein misfolding, oxidative stress, and mitochondrial dysfunction. Understanding the molecular mechanisms and dynamics of the ISR in neurodegenerative diseases aids in the development of effective therapies. Here, we will provide a timely review on the cellular and molecular mechanisms of the ISR in neurodegenerative diseases. We will highlight the current knowledge on the dual role that ISR plays as a protective or disease worsening pathway and will discuss recent advances on the therapeutic approaches that have been developed to target ISR activity in neurodegenerative diseases.
GABA regulates metabolic reprogramming to mediate the development of brain metastasis in non-small cell lung cancer
Authors: Xie Mengqing , Qin Hao , Liu Li , Wu Jing , Zhao Zhikai , Zhao Yaodong , Fang Yujia , Yu Xin , Su Chunxia 
Published: February 2025

Abstract

Background
Brain metastasis (BrM) poses a significant challenge to the prognosis and quality of life for patients with non-small cell lung cancer (NSCLC). Gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system (CNS), has been implicated in the progression of various tumors. However, its potential role in BrM of NSCLC and the underlying mechanisms remain largely unexplored.

Methods
A multi-omics approach combined with in vivo and in vitro experiments identified GABA as a key target in BrM of NSCLC. Functional and mechanistic studies were conducted to investigate how GABA mediates brain metastasis through the activation of the NF-κB pathway.

Results
GABA levels were significantly elevated in both cells and serum of patients with NSCLC who had BrM. GABA markedly enhanced the brain metastatic capabilities and malignancy of NSCLC cells. Mechanistically, tumor cells with a tendency for brain metastasis can inhibit 4-aminobutyrate aminotransferase (ABAT) by downregulating forkhead box A2 (FOXA2) expression, leading to increased GABA accumulation. GABA subsequently activates the NF-κB pathway and the astrocytes, thus facilitating the brain metastasis of NSCLC.

Conclusions
Our findings indicate that GABA plays a crucial role in the development of NSCLC brain metastasis by activating the NF-κB pathway through the FOXA2/ABAT/GABA axis. Additionally, the interaction between NSCLC and astrocytes creates an inhibitory microenvironment that promotes tumor colonization.
Chromosomal and gonadal sex have differing effects on social motivation in mice
Authors: Chaturvedi Sneha M. , Sarafinovska Simona , Selmanovic Din , McCullough Katherine B. , Swift Raylynn G. , Maloney Susan E. , Dougherty Joseph D. 
Published: February 2025

Abstract

Background
Sex differences in brain development are thought to lead to sex variation in social behavior. Sex differences are fundamentally driven by both gonadal hormones and sex chromosomes, yet little is known about the independent effects of each on social behavior. Further, mouse models of the genetic liability for the neurodevelopmental disorder MYT1L Syndrome have shown sex-specific deficits in social motivation. In this study, we aimed to determine if gonadal hormones or sex chromosomes primarily mediate the sex differences seen in mouse social behavior, both at baseline and in the context of Myt1l haploinsufficiency.

Methods
Four-core genotypes (FCG) mice, which uncouple gonadal and chromosomal sex, were crossed with MYT1L heterozygous mice to create eight different groups with unique combinations of sex factors and MYT1L genotype. A total of 131 mice from all eight groups were assayed for activity and social behavior via the open field and social operant paradigms. Measures of social seeking and orienting were analyzed for main effects of chromosome, gonads, and their interactions with Myt1l mutation.

Results
The FCGxMYT1L cross revealed independent effects of both gonadal and chromosomal sex on activity and social behavior. Specifically, the presence of ovarian hormones led to greater overall activity, social seeking, and social orienting regardless of MYT1L genotype. In contrast, sex chromosomes affected social behavior mainly in the MYT1L heterozygous group, with XX MYT1L mutant mice demonstrating elevated levels of social orienting and seeking compared to XY MYT1L mutant mice.

Conclusions
Gonadal and chromosomal sex have independent mechanisms of driving greater social motivation in females. Additionally, genes on the sex chromosomes may interact with neurodevelopmental risk genes to influence sex variation in atypical social behavior.
Lipodystrophy Severity Score to Assess Disease Burden in Lipodystrophy
Authors: Brown Rebecca J , Akinci Baris , Yosef Matheos , Phillips Helen , Khalatbari Shokoufeh , Sorkina Ekaterina , Santini Ferruccio , Vigouroux Corinne , Brush Maiah , Meral Rasimcan , Ceccarini Giovanni , Zeybel Mujdat , Prodam Flavia , von Schnurbein Julia , Sorice Gian P , Guler Merve C , Patni Nivedita , Tanrikulu Seher , Alyaarubi Saif , Ozgen Basak S , Foss-Freitas Maria C , Ozisik Secil , Segrestin Benerice , Ozcan Busra , Adiyaman Suleyman C , Musolino Gianluca , Sekizkardes Hilal , Musso Carla , Lebenthal Yael , Ozen Samim , Simha Vinaya , Simsir Ilgin Y , Stears Anna , Scherer Thomas , Gambineri Alessandra , Lima Josivan G , Semple Robert , Wabitsch Martin , Araujo-Vilar David , Hegele Robert A , Oral Elif A 
Published: February 2025

Abstract

Context
Lipodystrophy syndromes are rare disorders characterized by deficient adipose tissue, leading to insulin resistance, dyslipidemia, and organ system abnormalities.

Objective
Our goal was to develop a lipodystrophy severity score (LDS) to holistically capture the diverse manifestations of lipodystrophy into a numerical score to aid in prediction of clinical outcomes and/or treatment impact.

Design
An 8-domain LDS was developed by eight disease experts in consultation with patient organizations. The LDS was rated for feasibility and content validity by 28 additional clinicians and 9 patient representatives. LDS was compared to Clinical Global Impression (CGI) of severity for 20 putative patient profiles, each at two different time points, and by comparing change in LDS to global impression of change. For external validation, LDS was calculated in two cohorts of patients with lipodystrophy treated with metreleptin.

Results
LDS domains include Diabetes/Insulin Resistance, Microvascular Complications of Diabetes, Lipids, Cardiovascular, Liver, Kidney, Reproductive, and Other. Each domain is assessed by one or more questions assessing both lifetime and recent complications of lipodystrophy. The LDS had high content validity and feasibility, and high reliability by intraclass correlation coefficients (&gt;0.95). Global and domain-specific LDS were strongly correlated with CGI, as were changes in scores across visits (R=0.79-0.99, P&lt;0.001 for all). In generalized lipodystrophy, metreleptin significantly reduced LDS (from 46 to 26 at 12 months, P&lt;0.001). The reductions were smaller in partial lipodystrophy (from 65 to 61 at 12 months, P=0.04).

Conclusions
The LDS can reflect the severity of diverse manifestations of lipodystrophy and monitor changes following interventions.
A rare case of right-sided chylothorax induced by vertebral osteophytosis in a nonagenarian patient
Authors: Galasso Umberto Giuseppe , Del Giudice Elena , Ialongo Pasquale , Fimognari Filippo Luca , Desideri Giovambattista , Ettorre Evaristo , Palleschi Lorenzo 
Published: February 2025

Background: Chylothorax is an abnormal accumulation of lymphatic fluid in the pleural cavity, and it develops because of chyle leaking from the thoracic duct. The clinical presentation can be varied, while symptoms depend on its size and the rate of accumulation in the pleural space. Diagnosis is based on pleural fluid analysis, supported by various imaging studies to help determine the underlying pathology and locate the site of chyle leak. Case report: We report an extremely rare case of non-iatrogenic right-sided chylothorax in the absence of radiographically demonstrated bony damage which was related to vertebral osteophytosis in a 90-year-old man, who presented with worsening shortness of breath after a blunt trauma. On physical examination, the patient was found to be suffering from substantial right-sided pleural effusion with no radiographic evidence of traumatic injury. Conclusion: Imaging demonstrated diffused osteophytosis at the level of the lower thoracic vertebrae, which were puncturing the thoracic duct. We adopted conservative treatment, including thoracentesis and total parenteral nutrition, which resulted in the improvement and resolution of symptoms.
Decisions in end-of-life care: perspectives from family caregivers
Authors: Othman Elham H , Alosta Mohammad , Atiyeh Huda , Khalaf Inaam Abdallah , Zeilani Ruqayya 
Published: February 2025

Background: Making healthcare decisions on behalf of loved ones can be highly stressful for family members to act as surrogate decision makers, especially when decisions are relevant to terminal care. Aim: To understand the challenges that caregivers face when making decisions for family members at the end of life. Methods: A descriptive phenomenological approach using semi-structured interviews with seven family caregivers recruited from two palliative care institutions in Amman. Results: Family caregivers mentioned several reasons to avoid participating in decisions near their relative's end-of-life, such as holding on to hope that their family member would recover and fearing loss. Others expressed that they felt their relationship to the patient impaired their ability to make reliable judgments and they found it hard to know what the right decisions were. They were worried about being held responsible for the result of decisions and were concerned about felling guilty. Conclusion: To conclude, caregivers do not feel prepared to make decisions about their relative's care and feel that they are too emotional and attached to the patient, or are afraid of the consequences of their decisions.
Impact of Air Temperature and Root-Zone Cooling on Heat-Tolerant Lettuce Production in Indoor Farming Under Low-Speed Air Flow Conditions
Authors: Pompeo Jean Paul , Zhang Ying , Yu Ziwen , Gomez Celina , Correll Melanie , Bliznyuk Nikolay 
Published: February 2025

HighlightsRoot-zone cooling did not benefit lettuce yields in warmer air temperatures up to 30°C.Lettuce genotype was a significant factor affecting overall plant performance.Growing heat-tolerant lettuce in indoor farming has potential for enhancing energy and light use efficiencies.Abstract. Indoor farms are increasingly being used for lettuce production worldwide, but the high operating costs associated with temperature control via air cooling limit their profitability. In this study, we investigated the effect of adapting higher air temperature setpoints, heat-tolerant crops, and root-zone cooling (RZC) for improving the resource use efficiency of indoor farming systems in terms of biomass production, energy, and water use efficiency. Three lettuce cultivars with known heat tolerance were selected for this study: Skyphos, Muir, and Rex (control). Trials were conducted where all lettuce was grown under warm air temperature settings of 24°C, 26°C, 28°C, and 30°C with root zones either cooled to 22°C or left without cooling. Results indicate that cultivar significantly influences lettuce quality regardless of air temperatures. RZC lowered biomass production and light and energy use efficiencies but improved the water use efficiency at all air temperatures. Heat-tolerant lettuce had better fresh biomass production, with Muir yielding the highest shoot fresh weight in the higher temperatures, including the 28°C and 30°C control groups compared to both root-zone conditions for 24°C and 26°C and the 30°C RZC group. There was no significant difference in fresh biomass yields between the Rex and Skyphos control groups at different air temperatures. However, Skyphos in the 28°C control group yielded significantly higher fresh biomass than the RZC groups of Rex and Muir at 24°C and 26°C and both root-zone conditions for Muir at 28°C. Findings suggest that while RZC to 22°C did not enhance biomass production or tipburn prevalence, selecting heat-tolerant cultivars may optimize yield under higher temperature conditions. Keywords: Heat tolerance, Indoor farm, Lettuce, Resource use efficiency, Root-zone cooling, Tipburn.
Statin Use Is Associated With Protection Against Acute Cholangitis in Patients With Primary Sclerosing Cholangitis: A Multicenter Retrospective Cohort Study
Authors: Kulkarni Chiraag , Cholankeril George , Fardeen Touran , Rathkey Joseph , Khan Samir , Murag Soumya , Lerrigo Robert , Kamal Ahmad , Mannalithara Ajitha , Jalal Prasun , Ahmed Aijaz , Vierling John , Goel Aparna , Sinha Sidhartha R. 
Published: February 2025

INTRODUCTION:
Patients with primary sclerosing cholangitis (PSC) are at increased risk of acute cholangitis. The epidemiological risks of cholangitis are poorly studied despite the high morbidity associated with this infection. The aim of this study was to understand the impact of statins on acute cholangitis in PSC.

METHODS:
This multicenter, retrospective cohort study assessed data from 294 patients with PSC at Stanford Medical Center, Baylor Medical Center, and Valley Medical Center. Clinical factors associated with the development of cholangitis were identified using multivariable Cox regression.

RESULTS:
The patients were predominantly male (68.7%) with a median age at enrollment of 48 years (interquartile range [IQR]: 31.0–60.8). Fifty patients (17.0%) were prescribed statins. The median follow-up time was 6 years (IQR: 2.0–12.0), in which 29.6% (n = 87) developed cholangitis. In multivariable analysis, statins were associated with an 81% reduction in cholangitis (HR 0.19, 95% confidence interval 0.03–0.64). Statins were associated with a lower adjusted incidence of cholangitis at 36 months compared with patients not on statin therapy (incidence of 2.8% vs 12.2%, P < 0.001). Statins were also associated with increased time-to-stricture (P = 0.004), an outcome known to be associated with PSC complications.

DISCUSSION:
Statin therapy is associated with reduced risk of cholangitis in PSC, possibly by delaying the time to develop dominant or high-grade strictures. In patients with PSC, use of statin therapy may be a beneficial modality to prevent the development of cholangitis and warrants further investigation.
Exploring the interplay of trait-like L2 willingness to communicate, international posture, language anxiety and fluency in monologue L2 speech
Authors: Szyszka Magdalena , Lintunen Pekka 
Published: February 2025

Abstract
Willingness to communicate in a second language (L2 WTC) refers to the readiness to initiate speech and is influenced by psychological, linguistic, and contextual factors contributing to both stable and dynamic states in L2 WTC. The present study investigates the relationship between L2 utterance fluency and trait-like L2 WTC with its selected antecedents: international posture (IP) and language anxiety (LA). L2 speech samples (n = 102) were examined for speech rate (SR), articulation rate (AR), frequency of silent and filled pauses and repetitions. Trait-like L2 WTC and IP were determined using the Willingness to Communicate Inventory (Mystkowska-Wiertelak, Anna & Mirosław Pawlak. 2017. Willingness to communicate in instructed second language acquisition: Combining a macro- and micro-perspective. Bristol: Multilingual Matters), whereas LA was measured with the Foreign Language Classroom Anxiety Scale (Horwitz, Elaine K., Michael B. Horwitz & Joann Cope. 1986. Foreign language classroom anxiety. The Modern Language Journal 70(2). 125–132). Correlational analyses were conducted between the fluency measures, unplanned in-class L2 WTC, planned in-class L2 WTC, L2 WTC outside the classroom and practice-seeking L2 WTC, as well as IP-openness to experience, IP-interest in international affairs and LA. The study revealed positive correlations between SR, AR and practice-seeking L2 WTC, as well as AR and L2 WTC outside the classroom. Negative relationships were found between SR, AR and LA. Higher levels of LA were linked to an increased use of filled pauses.
Comparing intubation techniques of Klippel–Feil syndrome patients in the last 10 years: a systematic review
Authors: Fisher Mitchell , Simonsen Andrew , Stewart Christopher , Alkhatib Salma , Niewchas Abbigail , Otto Alex , Hansen Randall , McIntire Kent , Sukpraprut-Braaten Suporn 
Published: February 2025

Abstract

Context
Klippel–Feil syndrome (KFS) is a rare congenital abnormality characterized by cervical vertebral fusion. Patients typically present with a triad of short neck, low posterior hairline, and limited cervical range of motion. The location and quantity of vertebral fusions in KFS makes airway management challenging in the field of anesthesia. Anesthesiologists select intubation methods based on perceived difficulty, making this paper essential to the field.

Objectives
The purpose of this study is to analyze first-attempt intubation success rates of KFS patients by intubation technique and stratified by location and quantity of cervical fusions and a Mallampati score if reported.

Methods
This is a systematic review of all case reports on PubMed in the last 10 years utilizing the keywords “KFS,” and subsequently screened searching “anesthesia” and “intubation.” Examiners reviewed the remaining 27 articles for fusion abnormalities and intubation techniques utilized. The articles detail fiberoptic, direct, laryngeal mask airway (LMA), and video-guided intubation techniques, and the success rates were analyzed.

Results
Of the 1234 KFS articles found, 657 were case reports with 157 being in the last 10 years. After review, 27 case reports presenting 30 cases were included. The average age reported was 25.4 ± 21.6 and 73.3 % were female. Direct (n=10), fiberoptic (n=12), video-guided (n=6), and LMA (n=2) were the chosen first-attempt intubation maneuvers. Fiberoptic and video-guided intubations reported 83 % success, while direct and LMA reported 50 % success. Higher success rates were found in patients with two cervical segment fusions (70 %) when compared to three or more fusions (33 %). Inferior vertebral fusions (C5-T1) reported higher success than midcervical fusions (C3-C5), 100 % and 33 %, respectively. Mallampati class 4 had the highest success (100 %), although further analysis showed fiberoptic intubation was utilized in each of these cases, skewing the data.

Conclusions
Fiberoptic and video-guided intubation in KFS patients offers the highest success rates of intubation. There were limitations in this study due to the number of case reports available. Although there may be confounding variables to consider based on the case presentation and surgery performed, fiberoptic endotracheal intubation should be considered the gold standard when intubating KFS patients.
Must Exploiters Objectively Benefit from Exploitation?
Authors: Ehring Douglas 
Published: February 2025

Abstract
Various philosophers have claimed that a necessary condition for A to wrongfully exploit B is for A to benefit from interacting with B. On a subjective understanding of benefits, A benefits from an interaction only if that interaction contributes to the satisfaction of one of A’s actual and current goals or desires. On the other hand, interests may be read as objective or real interests. Proposals for characterizing real interests range from those that restrict real interests to psychological states to those that involve states that are not psychological. On the objective understanding, A benefits from an interaction with B only if that interaction promotes one of A’s real interests. I dispute the claim that a requirement of wrongful exploitation is an objective benefit to the exploiter.