bluuebunny/crossref_metadata_2025_split huggingface dataset:
ΔNp63 bookmarks and creates an accessible epigenetic environment for TGFβ-induced cancer cell stemness and invasiveness
Authors: Vasilaki Eleftheria , Bai Yu , Ali Mohamad Moustafa , Sundqvist Anders , Moustakas Aristidis , Heldin Carl-Henrik 
Published: August 2024

Abstract
Background
p63 is a transcription factor with intrinsic pioneer factor activity and pleiotropic functions. Transforming growth factor β (TGFβ) signaling via activation and cooperative action of canonical, SMAD, and non-canonical, MAP-kinase (MAPK) pathways, elicits both anti- and pro-tumorigenic properties, including cell stemness and invasiveness. TGFβ activates the ΔNp63 transcriptional program in cancer cells; however, the link between TGFβ and p63 in unmasking the epigenetic landscape during tumor progression allowing chromatin accessibility and gene transcription, is not yet reported.

Methods
Small molecule inhibitors, including protein kinase inhibitors and RNA-silencing, provided loss of function analyses. Sphere formation assays in cancer cells, chromatin immunoprecipitation and mRNA expression assays were utilized in order to gain mechanistic evidence. Mass spectrometry analysis coupled to co-immunoprecipitation assays revealed novel p63 interactors and their involvement in p63-dependent transcription.

Results
The sphere-forming capacity of breast cancer cells was enhanced upon TGFβ stimulation and significantly decreased upon ΔNp63 depletion. Activation of TGFβ signaling via p38 MAPK signaling induced ΔNp63 phosphorylation at Ser 66/68 resulting in stabilized ΔNp63 protein with enhanced DNA binding properties. TGFβ stimulation altered the ratio of H3K27ac and H3K27me3 histone modification marks, pointing towards higher H3K27ac and increased p300 acetyltransferase recruitment to chromatin. By silencing the expression of ΔNp63, the TGFβ effect on chromatin remodeling was abrogated. Inhibition of H3K27me3, revealed the important role of TGFβ as the upstream signal for guiding ΔNp63 to the TGFβ/SMAD gene loci, as well as the indispensable role of ΔNp63 in recruiting histone modifying enzymes, such as p300, to these genomic regions, regulating chromatin accessibility and gene transcription. Mechanistically, TGFβ through SMAD activation induced dissociation of ΔNp63 from NURD or NCOR/SMRT histone deacetylation complexes, while promoted the assembly of ΔNp63-p300 complexes, affecting the levels of histone acetylation and the outcome of ΔNp63-dependent transcription.

Conclusions
ΔNp63, phosphorylated and recruited by TGFβ to the TGFβ/SMAD/ΔNp63 gene loci, promotes chromatin accessibility and transcription of target genes related to stemness and cell invasion.
IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency
Authors: Dong Qiyu , Yin Xiaojie , Fan Shuanglong , Zhong Sheng , Yang Wenxin , Chen Keer , Wang Qian , Ma Xue , Mahlatsi Refiloe Laurentinah , Yang Yanling , Lyu Jianxin , Fang Hezhi , Wang Ya 
Published: August 2024

Abstract
Background
Leigh syndrome (LS) is a common mitochondrial disease caused by mutations in both mitochondrial and nuclear genes. Isoleucyl-tRNA synthetase 2 (IARS2) encodes mitochondrial isoleucine-tRNA synthetase, and variants in IARS2 have been reported to cause LS. However, the pathogenic mechanism of IARS2 variants is still unclear.

Methods
Two unrelated patients, a 4-year-old boy and a 5-year-old boy diagnosed with LS, were recruited, and detailed clinical data were collected. The DNA of the patients and their parents was isolated from the peripheral blood for the identification of pathogenic variants using next-generation sequencing and Sanger sequencing. The ClustalW program, allele frequency analysis databases (gnomAD and ExAc), and pathogenicity prediction databases (Clinvar, Mutation Taster and PolyPhen2) were used to predict the conservation and pathogenicity of the variants. The gene expression level, oxygen consumption rate (OCR), respiratory chain complex activity, cellular adenosine triphosphate (ATP) production, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (ROS) levels were measured in patient-derived lymphocytes and IARS2-knockdown HEK293T cells to evaluate the pathogenicity of the variants.

Results
We reported 2 unrelated Chinese patients manifested with LS who carried biallelic IARS2 variants (c.1_390del and c.2450G > A from a 4-year-old boy, and c.2090G > A and c.2122G > A from a 5-year-old boy), of which c.1_390del and c.2090G > A were novel. Functional studies revealed that the patient-derived lymphocytes carrying c.1_390del and c.2450G > A variants exhibited impaired mitochondrial function due to severe mitochondrial complexes I and III deficiencies, which was also found in IARS2-knockdown HEK293T cells. The compensatory experiments in vitro cell models confirmed the pathogenicity of IARS2 variants since re-expression of wild-type IARS2 rather than mutant IARS2 could rescue complexes I and III deficiency, oxygen consumption, and cellular ATP content in IARS2 knockdown cells.

Conclusion
Our results not only expand the gene mutation spectrum of LS, but also reveal for the first time the pathogenic mechanism of IARS2 variants due to a combined deficiency of mitochondrial complexes I and III, which is helpful for the clinical diagnosis of IARS2 mutation-related diseases.
Oxygenator assisted dynamic microphysiological culture elucidates the impact of hypoxia on valvular interstitial cell calcification
Authors: Dittfeld Claudia , Schmieder Florian , Behrens Stephan , Jannasch Anett , Matschke Klaus , Sonntag Frank , Tugtekin Sems-Malte 
Published: August 2024

Abstract
Introduction
Microphysiological systems (MPS) offer simulation of (patho)physiological parameters. Investigation includes items which lead to fibrosis and calcification in development and progress of calcific aortic valve disease, based e.g. on culturing of isolated valvular interstitial cells (VICs). Hypoxia regulated by hypoxia inducible factors impacts pathological differentiation in aortic valve (AV) disease. This is mimicked via an MPS implemented oxygenator in combination with calcification inducing medium supplementation.

Methods
Human valvular interstitial cells were isolated and dynamically cultured in MPS at hypoxic, normoxic, arterial blood oxygen concentration and cell incubator condition. Expression profile of fibrosis and calcification markers was monitored and calcification was quantified in induction and control media with and without hypoxia and in comparison to statically cultured counterparts.

Results
Hypoxic 24-hour culture of human VICs leads to HIF1α nuclear localization and induction of EGLN1, EGLN3 and LDHA mRNA expression but does not directly impact expression of fibrosis and calcification markers. Dependent on medium formulation, induction medium induces monolayer calcification and elevates RUNX2, ACTA2 and FN1 but reduces SOX9 mRNA expression in dynamic and static MPS culture. But combining hypoxic oxygen concentration leads to higher calcification potential of human VICs in calcification and standard medium formulation dynamically cultured for 96 h.

Conclusion
In hypoxic oxygen concentration an increased human VIC calcification in 2D VIC culture in an oxygenator assisted MPS was detected. Oxygen regulation therefore can be combined with calcification induction media to monitor additional effects of pathological marker expression. Validation of oxygenator dependent VIC behavior envisions future advancement and transfer to long term aortic valve tissue culture MPS.
Prehospital guidelines on in-water traumatic spinal injuries for lifeguards and prehospital emergency medical services: an international Delphi consensus study
Authors: Breindahl Niklas , Bierens Joost L. M. , Wiberg Sebastian , Barcala-Furelos Roberto , Maschmann Christian 
Published: August 2024

Abstract
Background
Trauma guidelines on spinal motion restriction (SMR) have changed drastically in recent years. An international group of experts explored whether consensus could be reached and if guidelines on SMR performed by trained lifeguards and prehospital EMS following in-water traumatic spinal cord injury (TSCI) should also be changed.

Methods
An international three-round Delphi process was conducted from October 2022 to November 2023. In Delphi round one, brainstorming resulted in an exhaustive list of recommendations for handling patients with suspected in-water TSCI. The list was also used to construct a preliminary flowchart for in-water SMR. In Delphi round two, three levels of agreement for each recommendation and the flowchart were established. Recommendations with strong consensus (≥ 85% agreement) underwent minor revisions and entered round three; recommendations with moderate consensus (75–85% agreement) underwent major revisions in two consecutive phases; and recommendations with weak consensus (< 75% agreement) were excluded. In Delphi round 3, the level of consensus for each of the final recommendations and each of the routes in the flowchart was tested using the same procedure as in Delphi round 2.

Results
Twenty-four experts participated in Delphi round one. The response rates for Delphi rounds two and three were 92% and 88%, respectively. The study resulted in 25 recommendations and one flowchart with four flowchart paths; 24 recommendations received strong consensus (≥ 85%), and one recommendation received moderate consensus (81%). Each of the four paths in the flowchart received strong consensus (90–95%). The integral flowchart received strong consensus (93%).

Conclusions
This study produced expert consensus on 25 recommendations and a flowchart on handling patients with suspected in-water TSCI by trained lifeguards and prehospital EMS. These results provide clear and simple guidelines on SMR, which can standardise training and guidelines on SMR performed by trained lifeguards or prehospital EMS.
MulTI-domain self-management in older People wiTh OstEoarthritis and multi-morbidities: protocol for the TIPTOE randomised controlled trial
Authors: Deere Rachel , Pallmann Philip , Shepherd Victoria , Brookes-Howell Lucy , Carson-Stevens Andrew , Davies Ffion , Dunphy Emma , Gupta Preeti , Hickson Mary , Hill Val , Ingarfield Kate , Ivins Nicola , Jones Fiona , Letchford Robert , Lowe Rachel , Nash Sarah , Otter Paula , Prout Hayley , Randell Elizabeth , Sewell Bernadette , Smith Debs , Trubey Robert , Wainwright Tom , Busse Monica , Button Kate 
Published: August 2024

Abstract

Background
Four out of five people living with osteoarthritis (OA) also suffer with at least one other long-term health condition. The complex interaction between OA and multiple long-term conditions (MLTCs) can result in difficulties with self-care, restricted mobility, pain, anxiety, depression and reduced quality of life. The aim of the MulTI-domain Self-management in Older People wiTh OstEoarthritis and Multi-Morbidities (TIPTOE) trial is to evaluate the clinical and cost-effectiveness of the Living Well self-management support intervention, co-designed with people living with OA, integrated into usual care, in comparison to usual care alone.

Methods
TIPTOE is a multi-centre, two-arm, individually randomised controlled trial where 824 individuals over 65 years old with knee and/or hip joint pain from their OA affected joint and at least one other long-term health condition will be randomised to receive either the Living Well Self-Management support intervention or usual care. Eligible participants can self-refer onto the trial via a website or be referred via NHS services across Wales and England. Those randomised to receive the Living Well support intervention will be offered up to six one-to-one coaching sessions with a TIPTOE-trained healthcare practitioner and a co-designed book. Participants will be encouraged to nominate a support person to assist them throughout the study. All participants will complete a series of self-reported outcome measures at baseline and 6- and 12-month follow-up. The primary outcome is symptoms and quality of life as assessed by the Musculoskeletal Health Questionnaire (MSK-HQ). Routine data will be used to evaluate health resource use. A mixed methods process evaluation will be conducted alongside the trial to inform future implementation should the TIPTOE intervention be found both clinically and cost-effective. An embedded ‘Study Within A Project’ (SWAP) will explore and address barriers to the inclusion of under-served patient groups (e.g. oldest old, low socioeconomic groups, ethnic groups).

Discussion
TIPTOE will evaluate the clinical and cost-effectiveness of a co-designed, living well personalised self-management support intervention for older individuals with knee and/or hip OA and MLTCs. The trial has been designed to maximise inclusivity and access.

Trial registration
ISRCTN 16024745. Registered on October 16, 2023.
Associations of physical activity and physical education enjoyment with self-concept domains among Hungarian adolescents
Authors: Berki Tamás , Csányi Tamás , Tóth László 
Published: August 2024

Abstract
Background
Sport enjoyment is one of the most important factors in physical activity (PA) and physical education (PE) domains. It is not only beneficial for regular participation but also has a positive effect on mental health. Due to these benefits, this study aims to understand the relationships between PA, two forms of enjoyment, and the dimension of self-concept.

Methods
The sample consisted of 315 students (Mage=12.63). The Self-Description Questionnaire-I was used to measure the domains of self-concept. Enjoyment was measured with two scales. The Physical Activity Enjoyment Scale reflects extracurricular PA enjoyment, and the Factors Influencing Enjoyment of Physical Education Questionnaire reflects school PE enjoyment. The International Physical Activity Questionnaire was used to assess vigorous, moderate, and walking types of extracurricular PA enjoyment.

Results
Hierarchical multivariate regression analysis revealed that vigorous PA predicted physical ability (β = 0.19) and physical appearance (β = 0.15). PA enjoyment was a significant predictor of general self-concept (β = 0.29), physical ability (β = 0.28), physical appearance (β = 0.16), peer relation (β = 0.16), and parental relations (β = 0.14). PE enjoyment significantly predicted general school (β = 0.17), physical ability (β = 0.27), peer relations (β = 0.21) and parental relations (β = 0.22). Furthermore, boys scored at a higher level on most of self-concept domains.

Conclusions
The present study suggested that enjoyment plays a more important role in self-concept than PA. PE enjoyment mainly strengthens boys’ self-concept, but PA enjoyment is an important predictor of general self-concept in both genders. It is concluded that extracurricular PA enjoyment is beneficial, but increasing enjoyment of physical education could increase girls’ self-concepts as well.
Inverse analysis of seismic activity rate changes for severely incomplete sequences: comparison of aftershock activity patterns immediately following the 2023 M6.5 and 2024 M7.6 Noto Peninsula earthquakes
Authors: Ogata Yosihiko , Kumazawa Takao 
Published: August 2024

AbstractWe estimate the true aftershock activity rate from the detected initial aftershocks of the M7.6 Noto Peninsula earthquake on January 1, 2024, in addition to the preceding M6.5 Noto Peninsula earthquake on May 5, 2023. Estimating the initial aftershock activity rates has the serious problem of missing data, but in itself contains important clues to the physical structure associated with aftershocks and other external factors. We first estimate the detection rate models of the two aftershock sequences assuming the Gutenberg–Richter frequency laws, and we have found the contrasting time evolution of b-values immediately after the mainshocks, in addition to the contrasting detection rate evolutions. Furthermore, by applying the compensated nonstationary ETAS (epidemic-type aftershock sequence) model, we have revealed the contrasting time evolution of the background intensity rates, which characterizes the external factor of the original ETAS model besides the static triggering seismic activity. We discuss the implications of these differences of the analyzed outputs.
Graphical Abstract
Antidiabetic effects of aqueous leaf extract of Vernonia amygdalina on serum liver markers in streptozotocin-induced diabetic albino Rats: a new data to support its Anti-diabetic effect
Authors: Adekemi Falae Esther , Folake Jayesinmi Kikelomo , Omowumi Falae Philips 
Published: August 2024

Abstract
Background
Numerous plants have been explored for their potential antidiabetic properties, and Vernonia amygdalina (VA) stands among them. This study aims to investigate the antidiabetic activities of VA and validate its efficacy.

Methods
An aqueous extract of Vernonia amygdalina leaves was obtained through maceration. The antidiabetic effects of this plant extract were evaluated in vivo using diabetic model rats. Albino Wistar rats were induced into a diabetic state through intraperitoneal injection of streptozocin and subsequently treated with an optimal dose of 250 mg/kg aqueous extract of VA over a 21-day period. Parameters such as body weight, blood glucose levels, and serum marker enzymes were measured.

Results
The results demonstrated a significant reduction (p < 0.05) in the glucose levels of streptozocin-induced diabetic rats following treatment with VA extract, highlighting its potential as an antidiabetic agent that performed comparably to the reference drug, glimepiride. Additionally, a significant increase (p < 0.05) in the body weight of the treated diabetic rats was observed. Aqueous extracts also significantly (p < 0.05) altered the serum concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in a manner similar to the glimepiride-treated group.

Conclusion
This study affirms the anti-diabetic effects of the aqueous extract of Vernonia amygdalina in streptozotocin-induced diabetic rats and suggests that the extract holds promise as an important phytomedicine for the development of more effective treatments for diabetes.
Large macular hole and autologous retinal transplantation: a systematic review and meta-analysis
Authors: Hanai Mário , Amaral Dillan Cunha , Jacometti Raiza , Aguiar Eduardo Henrique Cassins , Gomes Fernando Cotrim , Cyrino Laura Goldfarb , Alves Milton Ruiz , Monteiro Mário Luiz Ribeiro , Fuganti Raphaela Masetto , Casella Antonio Marcelo Barbante , Louzada Ricardo Noguera 
Published: August 2024

Abstract
Introduction
Macular holes are breaks in the retinal tissue at the center of the macula, affecting central vision. The standard treatment involves vitrectomy with membrane peeling and gas tamponade. However, for larger or chronic holes, alternative techniques like autologous retinal graft have emerged. This meta-analysis evaluates the efficacy and safety of retinal transplantation in managing large macular holes.

Methods
We conducted a systematic review and meta-analysis following PRISMA guidelines. The study was prospectively registered in PROSPERO (CRD42024504801). We searched PubMed, Web of Science, Cochrane, and Embase databases for observational studies including individuals with large macular holes with or without retinal detachments and retinal transplantation as the main therapy. We used a random-effects model to compute the mean difference with 95% confidence intervals and performed statistical analysis using R software.

Results
We conducted a comprehensive analysis of 19 studies involving 322 patients diagnosed with various types of macular holes (MHs). These included cohorts with refractory MH, high myopia associated with MH, primary MH, and MH with retinal detachment (RD). The findings were promising, revealing an overall closure rate of 94% of cases (95% CI 88–98, I2 = 20%). Moreover, there was a significant improvement in postoperative visual acuity across all subgroups, averaging 0.45 (95% CI 0.33–0.58 ; I2 = 72%; p < 0.01) overall. However, complications occurred with an overall incidence rate of 15% (95% CI 7–25; I2 = 59%).

Conclusion
ART for large MH shows promising results, including significant improvements in visual acuity and a high rate of MH closure with low complication risks overall and for subgroups.
Complementary use of cardiac magnetic resonance and 18 F-FDG positron emission tomography imaging in suspected immune checkpoint inhibitor myocarditis
Authors: Tong Jieli , Vogiatzakis Nikolaos , Andres Maria Sol , Senechal Isabelle , Badr Ahmed , Ramalingam Sivatharshini , Rosen Stuart D. , Lyon Alexander R. , Nazir Muhummad Sohaib 
Published: August 2024

Abstract
Background
Immune checkpoint inhibitor (ICI) myocarditis is an uncommon but potentially fatal complication of immunotherapy. Cardiac imaging is essential to make timely diagnoses as there are critical downstream implications for patients.

Objective
To determine the agreement of cardiac magnetic resonance (CMR) and 18 F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in patients with suspected ICI myocarditis.

Methods
Patients with suspected ICI myocarditis, who underwent CMR and 18 F-FDG-PET imaging at a single cardio-oncology service from 2017 to 2023, were enrolled. CMR was performed according to recommended guidelines for assessment of myocarditis. 18 F-FDG-PET imaging was performed following 18 h carbohydrate-free fast. Imaging was analysed by independent reviewers to determine the presence or absence of ICI myocarditis.

Results
Twelve patients (mean age 60 ± 15 years old, 7 [58%] male) underwent both CMR and 18 F-FDG-PET imaging. Three (25%) met the 2018 Lake Louise Criteria for CMR diagnosis of myocarditis; 4 (33%) had evidence of myocardial inflammation as determined by 18 F-FDG-PET. Amongst those with positive 18 F-FDG-PET, mean standard uptake value (SUV) was 3.5 ± 1.7. There was agreement between CMR and PET in 7 cases (CMR and PET positive (n = 1), CMR and PET negative (n = 6)) and discordance in 5 cases (CMR positive and PET negative (n = 2), CMR negative and PET positive (n = 3)).

Conclusion
Both CMR and PET provide complementary clinical information in diagnostic of ICI myocarditis. CMR informs on myocardial oedema, whilst 18 F-FDG-PET provides information on glucose metabolism reflecting monocyte and lymphocytic activity. Future studies should investigate the role of hybrid PET-CMR for the timely diagnosis of ICI myocarditis.
“For them it’s not the work, it’s the life”: humanitarian leadership development in the Global South
Authors: Saha Manika , Zadeh-Cummings Nazanin , McGlasson Mary Ana , Brockington Sonia 
Published: August 2024

AbstractWhat are the leadership development needs of so-called ‘Global South’ humanitarian professionals? The humanitarian professionalisation agenda begun in the 1990s has evolved to include short courses and accredited programmes specifically aiming to build leadership skills. This paper explores how humanitarian professionals from the Global South understand the current context of leadership development, including its barriers of access, and potential for change to be more relevant to their lives and work. Using thematic analysis of eleven key informant interviews, the paper finds three levels of consideration: global politics and inequality, personal and professional enrichment, and practical support. The findings suggest that while humanitarian leadership training can be better tailored and made available to Global South leaders at all career stages, there is a wider, more crucial need to address systemic imbalances. This paper contributes to wider discussion on localisation and inequality in the humanitarian aid sector, and more specifically contributes to the literature on how systemic factors shape the limits of both professionalisation and expansion of humanitarian education initiatives.