bluuebunny/crossref_metadata_2025_split huggingface dataset:
How to strengthen societal impact of research and innovation? Lessons learned from an explanatory research-on-research study on participatory knowledge infrastructures funded by the Netherlands Organization for Health Research and Development
Authors: Oortwijn Wija , Reijmerink Wendy , Bussemaker Jet 
Published: July 2024

Abstract
Background
Scientific research and innovation can generate societal impact via different pathways. Productive interactions, such as collaboration between researchers and relevant stakeholders, play an important role and have increasingly gained interest of health funders around the globe. What works, how and why in research partnerships to generate societal impact in terms of knowledge utilisation is still not well-known. To explore these issues, the Netherlands Organization for Health Research and Development (ZonMw) initiated an exploratory research-on-research study with a focus on participatory knowledge infrastructures (PKIs) that they fund in the field of public health and healthcare. PKIs are sustainable infrastructures in which knowledge production, dissemination and utilisation takes place via committed collaboration between researchers and stakeholders from policy, practice and/or education. Examples are learning networks, academic collaborative centres, care networks and living labs. The aim of the study was twofold: to gain insights in what constitutes effective collaboration in PKIs; and to learn and improve the research governance, particularly of ZonMw as part of their dissemination and implementation activities.

Methods
During 2020–2022, we conducted a literature review on long-term research partnerships, analysed available documentation of twenty ZonMw-funded PKIs, surveyed participants of the 2021 European Implementation Event, interviewed steering committee members, organized a Group Decision Room with lecturers, and validated the findings with key experts.

Results
We identified eight mechanisms (‘how and why’) that are conditional for effective collaboration in PKIs: transdisciplinary collaboration; defining a shared ambition; doing justice to everyone’s interests; investing in personal relationships; a professional organisation or structure; a meaningful collaborative process; mutual trust, sufficient time for and continuity of collaboration. Several factors (‘what’) may hinder (e.g., lack of ownership or structural funding) or facilitate (e.g., stakeholder commitment, embeddedness in an organisation or policy) effective collaboration in research partnerships.

Conclusion
To use the study results in policy, practice, education, and/or (further) research, cultural and behavioural change of all stakeholders is needed. To facilitate this, we provide recommendations for funding organisations, particularly ZonMw and its partners within the relevant knowledge ecosystem. It is meant as a roadmap towards the realisation and demonstration of societal impact of (health) research and innovation in the upcoming years.
Ningetinib, a novel FLT3 inhibitor, overcomes secondary drug resistance in acute myeloid leukemia
Authors: Hu Chuhong , Zhang Yvyin , Yang Jie , Xu Yanli , Deng Tingfen , Li Yumiao , Xu Shilin , Wang Shunqing , Wang Peihong 
Published: July 2024

Abstract
Background
FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is a common mutation type in acute myeloid leukemia (AML) and is usually associated with poor patient prognosis. With advancements in molecular diagnostics and the development of tyrosine kinase inhibitors (TKI), the overall survival (OS) of AML patients with FLT3-ITD mutations has been prolonged to some extent, but relapse and drug resistance are still substantial challenges. Ningetinib is a novel TKI against various kinases in relation to tumour pathogenesis and is undergoing clinical trials of lung cancer. In this study, we explored the antitumor activity of ningetinib against AML with FLT3 mutations both in vivo and in vitro.

Methods
Cell proliferation assays were performed in AML cell lines and Ba/F3 cells expressing various FLT3 mutations to validate the antileukemic activity of ningetinib in vitro. Immunoblot assays were used to verify the effect of ningetinib on the FLT3 protein and downstream pathways. Molecular docking and CETSA were used to validate the interaction of ningetinib with target proteins. The survival benefit of ningetinib in vivo was assessed in Ba/F3-FLT3-ITD-, MOLM13, Ba/F3-FLT3-ITD-F691L-, MOLM13-FLT3-ITD-F691L-induced leukemia mouse models. We also used patient-derived primary cells to determine the efficacy of ningetinib.

Results
Ningetinib inhibited cell proliferation, blocked the cell cycle, induced apoptosis and bound FLT3 to inhibit its downstream signaling pathways, including the STAT5, AKT and ERK pathways, in FLT3-ITD AML cell lines. In the mouse models with FLT3-ITD and FLT3-ITD-F691L mutation, ningetinib showed superior anti-leukemia activity to existing clinical drugs gilteritinib and quizartinib, significantly prolongating the survival of mice. In addition, ningetinib exhibited activity against patient-derived primary cells harboring FLT3-ITD mutations.

Conclusion
Overall, our study confirmed the therapeutic role of ningetinib in AML with FLT3-ITD mutations, providing a potential new option for clinically resistant patients.
Improving student diet and food security in higher education using participatory and co-creation approaches: a systematic review
Authors: Assilian Tamar , Dehove Henri , Charreire Hélène , Baudry Julia , Kesse-Guyot Emmanuelle , Péneau Sandrine , Julia Chantal , Gross Olivia , Oppert Jean-Michel , Bellicha Alice 
Published: July 2024

Abstract
Background
Higher education students are an important target group for public health nutrition interventions. When designing tailored and contextually relevant interventions, participatory and co-creation approaches are increasingly recognized as promising but their use and effectiveness has not been assessed in this type of population. We systematically reviewed interventions aiming to improve dietary quality and/or food security in higher education settings with the aims 1) to identify and describe their participatory and co-creation approaches and 2) to compare the effectiveness of interventions using or not using participatory and co-creation approaches.

Methods
Our search in PubMed, Google Scholar, Web of Science, EMBASE was performed in January 2023 and yielded 3658 unique records, out of which 42 articles (66 interventions) were included. Effectiveness of interventions was assessed at the individual level (longitudinal evaluations) or at the group level (repeated cross-sectional evaluations). A five-level classification was used to describe a continuum of engagement from students and other partners in the intervention design and implementation: no participation (level one), consultation, co-production, co-design and co-creation (levels two to five). To synthetize effectiveness, comparisons were made between studies without participation (level one) or with participation (levels two-five).

Results
Ten (24%) out of 42 studies used a participatory and co-creation approach (levels two-five). Studies using a participatory and co-creation approach reported a positive finding on individual-level outcome (i.e. overall diet quality or food group intake or food security) in 5/13 (38%) intervention arms (vs 13/31 or 42% for those without participation). Studies using a participatory and co-creation approach reported a positive finding on group-level outcomes (i.e. food choices in campus food outlets) in 4/7 (57%) (vs 8/23 or 35% in those without participation).

Conclusions
Participatory and co-creation approaches may improve the effectiveness of nutrition interventions in higher education settings but the level of evidence remains very limited. More research is warranted to identify best co-creation practices when designing, implementing and evaluating nutritional interventions in the higher education setting.

Trial registration
PROSPERO registration number CRD42023393004.
CDCA5 accelerates progression of breast cancer by promoting the binding of E2F1 and FOXM1
Authors: Xiong Yiquan , Shi Lan , Li Lei , Yang Wen , Zhang Huiqiong , Zhao Xiangwang , Shen Na 
Published: July 2024

Abstract
Background
Breast cancer is one of the most common malignant tumors in women. Cell division cycle associated 5 (CDCA5), a master regulator of sister chromatid cohesion, was reported to be upregulated in several types of cancer. Here, the function and regulation mechanism of CDCA5 in breast cancer were explored.

Methods
CDCA5 expression was identified through immunohistochemistry staining in breast cancer specimens. The correlation between CDCA5 expression with clinicopathological features and prognosis of breast cancer patients was analyzed using a tissue microarray. CDCA5 function in breast cancer was explored in CDCA5-overexpressed/knockdown cells and mice models. Co-IP, ChIP and dual-luciferase reporter assay assays were performed to clarify underlying molecular mechanisms.

Results
We found that CDCA5 was expressed at a higher level in breast cancer tissues and cell lines, and overexpression of CDCA5 was significantly associated with poor prognosis of patients with breast cancer. Moreover, CDCA5 knockdown significantly suppressed the proliferation and migration, while promoted apoptosis in vitro. Mechanistically, we revealed that CDCA5 played an important role in promoting the binding of E2F transcription factor 1 (E2F1) to the forkhead box M1 (FOXM1) promoter. Furthermore, the data of in vitro and in vivo revealed that depletion of FOXM1 alleviated the effect of CDCA5 overexpression on breast cancer. Additionally, we revealed that the Wnt/β-catenin signaling pathway was required for CDCA5 induced progression of breast cancer.

Conclusions
We suggested that CDCA5 promoted progression of breast cancer via CDCA5/FOXM1/Wnt axis, CDCA5 might serve as a novel therapeutic target for breast cancer treatment.
Epidemiology, economic, and humanistic burden of hereditary angioedema: a systematic review
Authors: Guan Xin , Sheng Yanan , Liu Shuang , He Miao , Chen Tianxiang , Zhi Yuxiang 
Published: July 2024

Abstract
Background
This systematic study aims to assess the global epidemiologic, economic, and humanistic burden of illness associated with all types of hereditary angioedema.

Methods
A systematic search for articles reporting the epidemiologic, economic, and humanistic burden associated with patients with HAE was conducted using English and Chinese literature databases from the inception to May 23, 2022. The selected studies were assessed for their quality and risk of bias. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022352377).

Results
In total, 65 articles that met the search inclusion criteria reported 10,310 patients with HAE, of whom 5861 were female patients. Altogether, 4312 patients (81%) and 479 patients (9%) had type 1 and type 2 HAE, respectively, whereas 422 patients (8%) had HAE-normal C1-INH. The overall prevalence of all types of HAE was between 0.13 and 1.6 cases per 100,000. The mean or median delay from the first onset of a symptom of HAE to confirmed diagnosis ranged from 3.9 to 26 years. The estimated risk of death from asphyxiation was 8.6% for patients with HAE. Hospitalization, medication, unnecessary surgeries, doctor visits, specialist services, and nursing costs are direct expenses that contribute to the growing economic burden. The indirect cost accounted mostly due to missing work ($3402/year) and loss of productivity ($5750/year). Furthermore, impairment of QoL as reported by patient-reported outcomes was observed. QoL measures identified depression, anxiety, and stress to be the most common symptoms for adult patients and children.

Conclusion
This study highlights the importance of early diagnosis and the need for improving awareness among health care professionals to reduce the burden of HAE on patients and society.
Healthcare resource utilization and costs associated with psychiatric comorbidities in pediatric patients with attention-deficit/hyperactivity disorder: a claims-based case-cohort study
Authors: Schein Jeff , Cloutier Martin , Gauthier-Loiselle Marjolaine , Bungay Rebecca , Chen Kathleen , Chan Deborah , Guerin Annie , Childress Ann 
Published: July 2024

Abstract
Background
Attention-deficit/hyperactivity disorder (ADHD) has been shown to pose considerable clinical and economic burden; however, research quantifying the excess burden attributable to common psychiatric comorbidities of ADHD among pediatric patients is scarce. This study assessed the impact of anxiety and depression on healthcare resource utilization (HRU) and healthcare costs in pediatric patients with ADHD in the United States.

Methods
Patients with ADHD aged 6–17 years were identified in the IQVIA PharMetrics Plus database (10/01/2015-09/30/2021). The index date was the date of initiation of a randomly selected ADHD treatment. Patients with ≥ 1 diagnosis for anxiety and/or depression during both the baseline (6 months pre-index) and study period (12 months post-index) were classified in the ADHD+anxiety/depression cohort; those without diagnoses for anxiety nor depression during both periods were classified in the ADHD-only cohort. Entropy balancing was used to create reweighted cohorts. All-cause HRU and healthcare costs during the study period were compared using regression analyses. Cost analyses were also performed in subgroups by comorbid conditions.

Results
The reweighted ADHD-only cohort (N = 204,723) and ADHD+anxiety/depression cohort (N = 66,231) had similar characteristics (mean age: 11.9 years; 72.8% male; 56.2% had combined inattentive and hyperactive ADHD type). The ADHD+anxiety/depression cohort had higher HRU than the ADHD-only cohort (incidence rate ratios for inpatient admissions: 10.3; emergency room visits: 1.6; outpatient visits: 2.3; specialist visits: 5.3; and psychotherapy visits: 6.1; all p < 0.001). The higher HRU translated to greater all-cause healthcare costs; the mean per-patient-per-year (PPPY) costs in the ADHD-only cohort vs. ADHD+anxiety/depression cohort was $3,988 vs. $8,682 (p < 0.001). All-cause healthcare costs were highest when both comorbidities were present; among patients with ADHD who had only anxiety, only depression, and both anxiety and depression, the mean all-cause healthcare costs were $7,309, $9,901, and $13,785 PPPY, respectively (all p < 0.001).

Conclusions
Comorbid anxiety and depression was associated with significantly increased risk of HRU and higher healthcare costs among pediatric patients with ADHD; the presence of both comorbid conditions resulted in 3.5 times higher costs relative to ADHD alone. These findings underscore the need to co-manage ADHD and psychiatric comorbidities to help mitigate the substantial burden borne by patients and the healthcare system.
Massively integrated coexpression analysis reveals transcriptional regulation, evolution and cellular implications of the yeast noncanonical translatome
Authors: Rich April , Acar Omer , Carvunis Anne-Ruxandra 
Published: July 2024

AbstractBackgroundRecent studies uncovered pervasive transcription and translation of thousands of noncanonical open reading frames (nORFs) outside of annotated genes. The contribution of nORFs to cellular phenotypes is difficult to infer using conventional approaches because nORFs tend to be short, of recent de novo origins, and lowly expressed. Here we develop a dedicated coexpression analysis framework that accounts for low expression to investigate the transcriptional regulation, evolution, and potential cellular roles of nORFs inSaccharomyces cerevisiae.ResultsOur results reveal that nORFs tend to be preferentially coexpressed with genes involved in cellular transport or homeostasis but rarely with genes involved in RNA processing. Mechanistically, we discover that young de novo nORFs located downstream of conserved genes tend to leverage their neighbors’ promoters through transcription readthrough, resulting in high coexpression and high expression levels. Transcriptional piggybacking also influences the coexpression profiles of young de novo nORFs located upstream of genes, but to a lesser extent and without detectable impact on expression levels. Transcriptional piggybacking influences, but does not determine, the transcription profiles of de novo nORFs emerging nearby genes. About 40% of nORFs are not strongly coexpressed with any gene but are transcriptionally regulated nonetheless and tend to form entirely new transcription modules. We offer a web browser interface (https://carvunislab.csb.pitt.edu/shiny/coexpression/) to efficiently query, visualize, and download our coexpression inferences.ConclusionsOur results suggest that nORF transcription is highly regulated. Our coexpression dataset serves as an unprecedented resource for unraveling how nORFs integrate into cellular networks, contribute to cellular phenotypes, and evolve.
Detection of allele-specific expression in spatial transcriptomics with spASE
Authors: Zou Luli S. , Cable Dylan M. , Barrera-Lopez Irving A. , Zhao Tongtong , Murray Evan , Aryee Martin J. , Chen Fei , Irizarry Rafael A. 
Published: July 2024

AbstractSpatial transcriptomics technologies permit the study of the spatial distribution of RNA at near-single-cell resolution genome-wide. However, the feasibility of studying spatial allele-specific expression (ASE) from these data remains uncharacterized. Here, we introduce spASE, a computational framework for detecting and estimating spatial ASE. To tackle the challenges presented by cell type mixtures and a low signal to noise ratio, we implement a hierarchical model involving additive mixtures of spatial smoothing splines. We apply our method to allele-resolved Visium and Slide-seq from the mouse cerebellum and hippocampus and report new insight into the landscape of spatial and cell type-specific ASE therein.
YTHDC1 aggravates high glucose-induced retinal vascular endothelial cell injury via m6A modification of CDK6
Authors: Zhou Qi , Tian Min , Cao Yang , Tang Min , Xiang Xiaohong , Guo Lu , Lv Hongbin 
Published: July 2024

Abstract
Objective
Retinal vascular endothelial cell (RVECs) injury is a major cause of morbidity and mortality among the patients with diabetes. RVECs dysfunction is the predominant pathological manifestation of vascular complication in diabetic retinopathy. N6-methyladenosine (m6A) serves as the most prevalent modification in eukaryotic mRNAs. However, the role of m6A RNA modification in RVECs dysfunction is still unclear.

Methods
RT-qPCR analysis and western blot were conducted to detect the change of m6A RNA modification in diabetic retinopathy. CCK-8 assay, transwell experiment, wound healing assay, tube formation experiment, m6A-IP-qPCR were performed to determine the role of YTHDC1 in RVECs. Retinal trypsin digestion test and H&E staining were used to evaluate histopathological changes.

Results
The levels of m6A RNA methylation were significantly up-regulated in HG-induced RVECs, which were caused by increased expression of YTHDC1. YTHDC1 regulated the viability, proliferation, migration and tube formation ability in vitro. YTHDC1 overexpression impaired RVECs function by repressing CDK6 expression, which was mediated by YTHDC1-dependent mRNA decay. Moreover, it showed sh-YTHDC1 inhibited CDK6 nuclear export. Sh-YTHDC1 promotes the mRNA degradation of CDK6 in the nucleus but does not affect the cytoplasmic CDK6 mRNA. In vivo experiments showed that overexpression of CDK6 reversed the protective effect of sh-YTHDC1 on STZ-induced retinal tissue damage.

Conclusion
YTHDC1-mediated m6A methylation regulates diabetes-induced RVECs dysfunction. YTHDC1-CDK6 signaling axis could be therapeutically targeted for treating DR.
First instar and adult male bed bugs, Cimex lectularius (Hemiptera: Cimicidae), increase feeding activity in the presence of adult females
Authors: Crawley Sydney E. , Borden John H. , Ritchey Josiah P. , Haynes Kenneth F. 
Published: July 2024

Abstract
Background
Bed bugs, Cimex lectularius, form day-time aggregations from which they depart at night to feed on human blood. Obtaining an initial blood meal is a critical step in the development of first instars. Previous research had shown that first instars had greater success in obtaining this essential meal when in the presence of adults than when they were alone.

Methods
Feeding by bed bugs was tested in upright vertical cylindrical chambers fitted with a paper ramp to aid in climbing toward a blood feeder suspended across the upper end of the cylinder. Feeding success by the first instars was tested when they were alone in the chamber or when they were in the presence of adult females, males, or both together.

Results
The mean proportions of the first instars that fed were significantly higher when they were confined with adults of both sexes or adult females than when they were confined alone or with males. Feeding by adult males was also enhanced by confinement with females. When first instars and adult females were confined together, the mean duration before first instars began feeding was longer than for females. There was no difference in feeding success by first instars confined with their mothers or nonmothers.

Conclusions
Elevated feeding by first instars and adult males in the presence of females may be adaptive traits that enhance fitness. First instars must feed to avoid dehydration and starvation and to obtain resources needed for development. Adult males would benefit not only by increased feeding success but also by greater likelihood of finding a recently engorged female with which to mate. The lack of any difference in feeding success of first instars in the presence of their mothers or nonmothers argues against parental care in this species.

Graphical Abstract