bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liraglutide prevents hyperglycemia-induced senescence and proinflammatory monocyte differentiation in CD34+ hematopoietic stem cells
Authors: Damiano G , Rinaldi R , Pompilio G , Vinci M C 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Health- Ricerca Finalizzata

Background
Diabetes mellitus (DM) is known to promote aberrant activation of immune cells that contribute to the onset and progression of chronic inflammation and atherosclerosis in DM patients (1). This phenomenon, termed 'trained immunity', appears to be initiated in hematopoietic stem/progenitor cells (HSPCs). In recent years, there has been great interest in investigating the pleiotropic effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs), including anti-inflammatory and immunological properties. We have recently demonstrated that HSPCs express the GLP-1R whose stimulation with the agonist liraglutide (LIRA) prevents oxidative stress and functional impairment induced by hyperglycemic conditions (HG) (2). On this basis, we hypothesized that LIRA treatment can also avert HG-induced senescence and proinflammatory myeloid differentiation of HSPCs.

Purpose
To evaluate senescence and inflammatory myeloid differentiation of CD34+ HSPCs after HG exposure in the presence or not of GLP1R agonist.

Methods
CD34+ HSPCs derived from cord blood of healthy donors were expanded in normal-glucose (NG; with 30 mM mannitol for osmotic control) or high-glucose (HG; 30 mM) and treated or not with LIRA (100nM) in serum-free medium plus cytokines (FLT3, SCF, IL3 and IL6) for up to 20 days. The expression of p21, p27, IL6, TNFα, and NFkB-p65 genes was assessed by qPCR. ROS production and CD34+ HSPC-derived monocyte subsets were evaluated by flow cytometry whereas cytokine secretion after LPS stimulation was measured by ELISA assay.

Results
LIRA treatment showed to significantly prevent the impairment of CD34+ HSPC proliferation as well as the upregulation of senescence-associated secretory phenotype (SASP) genes such as p21, p27, NFkB-p65, IL6, and TNFα in HG-CD34+ HSPCs when compared to HG cell alone (one-way ANOVA; p≤0.05). Interestingly, these pharmacological effects were associated with a significant reduction in HG-induced ROS production. Myeloid differentiation in vitro of HG-CD34+ HSPCs generated monocytes composed mainly of an inflammatory and highly reactive intermediate (CD14++CD16+) subpopulation characterized by higher LPS-induced release of IL6 and TNFα. LIRA treatment significantly prevented both the accumulation of intermediate (CD14++CD16+) monocyte subpopulation from differentiating HG-CD34+ HSPCs and their inflammatory phenotype (one-way ANOVA; p≤0.05).

Conclusions
These results demonstrate that HG exposure alters the differentiation program of CD34+ HSPCs towards more inflammatory immune cell components and suggest that GLP1R agonists are endowed with immunomodulatory properties that could be further developed and exploited for the treatment of immune system dysregulation in diabetes.
The effects of siRNA-mediated knockdown of AP-1 on pulmonary arterial and right ventricular dysfunction associated with cardiac and pulmonary fibrosis in cardiopulmonary disease
Authors: Comarita I K , Anghelache I L , Tanko G , Georgescu A 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Romania’s National Recovery and Resilience Plan, PNRR-III-C9-2022-I8, CF 93/15.11.2022, Financing Contract no. 760063/23.05.2023, and by the Romanian Academy

Background
Pulmonary hypertension (PH) is a complex multifactorial vascular pathology characterized by an increased pulmonary arterial pressure, vasoconstriction, remodelling of the pulmonary vasculature, thrombosis in situ and inflammation associated with right-side heart failure.

Purpose
Herein, we explored the potential beneficial effects of treatment with siRNA AP-1 on pulmonary arterial and right ventricular dysfunction and perivascular and interstitial fibrosis in pulmonary artery (PA), right ventricle (RV) and lung in an experimental animal model of monocrotaline (MCT)-induced pulmonary arterial hypertension.

Methods
Golden Syrian hamsters were divided into: (1) C group; (2) MCT group obtained by a single subcutaneous injection of 60 mg/kg MCT at the beginning of the experiment; (3) MCT- siRNA AP-1 group received a one-time subcutaneous dose of MCT and subcutaneous injections containing 100nM siRNA AP-1, every two weeks. All animal groups received water and standard chow ad libitum for 3 months.

Results
In comparison with the MCT group, siRNA AP-1 treatment had significant beneficial effects contributing to: (1) a reduction in TGF-β1/ET-1/IL-1β plasma concentrations; (2) a reduced level of cytosolic ROS production in PA, RV and lung, and ultrastructural improvements of these tissues; (3) a decrease of inflammatory and fibrotic marker expressions in PA (COL1A, Fibronectin, Vimentin, α-SMA, CTGF, Calponin, MMP-9), RV (COL1A, CTGF, Fibronectin, α-SMA, F-actin, OB-cadherin) and lung (COL1A, CTGF, Fibronectin, α-SMA, OB-cadherin), and an increase of endothelial marker expressions (CD31/VE-cadherin) in PA; (4) structural and functional recoveries of PA (reduced VTI/Vel, restored vascular response) and RV (enlarged internal cavity diameter in diastole, increased TAPSE/PRVOFs) associated with a decrease in systolic/diastolic blood pressure, and heart rate; (5) a reduced protein expression profile of AP-1S3/ pFAK/FAK/pERK/ERK and a significant decrease in the expression levels of miRNA-145, miRNA-210, miRNA-21, and miRNA-214 along with an increase of miRNA-124 and miRNA-204.

Conclusion
The siRNA AP-1-based therapy led to an improvement of pulmonary arterial and right ventricular function accompanied by a regression of perivascular and interstitial fibrosis in PA, RV and lung and a down-regulation of key inflammatory and fibrotic markers in MCT-treated hamsters.
Leukemia inhibitory factor receptor inhibition reduces stenosis grade and total serum cholesterol levels in a mouse model for atherosclerosis
Authors: Hemme E , Depuydt M A C , Van Santbrink P J , Delfos L , Kuiper J , Bot I 
Published: May 2024

Abstract
Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation
Atherosclerosis is characterized by the accumulation of lipids and immune cells in the arterial wall and it is the main underlying pathology causing cardiovascular diseases (CVD). Cytokines are involved in all stages of atherosclerosis and most cytokines contribute to disease progression. For instance, IL-6 cytokine family members, such as IL-6, oncostatin-M and cardiotrophin-1, are closely related to CVDs. However, the role of leukemia inhibitory factor (LIF), a member of the IL-6 cytokine family, and its receptor (LIFR) in atherosclerosis remains unknown. Therefore, the aim of this study is to assess the contribution of LIFR signaling to atherosclerosis development by systemically inhibiting LIFR in an atherosclerotic mouse model.
First, the expression of LIF and LIFR was examined using single-cell RNA sequencing data of human carotid artery plaques. Mast cells highly and exclusively express LIF, whereas LIFR was specifically expressed by activated endothelial cells. To validate LIFR signaling in vivo, female western-type diet fed Ldlr-/- mice were treated with LIFR inhibitor EC359 (5 mg/kg s.c., n=15) or control solvent (n=15) three times per week for eight weeks. During the experiment, weights of the mice did not differ between groups, whereas total serum cholesterol levels were significantly reduced in EC359 treated mice (p=0.03). In particular, EC359 treatment reduced VLDL levels. Additionally, EC359 treatment significantly reduced Sr1, Abca1 and Lrp1 expression in the liver, suggesting an altered lipid metabolism in EC359 treated mice. Furthermore, LIFR inhibition affected innate immunity, both systemically and locally in the plaque. Neutrophil numbers were significantly increased in the circulation (ctrl 18.7±1.7%; EC359 28.0±2.0%; p=0.002) and aortic plaques (ctrl 3.9±0.8%; EC359 9.9±1.9%; p=0.003) of mice treated with EC359 compared to control mice. Moreover, LIFR inhibition affected circulating monocytes resulting in less inflammatory monocytes. The adaptive immune cells, such as T and B cells, remained largely unaffected. Collectively, the reduction of serum total cholesterol and increase in neutrophil numbers in EC359 treated mice resulted in a trend towards reduced atherosclerotic stenosis grade compared to control mice (39.8±1.4% versus 34.9±1.9%; p=0.054), but it did not affect plaque collagen and monocyte/macrophage content in the aortic root. Conclusively, LIFR signaling inhibition reduces atherosclerotic stenosis grade, lowers plasma total cholesterol levels and affects innate immunity.
The novel bispecific anti-NLRP3 inflammasome antibody InflamAb inhibits atherosclerosis in apolipoprotein E-deficient mice
Authors: Delfos L , Depuydt M A C , Bernabe Kleijn M N A , Foks A C , Kuiper J , Chemaly M , Peace A , Mcgilligan V , Bot I 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation

Background/Introduction
Atherosclerosis is the underlying pathology of many cardiovascular diseases and is characterized by chronic inflammation in the larger arteries. Activation of the NLRP3 inflammasome is one of the drivers of inflammation during atherosclerosis.

Purpose
Therefore, we aimed to determine the ability of the novel bispecific anti-NLRP3 inflammasome antibody, called InflamAb, to inhibit atherosclerosis.

Methods and Results
In vitro treatment of bone marrow derived macrophages with 25 ng/mL InflamAb effectively inhibited the IL-1β release induced by NLRP3 inflammasome activation with LPS and Aluminium hydroxide (P&lt;0.05). In addition, InflamAb administration in western-type diet fed Apoe-/- mice significantly reduced circulating IL-1β at 4 hours post inflammasome activation (P&lt;0.05), thereby showing in vivo efficacy of InflamAb. Subsequently, we assessed the effect of InflamAb on both the development of atherosclerosis and on pre-existing plaques. Treatment of western-type diet fed female Apoe-/- mice with 100 µg InflamAb or isotype control antibody (3x per week i.p) significantly inhibited collar-induced atherosclerotic plaque development in the carotid artery from 59±8*10^3 µm^2 in control mice to 36±5*10^3 µm^2 (P&lt;0.05), which coincided with a reduction in relative macrophage (control: 36±2% versus InflamAb: 28±3%, P&lt;0.05) and necrotic core content (control: 16±2% versus InflamAb: 8±1%, P&lt;0.05). InflamAb treatment of male Apoe-/- with pre-existing atherosclerosis did not affect lesion size, but improved plaque stability parameters as illustrated by a reduced relative macrophage (control: 48±2% versus InflamAb: 42±2%, P&lt;0.05) and necrotic core (control: 21±1% versus InflamAb: 18±1%, P&lt;0.05) content. In addition, we observed a trend towards increased collagen levels upon InflamAb treatment (control: 39±2% versus InflamAb: 44±2%, P=0.08).

Conclusion
To conclude, NLRP3 inflammasome inhibition by the bispecific antibody InflamAb shows promising efficacy in inhibiting atherosclerotic plaque development and destabilization.
Generation of isogenic allelic series of LMNA-mutated hiPSC lines using the novel and highly-efficient targeting platform, STRAIGHT-IN
Authors: Meraviglia V , Blanch-Asensio A , Davis R , Mummery C L , Bellin M 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Netherlands Organisation for Health Research and Development ZonMW

Background
Human induced pluripotent stem cells (hiPSCs) have demonstrated enormous potential for advancing in vitro disease modelling and genetically modified hiPSCs carrying disease-associated variants are particularly useful tools for this purpose. Until now, strategies for efficient and rapid integration of large DNA payloads (&gt;10 kb) into specific genomic regions are still limited, thus precluding efficient and rapid targeting of hiPSC lines.

Purpose and Methods
To overcome this, the STRAIGHT-IN platform (Serine and Tyrosine Recombinase Assisted Integration of Genes for High-Throughput INvestigation) was developed that combined different classes of site-specific recombinases with CRISPR-Cas9 mediated homologous recombination and allowed stringent site-specific replacement of large genomic fragments in hiPSCs.
Here, we use STRAIGHT-IN to simultaneously generate a library of genetically matched hiPSC lines carrying multiple heterozygous mutations in LMNA gene. Mutations in LMNA, encoding Lamin A/C protein, have been associated with 5-10% cases of dilated cardiomyopathy (DCM) with conduction defects.

Results
Through detailed online searches of the LMNA database and literature, we identified and selected 11 LMNA mutations to insert into a wild-type hiPSC line based on the following criteria: (i) mutations associated with cardiac abnormalities, in terms of structural (DCM/heart failure) and arrhythmic phenotypes; (ii) mutations with known familiar/pedigree-relationship; (iii) different types of mutations (missense and nonsense). We then applied the workflow of STRAIGHT-IN consisting of: (1) replacing the entire LMNA genomic locus (33 kb) on one allele with a Landing Pad (LP) cassette containing Serine Recombinase (Bxb1) recognition sites; (2) reintroducing LMNA gene into the LP cassette through integration of Bxb1-Donor plasmids carrying the LMNA variants of interest via Bxb1 expression; (3) expressing a tyrosine recombinase (Cre) to excise the majority of the auxiliary exogenous DNA sequences.

Conclusions
STRAIGHT-IN allows simultaneous generation of a panel of 11 isogenic hiPSC lines carrying selected LMNA mutations rapidly (5-6 weeks), efficiently and cost-effectively, thus facilitating the production of specific mutated hiPSC lines for disease modelling and personalized medicine applications.
What Good Are Treatment Effects Without Treatment? Mental Health and the Reluctance to Use Talk Therapy
Authors: Cronin Christopher J , Forsstrom Matthew P , Papageorge Nicholas W 
Published: May 2024

Abstract
Evidence across disciplines suggests that talk therapy is more curative than antidepressants for mild-to-moderate depression and anxiety. Yet, few patients use it. We develop a dynamic choice model to analyse patient demand for the treatment of depression and anxiety. The model incorporates myriad potential impediments to therapy use along with links between mental health improvements and earnings. The estimated model reveals that mental health improvements are valuable, directly through utility and indirectly through earnings. However, patient reluctance to use therapy is nearly impervious to reasonable counterfactual policies (e.g. lowering prices or removing other costs). Patient behaviour might reflect stigma, biases in beliefs about the effectiveness of therapy, or a distaste for discussing personal or painful issues with a stranger. More broadly, the benefits of therapy estimated in randomized trials tell only half the story. If patients do not use treatments outside of an experimental setting—and we fail to understand why or how to get them to—estimated treatment effects cannot be leveraged.
Mitigating Microaggressions in Medical Education Through the TRAUMA Framework
Authors: Johnson Christen D. , Mike Elise V. , Jean-Charles Antoinette Leonard 
Published: May 2024

Abstract
Microaggressions are defined as brief communications directed at members of a stigmatized group that are received as derogatory but are unrecognized by the offender. Studies show that microaggressions are detrimental to those of all identities who endure them. Given that microaggressions can result in specific emotional, psychological, and physical challenges for underrepresented medical students from minoritized backgrounds, it is imperative that the medical education community focus efforts on reducing them and their impact through appropriate responses. The TRAUMA framework was developed by the authors and can be used to organize a thorough response to the threat that microaggressions create for all students. The framework includes improved student support, guidelines for faculty and institutional responses to microaggressions, improved faculty development for addressing microaggressions, recommendations to improve classroom environments, and interventions both to create and measure culture change in medical education.
Conceptualizing Educational Comparability in Distributed Health Professions Education: A Scoping Review
Authors: Hsu Helen C.H. , Martin Tyler , Teunissen Pim W. , Eva Kevin W. 
Published: May 2024

Abstract

Purpose
This study aimed to create greater clarity about the current understanding and formulate a model of how educational comparability has been used in the literature to inform practice.

Method
The authors conducted a literature search of 9 online databases, seeking articles published on comparability in distributed settings in health professions education before August 2021, with an updated search conducted in May 2023. Using a structured scoping review approach, 2 reviewers independently screened articles for eligibility with inclusion criteria and extracted key data. All authors participated in the descriptive analysis of the extracted data.

Results
Twenty-four articles published between 1987 and 2021 met the inclusion criteria. Most articles were focused on medical education programs (n = 21) and located in North America (n = 18). The main rationale for discussing comparability was accreditation. These articles did not offer definitions or discussions about what comparability means. The program logic model was used as an organizing framework to synthesize the literature on practices that schools undertake to facilitate and demonstrate comparability in the design (inputs), implementation (activities), and evaluation (outcomes) of distributed education. Inputs include common learning objectives, identical assessment tools and policies, governance models that enable clear communication, and reporting structure that is supported by technological infrastructure. Activities include faculty planning meetings and faculty development training. Outcomes include student experiences and academic performances.

Conclusions
This study demonstrated that a more complex understanding of the dynamics of educational processes and practices is required to better guide the practice of educational comparability within distributed education programs. In addition to highlighting the need to develop an accepted definition of educational comparability, further elucidation of the underlying dynamics among input, activities, and outcomes would help to better determine what drivers should be prioritized when considering educational change with attention to context within distributed education.
Clinician Educator Milestones: Assessing and Improving Educators’ Skills
Authors: Mahan John D. , Kaczmarczyk Joseph M. , Miller Juve Amy K. , Cymet Tyler , Shah Brijen J. , Daniel Rebecca , Edgar Laura 
Published: May 2024

Abstract
The importance of the clinician educator (CE) role in delivery of competency-based medical education is well recognized. There is, however, no formal mechanism to identify when faculty have the knowledge, skills, and attitudes to be successful CEs. In 2020, the Accreditation Council for Graduate Medical Education, Accreditation Council for Continuing Medical Education, Association of American Medical Colleges, and American Association of Colleges of Osteopathic Medicine convened a workgroup of 18 individuals representing multiple medical specialties and diverse institutions in the United States, including nonphysician educators, a medical student, and a resident, to develop a set of competencies, subcompetencies, and milestones for CEs.
A 5-step process was used to create the Clinician Educator Milestones (CEMs). In step 1, the workgroup developed an initial CEM draft. Through brainstorming, 141 potential education-related CE tasks were identified. Descriptive statements for each competency and developmental trajectories for each subcompetency were developed and confirmed by consensus. The workgroup then created a supplemental guide, assessment tools, and additional resources. In step 2, a diverse group of CEs were surveyed in 2021 and provided feedback on the CEMs. In step 3, this feedback was used by the workgroup to refine the CEMs. In step 4, the second draft of the CEMs was submitted for public comment, and the CEMs were finalized. In step 5, final CEMs were released for public use in 2022.
The CEMs consist of 1 foundational domain that focuses on commitment to lifelong learning, 4 additional domains of competence for CEs in the learning environment, and 20 subcompetencies. These milestones have many potential uses for CEs, including self-assessment, constructing learning and improvement plans, and designing systematic faculty development efforts. The CEMs will continue to evolve as they are applied in practice and as the role of CEs continues to grow and develop.
C/EBPβ-Lin28a positive feedback loop triggered by C/EBPβ hypomethylation enhances the proliferation and migration of vascular smooth muscle cells in restenosis
Authors: Zhou Xiaojun , Jiang Shan , Guo Siyi , Yao Shuai , Sheng Qiqi , Zhang Qian , Dong Jianjun , Liao Lin 
Published: May 2024

Abstract

Background:
The main cause of restenosis after percutaneous transluminal angioplasty (PTA) is the excessive proliferation and migration of vascular smooth muscle cells (VSMCs). Lin28a has been reported to play critical regulatory roles in this process. However, whether CCAAT/enhancer-binding proteins β (C/EBPβ) binds to the Lin28a promoter and drives the progression of restenosis has not been clarified. Therefore, in the present study, we aim to clarify the role of C/EBPβ–Lin28a axis in restenosis.

Methods:
Restenosis and atherosclerosis rat models of type 2 diabetes (n  =  20, for each group) were established by subjecting to PTA. Subsequently, the difference in DNA methylation status and expression of C/EBPβ between the two groups were assessed. EdU, Transwell, and rescue assays were performed to assess the effect of C/EBPβ on the proliferation and migration of VSMCs. DNA methylation status was further assessed using Methyltarget sequencing. The interaction between Lin28a and ten-eleven translocation 1 (TET1) was analysed using co-immunoprecipitation (Co-IP) assay. Student’s t-test and one-way analysis of variance were used for statistical analysis.

Results:
C/EBPβ expression was upregulated and accompanied by hypomethylation of its promoter in restenosis when compared with atherosclerosis. In vitro
C/EBP
β overexpression facilitated the proliferation and migration of VSMCs and was associated with increased Lin28a expression. Conversely, C/EBP
β knockdown resulted in the opposite effects. Chromatin immunoprecipitation assays further demonstrated that C/EBPβ could directly bind to Lin28a promoter. Increased C/EBPβ expression and enhanced proliferation and migration of VSMCs were observed after decitabine treatment. Further, mechanical stretch promoted C/EBPβ and Lin28a expression accompanied by C/EBP
β hypomethylation. Additionally, Lin28a overexpression reduced C/EBP
β methylation via recruiting TET1 and enhanced C/EBPβ-mediated proliferation and migration of VSMCs. The opposite was noted in Lin28a knockdown cells.

Conclusion:
Our findings suggest that the C/EBPβ–Lin28a axis is a driver of restenosis progression, and presents a promising therapeutic target for restenosis.