bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomic profiling reveals higher presence of glycolytic enzymes in vulnerable atherosclerotic lesions
Authors: Palm K C A , Theofilatos K , Van Der Laan S , Diez Benavente E , De Borst G J , De Kleijn D P V , Wotja J , Mayr M , Den Ruijter H , Mokry M , Pasterkamp G 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Leducq PlaqOmics

Background
Our definition of vulnerable plaques is predominantly driven by histological analysis. The molecular mechanisms behind the vulnerable histological characteristics are not fully understood. Here we use mass spectrometry-based proteomics data, to identify molecular mechanisms linked to vulnerable plaques.

Methods
Atherosclerotic lesions from two hundred patients undergoing endarterectomy surgery were collected (149 male and 51 female plaques). From a total of two hundred plaque samples, extracellular matrix proteins were extracted and processed for untargeted proteomics analysis. The resulting protein levels were linked to existing histological characteristics, transcriptomic, and clinical data.

Results
We detected 1499 proteins in atherosclerotic lesions, which were mostly affiliated with biological processes including extracellular matrix organization, coagulation, and peptidase activity. Linear regression identified 240 proteins associated with plaque vulnerability index (a semi-quantitative score summarizing the presence of SMC cells, macrophages, plaque hemorrhage, and fat in the plaque). Among the proteins associated with high plaque vulnerability index we identified an overrepresentation of enzymes involved in glycolysis – including the rate limiting enzymes HK3 (beta =0.40 p =0.003) and PKM (beta =0.19 p =0.009). This was driven by macrophage numbers and fat content in the plaque. Furthermore, data from a validation cohort of 120 patients from the Medical University of Vienna, Austria, revealed that HK3 and PKM were associated with plaque progression (p =&lt;0.001, p =0.017) and clinical symptoms (p = &lt;0.001, p = &lt;0.001).

Conclusion
Enzymes involved in the glycolysis process show higher presence in vulnerable plaques. This suggests an important role for energy metabolism in plaque vulnerability.
Increased bone morphogenetic protein 10 in precapillary pulmonary hypertension patients
Authors: Llucia-Valldeperas A , Van Wezenbeek J , Groeneveldt J A , Smal R , Sanchez-Duffhues G , Becher C , Handoko M L , Meijboom L , Marcus J T , Symersky P , Niessen H W M , Vonk-Noordegraaf A , Bogaard H J , Goumans M J , De Man F S 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Netherlands Organization for Scientific Research: NWO-VICI num. 918.16.610 and NWO-VIDI num. 917.18.338.
Dutch Heart Foundation Dekker senior post-doc grant num. 2018T059 and the Netherlands CardioVascular Research Initiative: CVON-2017-10 DOLPHIN-GENESIS and CVON-2018-29 PHAEDRA-IMPACT.
Fundació La Marató de TV3 num.202038.
The Spanish Ministry of Science through the Ramón y Cajal grant num.RYC2021-030866-I.

Introduction
Precapillary pulmonary hypertension (PH) results in increased right atrial (RA) stretch and pressure. The right atrium is the major source of bone morphogenetic protein (BMP) 10 (BMP10) in adults, mostly produced by RA cardiomyocytes. The major predisposing risk factor for PH involves loss-of-function mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, through which BMP10 and BMP9 transduce signals.

Purpose
The aim of this study was to investigate if BMP10 expression is altered in PH, and whether BMP10 signaling activity associates with right ventricular (RV) adaptation, RA function and disease progression.

Methods
We investigated BMP10 gene and protein expressions in RA tissue. We determined BMP10 and BMP9 plasma levels by ELISA. We studied BMP10 signaling activity in PH and CTEPH patients before and after pulmonary endarterectomy (PEA).

Results
BMP10 mRNA, protein and activity were significantly increased in the PH right atrium. While circulating levels of BMP10 and BMP9 proteins were increased, no significant changes were observed in BMP10 signaling activity between PH and controls. In a cohort of CTEPH patients, BMP10 signaling activity was reduced after PEA which coincided with improved hemodynamics and RV function. Interestingly, high BMP10 activity was associated with reduced RV function and adaptation, increased RA dilation and decreased RA function. No associations were observed with hemodynamics or general disease markers.

Conclusions
RA BMP10 expression and plasma levels are increased in precapillary PH. High BMP10 transcriptional activity was associated with worse RV function, RV adaptation, RA dilation and RA function. Future studies are needed to further understand the mechanism underlying BMP10 secretion and function in PH.
Modulation of mitochondrial dynamism in kupffer cells impacts systemic metabolism
Authors: Fantini F , Da Dalt L , Moregola A , Vingiani G B , Svecla M , Terenghi O , Nour J , Bellini R , Bonacina F , Norata G D 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): University of Milan

Background
Kupffer Cells (KC) are hepatic resident macrophages that are essential for liver physiology and contribute to the development of Non-Alcoholic Fatty Liver Disease (NAFLD). The liver of patients with NAFLD shows different expression of some key regulators of inner mitochondrial membrane fusion compared with healthy subjects, including OPA1 protein, which is a mitochondrial protein whose activity promotes mitochondrial fusion and positive modulation of oxidative phosphorylation.

Aim
Given that Kupffer Cells have both immune and metabolic roles, their mitochondria are critical for their and energy requirements and their functionality. This project aims to study how the inhibition of OPA1-driven mitochondrial fusion affects immune-metabolic response and progression of NAFLD by exploring the role of OPA1 in both a Standard and High-fat diet context.

Methods
mice selectively lacking OPA1 in Kupffer Cells were fed with either a Standard diet or a High-fat diet for 20 weeks. The metabolic phenotype was assessed by in vivo indirect calorimetry, measurement of plasma and tissue lipid profile, glucose and insulin sensitivity assays, and complete immunophenotype characterization. Single cell RNA sequencing was also performed to profile with higher resolution the impact of OPA1 deficiency on Kupffer Cell function and cross talk with other liver cells types within the hepatic niche.

Results
Under Standard diet conditions mice selectively lacking OPA1 in Kupffer Cells show a significant reduction in the KC1 pro-inflammatory subset, while the pro-resolutive KC2 increases significantly. In addition, mice lacking OPA1 in KCs show a metabolic preference towards carbohydrates, despite comparable energy expenditure, O2 consumption and CO2 production. The systemic immune profile was comparable between the two groups, with an expected reduction in KC total number under High-fat diet conditions, where no significant differences were observed between the two groups in plasma cholesterol and triglyceride levels, while a significant reduction in liver fibrosis was observed with liver histology.

Conclusions
Taken together these preliminary data suggest that OPA1-mediated inhibition of mitochondrial fusion in Kupffer Cells affects the systemic metabolic response under Standard diet with a reflection also on High-fat diet conditions, where systemic metabolism is comparable between the two groups, but the loss of OPA1 appears to influence the progression of NAFLD through a reduction in total liver fibrosis. Ongoing studies aim to understand the molecular mechanisms underlying these different immune-metabolic responses.
Unraveling the metabolic pattern of angiopoietin-like 3 knock-out mouse models under fasting and fed conditions
Authors: Terenghi O , Da Dalt L , Fantini F , Moregola A , Bonacina F , Norata G D 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): University of Milan

Background
Angiopoietin-like 3 (ANGPTL3) is a hepatokine and a regulator of lipid and lipoprotein metabolism through lipoprotein lipase and endothelial lipase inhibition, preventing the hydrolyzation of lipoprotein-derived triglycerides.
A lack of ANGPTL3 results into a hypolipidemic phenotype, with a lower profile of lipids and lipoproteins, and this is evident in humans carrying a loss of function mutation, or in cellular or in vivo models.
ANGPTL3 action, from the liver, is finely regulated between oxidative and storage tissues in the fasting and postprandial phases; from the current pharmacological treatments a possible ANGPTL3 intrahepatic role besides the lipases’ inhibition is emerging, thus possibly affecting the systemic metabolism with different implications.

Purpose
An axis between ANGPTL3 and other Angiopoietin-like proteins is known to regulate the triglyceride partitioning after a meal or during fasting, however the effect on tissues and the following metabolic and pathologic implications are still not known.
Therefore, we aim to describe the impact of ANGPTL3 deficiency in fasting or in a postprandial state, and in different compartments of the organism.

Methods
As models, we utilized Angptl3 Knock-out (KO) mice (C57BL6/J background) and their littermate controls (wild-type, WT) fed a chow diet for 16 weeks. We assessed the metabolic phenotype with indirect calorimetry and with lipids, glucose, and insulin tolerance tests; we evaluated changes in plasma lipids under fast, fed, and fast-refeed settings and we investigated the histology of key metabolic organs.

Results
ANGPTL3 KO mice fed ad libitum a chow diet are hypolipidemic (plasma triglycerides levels: 42,42±8,80 mg/dL in ANGPTL3 KO mice vs. 122,02±55,09 mg/dL in WT mice; plasma cholesterol levels: 44,00±9,11 mg/dL in ANGPTL3 KO mice vs. 76,51±15,87 mg/dL in WT mice). The oral charge lipid challenge suggests that KO mice have lower lipid levels at all time points.

Conclusions
This preliminary profiling of ANGPTL3 KO mice under fasting and fed conditions highlights the hypolipidemia of these models, and the potentially beneficial impact of ANGPTL3 deficiency on their metabolism compared to controls.
Endothelial cellular response to oxidative stress key to proteasome inhibitor cardiovascular toxicity profile
Authors: Mansson Broberg A G N E T A , Wardell E V A , Sjoborg Alpman M , Lund J L , Sylven C 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): Karolinska Institutet

Background/Introduction
Proteasome inhibitors (PI) have contributed to longer survival in multiple myeloma although PI related cardiovascular adverse events are common. Associated to carfilzomib hypertension, coronary ischemic events and heart failure (both with reduced and preserved left ventricular ejection fraction). Here we explore the effect of PIs on endothelial gene expression.

Methods
Human aortic endothelial cells (HAEC) were incubated for 24 h with carfilzomib or bortezomib at different concentrations. Gene expression determined using using bcl2fastq (v2.20.0), and read quality was assessed using FastQC (v0.11.8). For each group the 100 genes with highest ratio were used for analysis of gene ontology (GO), biological processes using ClusterProfiler. The carfilzomib / bortezomib &gt;1.5 was determined in the relevant GO groups.

Results
PIs induce gene expression related to inflammatory response and oxidative stress, more pronounced for carfilzomib. 44 / 31 genes related to "cytokine-mediated signaling pathway" and "response to oxidative stress pathway. NR4A3 was 15.5 fold above control while its increase with bortezomib was modest.

Discussion
Both carfilzomib and bortezomib induce genes related in inflammation and oxidative stress. Carfilzomib induced more pronounced upregulations in several genes, that stimulates expression of increased cellular respiration. Our result show a differentiated effect on endothelial cell gene expression by carfilzomib and bortezomib -a possible explanation to the differences in cardiovascular toxicity profile.
Figure 1.
Selected GO, Biological function characteristics calculated on the top 100 fold-change genes in each group. C2 high dose carfilzomib, B1 and B2 low and high dose bortezomib. C1 did not converge to any GO characteristics.
Impact of the 2022 pulmonary hypertension definition on haemodynamic classification and mortality in patients with aortic stenosis undergoing valve replacement
Authors: Maeder Micha T , Weber Lukas , Pohle Susanne , Chronis Joannis , Baty Florent , Rigger Johannes , Brutsche Martin , Haager Philipp , Rickli Hans , Brenner Roman 
Published: May 2024

Abstract

Aims
With the 2022 pulmonary hypertension (PH) definition, the mean pulmonary artery pressure (mPAP) threshold for any PH was lowered from ≥25 to &gt;20 mmHg, and the pulmonary vascular resistance (PVR) value to differentiate between isolated post-capillary PH (IpcPH) and combined pre- and post-capillary PH (CpcPH) was reduced from &gt;3 Wood units (WU) to &gt;2 WU. We assessed the impact of this change in the PH definition in aortic stenosis (AS) patients undergoing aortic valve replacement (AVR).

Methods and results
Severe AS patients (n = 503) undergoing pre-AVR cardiac heart catheterization were classified according to both the 2015 and 2022 definitions. The post-AVR mortality [median follow-up 1348 (interquartile range 948–1885) days] was assessed. According to the 2015 definition, 219 (44% of the entire population) patients had PH: 63 (29%) CpcPH, 125 (57%) IpcPH, and 31 (14%) pre-capillary PH. According to the 2022 definition, 321 (+47%) patients were diagnosed with PH, and 156 patients (31%) were re-classified: 26 patients from no PH to IpcPH, 38 from no PH to pre-capillary PH, 38 from no PH to unclassified PH, 4 from pre-capillary PH to unclassified PH, and 50 from IpcPH to CpcPH (CpcPH: +79%). With both definitions, only the CpcPH patients displayed increased mortality (hazard ratios ≈ 4). Among the PH-defining haemodynamic components, PVR was the strongest predictor of death.

Conclusion
In severe AS, the application of the 2022 PH definition results in a substantially higher number of patients with any PH as well as CpcPH. With either definition, CpcPH patients have a significantly increased post-AVR mortality.
Leprosy reactions: Unraveling immunological mechanisms underlying tissue damage in leprosy patients
Authors: Serrano-Coll Héctor , Wan Eric L , Restrepo-Rivera Lina , Cardona-Castro Nora 
Published: May 2024

Abstract
Leprosy is a chronic granulomatous infectious and disabling disease caused by two mycobacteria, Mycobacterium leprae and Mycobacterium lepromatosis. Acute inflammatory responses, known as leprosy reactions, are significant contributors to disabilities. Three types of leprosy reactions have been identified based on excessive cytokine release (e.g. type 1) or the accumulation of immune complexes in tissues inducing multiorgan damage (e.g. types 2 and 3). The type of leprosy reaction has implications on treatment and management strategies, yet are not well understood by health workers caring for leprosy patients. We attempt to describe the immunologic mechanisms behind the different leprosy reactions and the rationale for tailoring clinical treatment and management to the particular type of leprosy reaction based on the underlying immunologic situation.
Longitudinal Trajectories of Stress and Positive Aspects of Dementia Caregiving: Findings From the IDEAL Programme
Authors: Quinn Catherine , Gamble Laura D , Morris Robin G , Pentecost Claire , Rusted Jennifer M , Clare Linda 
Published: May 2024

Abstract

Objectives
Understanding what influences changes over time in caregiver well-being is important for the development of effective support. This study explores differences in trajectories of caregiver stress and positive aspects of caregiving (PAC).

Methods
Caregivers of community-dwelling individuals with mild-to-moderate dementia at baseline from the IDEAL cohort were interviewed at baseline (n = 1,203), 12 months (n = 917), and 24 months (n = 699). Growth mixture models identified multiple growth trajectories of caregiver stress and PAC in the caregiver population. Associations between study measures and trajectory classes were examined using multinomial logistic regression and mixed-effects models.

Results
Mean stress scores increased over time. A 4-class solution was identified: a “high” stable class (8.3%) with high levels of stress, a “middle” class (46.1%) with slightly increasing levels of stress, a “low” class (39.5%) with initial low levels of stress which slightly increased over time, and a small “increasing” class (6.1%) where stress level started low but increased at a steeper rate. Mean PAC scores remained stable over time. A 5-class solution was identified: 3 stable classes (“high,” 15.2%; “middle,” 67.6%; “low” 9.3%), a small “increasing” (3.4%) class, and 1 “decreasing” class (4.5%). For stable classes, positive ratings on study measures tended to be associated with lower stress or higher PAC trajectories and vice versa. Those with “increasing” stress also had worsening trajectories of several study measures including depression, relationship quality, competence, and ability to cope.

Discussion
The findings highlight the importance of identifying caregivers at risk of increased stress and declining PAC and offering them targeted support.
Loneliness Trajectories and Chronic Loneliness Around the World
Authors: Sheftel Mara Getz , Margolis Rachel , Verdery Ashton M 
Published: May 2024

Abstract

Objectives
We examine cross-national variation in (a) loneliness trajectories and (b) the association between common social risk factors and chronic loneliness in middle and older adulthood.

Methods
Using longitudinal data, we assess the country-level prevalence of loneliness trajectories (chronic, transitory, and no loneliness) and the extent of common social risk factors for loneliness (living alone, widowhood, divorce, no grandchildren, having chronic conditions, and never working) among adults 50 and older in 20 countries covering 47% of the global population in this age bracket. Additionally, we compare how the associations between social risk factors and chronic loneliness vary across countries.

Results
We find considerable variation in the prevalence of chronic loneliness cross-nationally, ranging between 4% (Denmark) and 15% (Greece) of adults 50 and older. Living arrangements have the most consistent association with the likelihood of chronic loneliness across countries, with those ever living alone having an 8% higher likelihood of chronic loneliness on average across countries, with a range of 2%–25%. Additionally, those who never report working and those with chronic conditions have a higher likelihood of chronic loneliness across more than a third of the countries.

Discussion
These results suggest that policies and interventions targeted to middle age and older adults living alone and with limited work histories or with chronic conditions are critical in reducing the public health challenges of chronic loneliness.
Practical Guidance and Workflows for Identifying Fast Evolving Non-Coding Genomic Elements Using PhyloAcc
Authors: Thomas Gregg W C , Gemmell Patrick , Shakya Subir B , Hu Zhirui , Liu Jun S , Sackton Timothy B , Edwards Scott V 
Published: May 2024

Synopsis
Comparative genomics provides ample ways to study genome evolution and its relationship to phenotypic traits. By developing and testing alternate models of evolution throughout a phylogeny, one can estimate rates of molecular evolution along different lineages in a phylogeny and link these rates with observations in extant species, such as convergent phenotypes. Pipelines for such work can help identify when and where genomic changes may be associated with, or possibly influence, phenotypic traits. We recently developed a set of models called PhyloAcc, using a Bayesian framework to estimate rates of nucleotide substitution on different branches of a phylogenetic tree and evaluate their association with pre-defined or estimated phenotypic traits. PhyloAcc-ST and PhyloAcc-GT both allow users to define a priori a set of target lineages and then compare different models to identify loci accelerating in one or more target lineages. Whereas ST considers only one species tree across all input loci, GT considers alternate topologies for every locus. PhyloAcc-C simultaneously models molecular rates and rates of continuous trait evolution, allowing the user to ask whether the two are associated. Here, we describe these models and provide tips and workflows on how to prepare the input data and run PhyloAcc.
Comparison of HTK-Custodiol and St-Thomas solution as cardiac preservation solutions on early and midterm outcomes following heart transplantation
Authors: Dulguerov Filip , Abdurashidowa Tamila , Christophel-Plathier Emeline , Ion Lucian , Gunga Ziyad , Rancati Valentina , Yerly Patrick , Tozzi Piergiorgio , Albert Adelin , Ltaief Zied , Rotman Samuel , Meyer Philippe , Lefol Karl , Hullin Roger , Kirsch Matthias 
Published: May 2024

Abstract

OBJECTIVES
The choice of the cardiac preservation solution for myocardial protection at time of heart procurement remains controversial and uncertainties persist regarding its effect on the early and midterm heart transplantation (HTx) outcomes. We retrospectively compared our adult HTx performed with 2 different solutions, in terms of hospital mortality, mid-term survival, inotropic score, primary graft dysfunction and rejection score.

METHODS
From January 2009 to December 2020, 154 consecutive HTx of adult patients, followed up in pre- and post-transplantation by 2 different tertiary centres, were performed at the University Hospital of Lausanne, Switzerland. From 2009 to 2015, the cardiac preservation solution used was exclusively St-Thomas, whereafter an institutional decision was made to use HTK-Custodiol only. Patients were classified in 2 groups accordingly.

RESULTS
There were 75 patients in the St-Thomas group and 79 patients in the HTK-Custodiol group. The 2 groups were comparable in terms of preoperative and intraoperative characteristics. Postoperatively, compared to the St-Thomas group, the Custodiol group patients showed significantly lower inotropic scores [median (interquartile range): 35.7 (17.5–60.2) vs 71.8 (31.8–127), P &lt; 0.001], rejection scores [0.08 (0.0–0.25) vs 0.14 (0.05–0.5), P = 0.036] and 30-day mortality rate (2.5% vs 14.7%, P = 0.007) even after adjusting for potential confounders. Microscopic analysis of the endomyocardial biopsies also showed less specific histological features of subendothelial ischaemia (3.8% vs 17.3%, P = 0.006). There was no difference in primary graft dysfunction requiring postoperative extracorporeal membrane oxygenation. The use of HTK-Custodiol solution significantly improved midterm survival (Custodiol versus St-Thomas: hazard ratio = 0.20, 95% confidence interval: 0.069–0.60, P = 0.004).

CONCLUSIONS
This retrospective study comparing St-Thomas solution and HTK-Custodiol as myocardial protection during heart procurement showed that Custodiol improves outcomes after HTx, including postoperative inotropic score, rejection score, 30-day mortality and midterm survival.