bluuebunny/crossref_metadata_2025 huggingface dataset:
Mother-reliant or self-reliant: the germination strategy of seeds in a species-rich alpine meadow is associated with the existence of pericarps
Authors: Li Xiao-Qing , Zhu Hong-Yu , He Yong-Deng , Ochola Anne Christine , Qiong La , Yang Chun-Feng
Published: May 2024

Background and Aims

Some plants germinate their seeds enclosed by a pericarp, whereas others lack the outer packaging. As a maternal tissue, the pericarp might impart seeds with different germination strategies. Plants in a community with different flowering times might separately disperse and germinate their seeds; therefore, flowering time can be considered as one manifestation of maternal effects on the offspring. The mass of the seed is another important factor influencing germination and represents the intrinsic resource of the seed that supports germination. Using seeds from a species-rich alpine meadow located in the Hengduan Mountains of China, a global biodiversity hotspot, we aimed to illustrate whether and how the type of seed (with or without a pericarp) modulates the interaction of flowering time and seed mass with germination.

Methods

Seeds were germinated in generally favourable conditions, and the speed of germination [estimated by mean germination time (MGT)] was calculated. We quantified the maternal conditions by separation of flowering time for 67 species in the meadow, of which 31 produced seeds with pericarps and 36 yielded seeds without pericarps. We also weighed 100 seeds of each species to assess their mass.

Key Results

The MGT varied between the two types of seeds. For seeds with pericarps, MGT was associated with flowering time but not with seed mass. Plants with earlier flowering times in the meadow exhibited more rapid seed germination. For seeds without a pericarp, the MGT depended on seed mass, with smaller seeds germinating more rapidly than larger seeds.

Conclusions

The distinct responses of germination to flowering time and seed mass observed in seeds with and without a pericarp suggest that germination strategies might be mother-reliant for seeds protected by pericarps but self-reliant for those without such protection. This new finding improves our understanding of seed germination by integrating ecologically mediated maternal conditions and inherent genetic properties.
Inferring gene regulatory networks from single-cell transcriptomics based on graph embedding
Authors: Gan Yanglan , Yu Jiacheng , Xu Guangwei , Yan Cairong , Zou Guobing
Published: May 2024

Motivation

Gene regulatory networks (GRNs) encode gene regulation in living organisms, and have become a critical tool to understand complex biological processes. However, due to the dynamic and complex nature of gene regulation, inferring GRNs from scRNA-seq data is still a challenging task. Existing computational methods usually focus on the close connections between genes, and ignore the global structure and distal regulatory relationships.

Results

In this study, we develop a supervised deep learning framework, IGEGRNS, to infer GRNs from scRNA-seq data based on graph embedding. In the framework, contextual information of genes is captured by GraphSAGE, which aggregates gene features and neighborhood structures to generate low-dimensional embedding for genes. Then, the k most influential nodes in the whole graph are filtered through Top-k pooling. Finally, potential regulatory relationships between genes are predicted by stacking CNNs. Compared with nine competing supervised and unsupervised methods, our method achieves better performance on six time-series scRNA-seq datasets.

Availability and implementation

Our method IGEGRNS is implemented in Python using the Pytorch machine learning library, and it is freely available at https://github.com/DHUDBlab/IGEGRNS.
MultiRNAflow: integrated analysis of temporal RNA-seq data with multiple biological conditions
Authors: Loubaton Rodolphe , Champagnat Nicolas , Vallois Pierre , Vallat Laurent
Published: May 2024

Motivation

The dynamic transcriptional mechanisms that govern eukaryotic cell function can now be analyzed by RNA sequencing. However, the packages currently available for the analysis of raw sequencing data do not provide automatic analysis of complex experimental designs with multiple biological conditions and multiple analysis time-points.

Results

The MultiRNAflow suite combines several packages in a unified framework allowing exploratory and supervised statistical analyses of temporal data for multiple biological conditions.

Availability and implementation

The R package MultiRNAflow is freely available on Bioconductor (https://bioconductor.org/packages/MultiRNAflow/), and the latest version of the source code is available on a GitHub repository (https://github.com/loubator/MultiRNAflow).
ReactomeGSA: new features to simplify public data reuse
Authors: Grentner Alexander , Ragueneau Eliot , Gong Chuqiao , Prinz Adrian , Gansberger Sabina , Oyarzun Inigo , Hermjakob Henning , Griss Johannes
Published: May 2024

Motivation

ReactomeGSA is part of the Reactome knowledgebase and one of the leading multi-omics pathway analysis platforms. ReactomeGSA provides access to quantitative pathway analysis methods supporting different ‘omics data types. Additionally, ReactomeGSA can process different datasets simultaneously, leading to a comparative pathway analysis that can also be performed across different species.

Results

We present a major update to the ReactomeGSA analysis platforms that greatly simplifies the reuse and direct integration of public data. In order to increase the number of available datasets, we developed the new grein_loader Python application that can directly fetch experiments from the GREIN resource. This enabled us to support both EMBL-EBI’s Expression Atlas and GEO RNA-seq Experiments Interactive Navigator within ReactomeGSA. To further increase the visibility and simplify the reuse of public datasets, we integrated a novel search function into ReactomeGSA that enables users to search for public datasets across both supported resources. Finally, we completely re-developed ReactomeGSA’s web-frontend and R/Bioconductor package to support the new search and loading features, and greatly simplify the use of ReactomeGSA.

Availability and implementation

The new ReactomeGSA web frontend is available at https://www.reactome.org/gsa with an built-in, interactive tutorial. The ReactomeGSA R package (https://bioconductor.org/packages/release/bioc/html/ReactomeGSA.html) is available through Bioconductor and shipped with detailed documentation and vignettes. The grein_loader Python application is available through the Python Package Index (pypi). The complete source code for all applications is available on GitHub at https://github.com/grisslab/grein_loader and https://github.com/reactome.
Representations of lipid nanoparticles using large language models for transfection efficiency prediction
Authors: Moayedpour Saeed , Broadbent Jonathan , Riahi Saleh , Bailey Michael , V. Thu Hoa , Dobchev Dimitar , Balsubramani Akshay , N.D. Santos Ricardo , Kogler-Anele Lorenzo , Corrochano-Navarro Alejandro , Li Sizhen , U. Montoya Fernando , Agarwal Vikram , Bar-Joseph Ziv , Jager Sven
Published: May 2024

Motivation

Lipid nanoparticles (LNPs) are the most widely used vehicles for mRNA vaccine delivery. The structure of the lipids composing the LNPs can have a major impact on the effectiveness of the mRNA payload. Several properties should be optimized to improve delivery and expression including biodegradability, synthetic accessibility, and transfection efficiency.

Results

To optimize LNPs, we developed and tested models that enable the virtual screening of LNPs with high transfection efficiency. Our best method uses the lipid Simplified Molecular-Input Line-Entry System (SMILES) as inputs to a large language model. Large language model-generated embeddings are then used by a downstream gradient-boosting classifier. As we show, our method can more accurately predict lipid properties, which could lead to higher efficiency and reduced experimental time and costs.

Availability and implementation

Code and data links available at: https://github.com/Sanofi-Public/LipoBART.
FMCA-DTI: a fragment-oriented method based on a multihead cross attention mechanism to improve drug–target interaction prediction
Authors: Zhang Qi , Zuo Le , Ren Ying , Wang Siyuan , Wang Wenfa , Ma Lerong , Zhang Jing , Xia Bisheng
Published: May 2024

Motivation

Identifying drug–target interactions (DTI) is crucial in drug discovery. Fragments are less complex and can accurately characterize local features, which is important in DTI prediction. Recently, deep learning (DL)-based methods predict DTI more efficiently. However, two challenges remain in existing DL-based methods: (i) some methods directly encode drugs and proteins into integers, ignoring the substructure representation; (ii) some methods learn the features of the drugs and proteins separately instead of considering their interactions.

Results

In this article, we propose a fragment-oriented method based on a multihead cross attention mechanism for predicting DTI, named FMCA-DTI. FMCA-DTI obtains multiple types of fragments of drugs and proteins by branch chain mining and category fragment mining. Importantly, FMCA-DTI utilizes the shared-weight-based multihead cross attention mechanism to learn the complex interaction features between different fragments. Experiments on three benchmark datasets show that FMCA-DTI achieves significantly improved performance by comparing it with four state-of-the-art baselines.

Availability and implementation

The code for this workflow is available at: https://github.com/jacky102022/FMCA-DTI.
bnglViz: online visualization of rule-based models
Authors: Liguori-Bills Noah , Blinov Michael L
Published: May 2024

Motivation

Rule-based modeling is a powerful method to describe and simulate interactions among multi-site molecules and multi-molecular species, accounting for the internal connectivity of molecules in chemical species. This modeling technique is implemented in BioNetGen software that is used by various tools and software frameworks, such as BioNetGen stand-alone software, NFSim simulation engine, Virtual Cell simulation and modeling framework, SmolDyn and PySB software tools. These tools exchange models using BioNetGen scripting language (BNGL). Until now, there was no online visualization of such rule-based models. Modelers and researchers reading the manuscripts describing rule-based models had to learn BNGL scripting or master one of these tools to understand the models.

Results

Here, we introduce bnglViz, an online platform for visualizing BNGL files as graphical cartoons, empowering researchers to grasp the nuances of rule-based models swiftly and efficiently, and making the exploration of complex biological systems more accessible than ever before. The produced visualizations can be used as supplemental figures in publications or as a way to annotate BNGL models on web repositories.

Availability and implementation

Available at https://bnglviz.github.io/.
Sodium–glucose cotransporter-2 inhibitors in diabetes and inflammatory skin diseases
Authors: Shen Chin-Hsuan , Yang Yi-Sun , Lee Irene Tai-Lin , Chiang Meng-Han , Chen Steven T , Ma Kevin Sheng-Kai
Published: May 2024

Treatment with sodium–glucose cotransporter-2 inhibitors (SGLT2i) is associated with a decreased risk of new-onset inflammatory skin diseases, including vitiligo, acne vulgaris, rosacea and urticaria in patients with diabetes. Prospective studies and clinical trials are warranted to validate the safety and efficacy of SGLT2i in patients with diabetes and concomitant inflammatory skin diseases.
Prostate specific membrane antigen PET avidity in a granular cell tumour of the left supraspinatus muscle: a case report
Authors: Hsieh Michael T , Fargah Farokh , Tahir Abdul Rahim Mohd , Le Ngo Tue , Shakespeare Thomas P
Published: May 2024

Granular cell tumour is a rare, mostly benign, soft tissue, neuroectodermal tumour, most commonly seen in the skin and peripheral soft tissue. There are no publications to date of PSMA-PET avidity in a granular cell tumour. In this 60 year old male, staging PSMA-PET for a localized intermediate risk prostate cancer incidentally identified a PSMA-avid left supraspinatus lesion, which was subsequently biopsy-proven as a granular cell tumour. We present the first case of PSMA-avid granular cell tumour and add to the growing literature documenting PSMA-PET avidity in benign and malignant lesions apart from prostate cancer.
The Impact of Social Work Supervision on Interns’ Employment Intention: New Evidence from Mainland China
Authors: Lan Zhensong , Mu Liping , Qiu Xue , Liu Huaqiang , Huang Xuefang
Published: May 2024

Supervision is a key link in social work practice and plays an important role in the cultivation of social work professionals. This study investigated the impact of social work internship supervision on the employment intention of 271 social work interns from five universities in Guangxi, China. The results show that the employment intention of male students is higher than that of female students, and the employment intention of interns with urban household registration is higher than that of interns with rural household registration; internship investment and school–enterprise cooperation have a positive impact on the exertion of the supervision function, but internship investment plays a full mediating role between the supervision function and employment intention, whilst school–enterprise cooperation regulates the relationship between the supervision function and internship investment. Real factors, such as economy and social status, continue to be important factors influencing social work students’ employment intention. When conducting social work internship educational activities, schools should create a favourable internship environment and working conditions for interns and maintain good cooperation with internship organisations. This will facilitate internship supervision and enhance employment intention.
Intraventricular haemorrhage in premature infants: the role of immature neuronal salt and water transport
Authors: Bahari Fatemeh , Dzhala Volodymyr , Balena Trevor , Lillis Kyle P , Staley Kevin J
Published: May 2024

Intraventricular haemorrhage is a common complication of premature birth. Survivors are often left with cerebral palsy, intellectual disability and/or hydrocephalus. Animal models suggest that brain tissue shrinkage, with subsequent vascular stretch and tear, is an important step in the pathophysiology, but the cause of this shrinkage is unknown. Clinical risk factors for intraventricular haemorrhage are biomarkers of hypoxic–ischaemic stress, which causes mature neurons to swell. However, immature neuronal volume might shift in the opposite direction in these conditions. This is because immature neurons express the chloride, salt and water transporter NKCC1, which subserves regulatory volume increases in non-neural cells, whereas mature neurons express KCC2, which subserves regulatory volume decreases. When hypoxic–ischaemic conditions reduce active ion transport and increase the cytoplasmic membrane permeability, the effects of these transporters are diminished. Consequentially, mature neurons swell (cytotoxic oedema), whereas immature neurons might shrink. After hypoxic–ischaemic stress, in vivo and in vitro multi-photon imaging of perinatal transgenic mice demonstrated shrinkage of viable immature neurons, bulk tissue shrinkage and blood vessel displacement. Neuronal shrinkage was correlated with age-dependent membrane salt and water transporter expression using immunohistochemistry. Shrinkage of immature neurons was prevented by prior genetic or pharmacological inhibition of NKCC1 transport. These findings open new avenues of investigation for the detection of acute brain injury by neuroimaging, in addition to prevention of neuronal shrinkage and the ensuing intraventricular haemorrhage, in premature infants.
The RGK protein rrad regulates cardiac calcium levels in zebrafish
Authors: Salgado-Almario J , Martinez-Sielva A , Mercedes P , Vicente M , Domingo B , Llopis J
Published: May 2024

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Science, Innovation and Universities, Spain

Background/Introduction

High voltage-activated Ca2+ (CaV) channels are essential for excitation-contraction coupling. RGK proteins (Gem, Rad, Rem, and Rem2) are small Ras-like G proteins that bind CaV β-subunits and profoundly inhibit CaV1/CaV2 channels. A recent study showed that Rad inhibits CaV1.2 channels in cardiomyocytes, thus mediating the enhanced inotropy and chronotropy by β-adrenergic agonists during the fight-or-flight response. The zebrafish has emerged as a useful in vivo animal model in cardiovascular physiology and pathophysiology. The role of zebrafish rrad, the orthologe of the human RAD, in the regulation of cardiac Ca2+ homeostasis in zebrafish has not been investigated.

Purpose

The aim of this study was to investigate the role of rrad in cardiac Ca2+ regulation in zebrafish.

Methods

We evaluated the cardiac Ca2+ dynamics, heart rhythm, and hemodynamics in transgenic zebrafish larvae that overexpress rrad in the heart, as well as in heterozygous rrad knockout larvae. Measurements were done in the beating heart of 3 dpf transgenic zebrafish larvae expressing the fluorescent Ca2+ biosensor Twitch-4.

Results

In some larvae, overexpression of rrad induced a severe enlargement of the atrium with pericardial edema and a high mortality rate. In addition, the ventricle displayed low Ca2+ levels and reduced contractility. The remaining larvae had no altered morphology, but the ventricular Ca2+ levels were reduced. On the other hand, preliminary results showed that down regulation of rrad in zebrafish larvae increased atrial and ventricular Ca2+ levels, like what was found in Rad knockout mice.

Conclusion

Taken together, these findings suggest that rrad in the zebrafish heart, as in mammals, is an inhibitor of the Ca2+ entry, presumably through CaV1/CaV2 channels, and demonstrate the zebrafish's utility as a model to study the involvement of rrad in cardiac function.
Modulating sialylation as therapeutic approach for preventing age-associated cardiac dysfunction
Authors: Tarantino A , Melgari D , Ghiroldi A , Lavota I , Rota P , Calamaio S , Piccoli M , Pappone C , Anastasia L
Published: May 2024

Funding Acknowledgements 

Type of funding sources: Public hospital(s). Main funding source(s): Ministry of Health

Voltage-gated sodium channel Nav1.5 plays a pivotal role in the proper functioning of cardiac muscle cells. Sialylation, a post-translational modification involving the addition of negatively charged sialic acid moieties, is essential for Nav1.5 functionality. Altered sialylation has been observed in various cardiovascular diseases, including Chagas disease and congenital disorders of glycosylation affecting the heart. Furthermore, sialylation status has been shown to change during human adult life, impacting brain and muscle structural properties. Cardiac arrhythmias increase in prevalence with age, contributing to higher morbidity and mortality in older people. Using an aging mouse model, we observed a decline in cardiac sialic acid levels and NaV1.5 associated with the aging process. In compelling in vitro experiments on HEK293 cells and induced pluripotent stem cell-derived cardiomyocytes, diminished external sialic acid induces Nav1.5 channel internalization, activating endocytic pathways and leading to proteasome-mediated degradation. Intriguingly, proteomic analysis revealed that introducing a specific sialic acid precursor increased membrane protein trafficking, restoring Nav1.5 protein levels and the sodium current. Electrophysiological experiments demonstrated functional recovery and highlighted the rapid response, observable within just 2 hours of sialic acid stimulation. In summary, this study provides novel insights into the complex relationship between sialic acid and NaV1.5 channel trafficking, offering new perspectives and promising therapeutic strategies to prevent cardiac dysfunction in elderly.Modulating sialylation on NaV1.5 channelOur project goal
Human induced pluripotent cardiomyocytes as a model for cardiomyopathy with a Myozap gene mutation
Authors: Zakzook F , Maria Cherian R , Aalto-Setala K
Published: May 2024

Funding Acknowledgements 

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): 1- Central Department of Missions, Egyptian Ministry of Higher education and Scientific Research. 2- small fund from Tampere University.

The contractility of the heart is based on cardiomyocytes (CM). These cardiomyocytes are connected through a complex network of proteins forming the intercalated disc (ID) which is crucial to ensure mechanical and electrochemical coupling. Dilated cardiomyopathy (DCM) is a disease of the myocardium that can lead to heart failure and life-threatening arrhythmias. Up to 30% of DCM cases are caused by mutations in genes encoding proteins of the sarcomere (the basic contractile unit) or desmosome (a cell-to-cell adhesion structure) and the structural cytoskeleton. Myozap (Myocardium-Enriched Zonula Occludens-1-Associated Protein) is a distinctive cardiac-enriched ID protein. It is crucial for biomechanical stress adaption in CMs due to its outstanding role in the Rho/SRF (Serum Response Factor) signalling pathway. In this study, we have identified two Finnish families with DCM and carrying a novel variant in myozap. Our aim is to characterize myozap gene mutation-both heterozygous and homozygous truncating variants-as well as its implication in DCM. We have established patient-specific human induced pluripotent stem-cell lines and derived cardiomyocyte (hiPSC-CM) to study the disease at the cellular level. Myozap expression, compared to the control cell line, was evaluated by immunohistochemistry. Electrophysiological methods, including microelectrode array (MEA) and patch clamping, were implemented to measure various parameters with emphasis on those ones related to cell-cell connection e.g., the conduction velocity. Moreover, metabolic stress indicators, including oxygen consumption rate (OCR), were estimated by Seahorse. Additionally, qPCR and ELISA were performed to measure the colocalised and closely related genes to ID and protein level of troponin, respectively. Immunohistochemistry revealed downregulation and absence of myozap expression in heterozygous and homozygous cell lines, respectively. Compared to the control one, differences in BPM, FPD were observed. Metabolic analysis of the myozap mutant elucidated mitochondrial impairment compared to the control. Some SRF and sarcomeric target genes, including MYH7, MYH6 and Myl-2 were downregulated. On the contrary, apoptotic genes (e.g., caspase 3) were upregulated. Tight junction protein (TJP) was upregulated, and this is very importance since it is closely related to the myozap in the ID proteins network. Moreover, troponin protein level, measured by ELISA, showed upregulation in mutant myozap. In conclusion, our study provides a new insight into understanding myozap’s significance in cardiac biology and in cardiomyopathy pathophysiology.
anti-interleukin-18 as therapy against atherosclerosis
Authors: Van Ingen E , Foks A C , Bernabe Kleijn M N A , Kuiper J , Bot I
Published: May 2024

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): Established Investigator of the Dutch Heart Foundation

Background

Interleukin-18 (IL-18) is a pro-inflammatory cytokine and is secreted by macrophages after NLRP3-inflammasome activation. IL-18 is important for the induction of the Th1 response and overexpression of IL-18 aggravates atherosclerosis, suggesting that inhibition of IL-18 may act atheroprotective. In this study, we investigated the therapeutic potential of an IL-18 neutralizing antibody (anti-IL18) on atherosclerosis development.

Methods and results

Female ApoE-/- mice were fed a Western-type diet for 8 weeks and simultaneously received an antibody against IL-18 (100 µg/mouse; n=15) or a rat IgG2a control (100 µg/mouse; n=15) 3x per week intraperitoneally, after which the mice were sacrificed. First, we assessed macrophage phenotype in the peritoneal cavity. Expression of the proinflammatory markers CD80 (control: 46.3±1.4 *103; p<0.05 vs. anti-IL18: 40.4 ±1.7 *103) and iNOS (control: 15.5±1.8 *102 vs. anti-IL18: 8.0±1.9 *102; p<0.01) were reduced. In the aorta, MFIs of anti-inflammatory macrophage markers Arginase-1 (control: 389±99 vs. anti-IL18: 654±85; p=0.06) and CD206 (control: 55.2±2.4 *103 vs. anti-IL18: 62.8±3.7 *103; p=0.1) tended to be increased expression in the ascending aorta of anti-IL18 mice compared to controls. In addition, anti-IL18 treatment promoted the number of CD4 T cells (control: 20±1% vs. anti-IL18: 28±1%; p<0.0001) in the mediastinal lymph node and increased it’s regulatory phenotype (Tregs; Foxp3+) of CD4 (control: 23±1% vs. anti-IL18: 26±1%; p=0.07) and CD8 T cells (control: 0.4±0.02% vs. anti-IL18: 0.9±0.09%; p<0.0001). These effects however, did not translate into an effect on plaque size in the aortic root, as measured using an Oil-Red-O staining, which did not differ between the control and anti-IL18 treatment group (control: 47.1±2.4 *104 µm2 vs. anti-IL18: 43.4±2.3 *104 µm2).

Conclusions

Anti-IL18 treatment reduced the proinflammatory phenotype of peritoneal macrophages and promoted Tregs in the mediastinal lymph node. Further analyses on plaque stability and intraplaque macrophage subsets are currently being performed.
Asporin expression is associated with human atherosclerotic plaque integrity
Authors: Fountas P , Gialeli C , Sun J , Nitulescu M , Persson A , Bengtsson E , Edsfeldt A , Goncalves I
Published: May 2024

Funding Acknowledgements

Type of funding sources: Other. Main funding source(s): This work was supported by the Swedish Research Council, the Swedish Heart and Lung Foundation, Skåne University Hospital funds

Background

Calcification serves as a clinical marker of atherosclerotic plaque burden. Recent studies have also shed light on its intricate association with plaque vulnerability, likely depend on calcification structures and the surrounding environment. Asporin (ASPN) is a member of the small-leucine-rich proteoglycans that contains a unique and well-conserved stretch of aspartate (D) residues, which mimic the role of glycosaminoglycans. Via its D-repeat, ASPN can interact with calcium and several other extracellular matrix molecules, thus influencing collagen mineralization and TGF-β signaling. ASPN expression has been shown to be higher in asymptomatic compared to symptomatic atherosclerotic plaques, suggesting a potential protective role. However, the role of ASPN in maintaining plaque integrity remains unknown.

Purpose

Here we aimed to explore the role of ASPN in atherosclerosis, by investigating if ASPN was expressed in human carotid plaques and by determining if ASPN is associated with risk for postoperative cardiovascular events and death.

Methods

ASPN and TGF-β protein levels were measured by ELISA and Milliplex in 176 human plaque tissue homogenates obtained from the Carotid Plaque Imaging Project (CPIP) biobank. Plaque tissue sections were stained for ASPN, destabilizing (CD68, oil red O, glycophorin A) and stabilizing plaque components (Movat, α-actin). Plaque tissue RNA expression levels were assessed in 82 plaques using bulk RNA sequencing. Plaque levels of phosphate, elastin and collagen were measured using ELISA.

Results

ASPN protein levels were higher in plaques from asymptomatic patients compared to symptomatic patients (p=0.011). ASPN RNA levels correlated positively to RNA levels of the smooth muscle cell markers ACTA2, MYH11 and TAGLN. Moreover, protein levels correlated with plaque levels of phosphate (r=0.258, p=0.001), elastin (r=0.423, p<0.001), collagen (r=0.248, p=0.002) and stability factors like the TGF-β family members, TGF-β1 (r=0.176, p=0.035), TGF-β2 (r=0.581, p<0.001) and TGF-β3 (r=0.396, p<0.001). Furthermore, plaque ASPN protein concentration, correlated inversely with a histological plaque vulnerability index (r=-0.265, p=0.0029), which is ratio between the plaque area of destabilizing (macrophages, lipids, intra-plaque hemorrhage) and stabilizing plaque components (collagen and smooth muscle cells). Additionally, above median ASPN levels were associated with lower risk for postoperative cardiovascular events (p=0.008) and death (p=0.009).

Conclusion

Our findings suggest that elevated levels of ASPN might have a crucial role in maintaining plaque stability, affecting plaque calcification.
Drug-interacting gene expression levels differ between atherosclerotic plaque subtypes
Authors: Palm K C A , Marsman J , Engels S , Boltjes A , De Borst G J , De Kleijn D P V , Den Ruijter H M , Van Steenbeek F G , Mokry M , Pasterkamp G
Published: May 2024

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): The Dutch Heart foundation

Recent transcriptomic-based clustering of human atherosclerotic plaques revealed that plaques have a diversity and complexity that cannot be accurately described by classical concepts. Previous plaque RNA sequencing that we performed in 654 lesions identified five major plaque types that reflect different mechanisms of progression of atherosclerotic disease. These include the following plaque subtypes: 0. Fibro-collagenous, 1. Intermediate, 2. Lipo-necrotic, 3. Fibro-inflammatory, and 4. Fibro-cellular. We hypothesize that these different plaque types may respond differentially upon drug treatment.

Objective

To assess differential expression levels of drug-responsive genes between the earlier described five plaque subtypes. For this in silico experiment, the differential expression of drug-responsive genes was examined after colchicine treatment in smooth muscle cells and endothelial cells.

Methods

To begin, a web-based search identified 46 published colchicine interacting genes. Then, colchicine was applied to cultured smooth muscle and endothelial cells to verify the publicly reported drug responsive genes. Next, we modelled the effect of colchicine on the five types of human atherosclerotic plaques for those genes that were considered drug responsive. This was achieved by projecting the in vitro derived expression changes onto the gene expression data from the carotid plaques of 654 patients who participated in the ATHERO-EXPRESS study. Besides colchicine, the same experimental approach was applied for atorvastatin and rofecoxib drug treatment. Finally, changes in drug responsive gene expression were validated with mice gene expression data.

Results

34 out of the 46 publicly known colchicine interacting genes were differently expressed between plaque types (Figure 1). These genes included established determinants of cell motility and atherosclerosis development (SCD, ITGB1, Tubulins). Furthermore, in-silico colchicine treatment revealed colchicine's strong effect on the atherosclerotic plaques' transcriptome. We are currently assessing if these perturbations may lead to shifts in plaque subtypes and if these changes are reflected in mice transcriptomic data.

Conclusion

The pilot data demonstrated major differences in drug-interacting gene expression levels in advanced atherosclerotic lesions. Therefore, novel and standard drugs used to treat atherosclerosis may have varying effects depending on the atherosclerotic plaque subtype.
Timing of capillary enlargement after adenoviral VEGF gene transfer does not support post-ischemic skeletal muscle recovery in hyperlipidemic mice
Authors: Wirth G , Juusola G , Laakso H , Korpisalo P , Yla-Herttuala S
Published: May 2024

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Finish Academy (Clinical Researcher 324070 and Research Project 339560). Finnish Foundation for Cardiovascular Research

Background

Transient capillary enlargement has been shown to be essential for successful post-ischemic tissue recovery as it may facilitate the return of arterial driving pressure by supporting collateral maturation. It also leads to an intussusceptive increase in capillary density that supports efficient oxygen delivery and muscle regeneration. Hyperlipidemia has been shown to blunt post-ischemic capillary reactivity and hinder skeletal muscle recovery from ischemia. Therefore, it can be hypothesized that correction of capillary reactivity might improve post-ischemic muscle recovery under hyperlipidemia.

Purpose

The aim of this study was to test the ability of angiogenic VEGF gene therapy in improving post-ischemic muscle recovery under hyperlipidemia.

Methods

AdVEGF gene transfer was performed into the calf muscles of aged, hyperlipidemic LDLR-/-ApoB100/100 mice after acute ischemia induction. The effects of AdVEGF on capillary phenotype, tissue edema, restoration of blood flow parameters, microvascular hemoglobin oxygenation and tissue damage/regeneration were evaluated for up to 29 days post-procedure as compared to AdLacZ control using immuno- and histological analyses, magnetic resonance, contrast-enhanced ultrasound and photoacoustic imaging, respectively.

Results

AdVEGF gene therapy was able to promote capillary enlargement that led to recovery of arterial driving pressure in ischemic LDLR-/-ApoB100/100 muscles. However, capillary enlargement induced by AdVEGF appeared late, lasted up to 29 days and did not promote intussusception. Consequently, the negative effect of long-lasting enlargement, i.e., massive tissue edema, delayed blood flow recovery and aggravated ischemic tissue damage.

Conclusion

Proper time of induction and duration of capillary enlargement are crucial to yield a functional vascular response supporting post-ischemic tissue recovery.
Unresectable cardiac metastasis from melanoma responds well to combination immunotherapy—a case report
Authors: Oh Ek Leone , Dias Peter , Al-Ogaili Zeyad , Otto Jacobus , Warburton Lydia
Published: May 2024

Background

Melanoma can metastasize to distal organs including the heart although presentation with a symptomatic cardiac metastasis is rare. The optimal management remains uncertain particularly in the era of immunotherapy.

Case summary

We report a case presenting with a large unresectable cardiac metastasis from melanoma that responded well to treatment with immunotherapy.

Conclusion

Melanoma can metastasize to the heart and is often challenging to diagnose. Combination immunotherapy can be an effective treatment option even in the setting of a symptomatic and unresectable cardiac metastasis.
Genomic analysis of Salmonella bacteriophages revealed multiple endolysin ORFs and importance of ligand-binding site of receptor-binding protein
Authors: Guzel Mustafa , Yucefaydali Aysenur , Yetiskin Segah , Deniz Aysu , Yaşar Tel Osman , Akçelik Mustafa , Soyer Yeşim
Published: May 2024

Salmonella is a prevalent foodborne pathogen causing millions of global cases annually. Antimicrobial resistance is a growing public health concern, leading to search for alternatives like bacteriophages. A total of 97 bacteriophages, isolated from cattle farms (n = 48), poultry farms (n = 37), and wastewater (n = 5) samples in Türkiye, were subjected to host-range analysis using 36 Salmonella isolates with 18 different serotypes. The broadest host range belonged to an Infantis phage (MET P1-091), lysing 28 hosts. A total of 10 phages with the widest host range underwent further analysis, revealing seven unique genomes (32−243 kb), including a jumbophage (>200 kb). Except for one with lysogenic properties, none of them harbored virulence or antibiotic resistance genes, making them potential Salmonella reducers in different environments. Examining open reading frames (ORFs) of endolysin enzymes revealed surprising findings: five of seven unique genomes contained multiple endolysin ORFs. Despite sharing same endolysin sequences, phages exhibited significant differences in host range. Detailed analysis unveiled diverse receptor-binding protein sequences, with similar structures but distinct ligand-binding sites. These findings emphasize the importance of ligand-binding sites of receptor-binding proteins. Additionally, bacterial reduction curve and virulence index revealed that Enteritidis phages inhibit bacterial growth even at low concentrations, unlike Infantis and Kentucky phages.
Streptococcal pyrogenic exotoxin B is a superantigen that induces murine splenocyte proliferation and secretion of IL-2 and IFN-γ ex vivo
Authors: Rasooly Reuven , Do Paula , He Xiaohua , Hernlem Bradley
Published: May 2024

Streptococcus pyogenes is a significant human pathogen, producing a range of virulence factors, including streptococcal pyrogenic exotoxin B (SpeB) that is associated with foodborne outbreaks. It was only known that this cysteine protease mediates cleavage of transmembrane proteins to permit bacterial penetration and is found in 25% of clinical isolates from streptococcal toxic shock syndrome patients with extreme inflammation. Its interaction with host and streptococcal proteins has been well characterized, but doubt remains about whether it constitutes a superantigen. In this study, for the first time it is shown that SpeB acts as a superantigen, similarly to other known superantigens such as staphylococcal enterotoxin A or streptococcal pyrogenic exotoxin type C, by inducing proliferation of murine splenocytes and cytokine secretion, primarily of interleukin-2 (IL-2), as shown by cytometric bead array analysis. IL-2 secretion was confirmed by enzyme-linked immunosorbent assay (ELISA) as well as secretion of interferon-γ. ELISA showed a dose-dependent relationship between SpeB concentration in splenocyte cells and IL-2 secretion levels, and it was shown that SpeB retains activity in milk pasteurized for 30 min at 63°C.
Medicare Advantage enrollees’ reports of unfair treatment during health care encounters
Authors: Mathews Megan , Beckett Megan K , Martino Steven C , Brown Julie A , Orr Nate , Gaillot Sarah , Elliott Marc N
Published: May 2024

We investigated unfair treatment among 1863 Medicare Advantage (MA) enrollees from 21 MA plans using 2022 survey data (40% response rate) in which respondents indicated whether they were treated unfairly in a health care setting based on any of 10 personal characteristics. We calculated reported unfair treatment rates overall and by enrollee characteristics. Nine percent of respondents reported any unfair treatment, most often based on health condition (6%), disability (3%), or age (2%). Approximately 40% of those reporting any unfair treatment endorsed multiple categories. People who qualified for Medicare via disability reported unfair treatment by disability, age, income, race and ethnicity, sex, sexual orientation, and gender/gender identity more often than those who qualified via age. Enrollees dually eligible for Medicare and Medicaid or eligible for a Low-Income Subsidy (DE/LIS) reported unfair treatment by disability, income, language/accent, race and ethnicity, culture/religion, and sex more often than non-DE/LIS enrollees. Compared with White respondents, racial and ethnic minority respondents more often reported unfair treatment by race and ethnicity, language/accent, culture/religion, and income. Female respondents were more likely than male respondents to report unfair treatment based on age and sex.
Non-invasive imaging techniques for diagnosis of pelvic deep endometriosis and endometriosis classification systems: an International Consensus Statement,
Authors: Condous G , Gerges B , Thomassin-Naggara I , Becker C , Tomassetti C , Krentel H , van Herendael B J , Malzoni M , Abrao M S , Saridogan E , Keckstein J , Hudelist G ,   Intersociety Consensus Group §, Aas-Eng K , Alcazar J L , Bafort C , Bazot M , Bielen D , Bokor A , Bourne T , Carmona F , Di Giovanni A , Djokovic D , Egekvist A , English J , Exacoustos C , Ferreira H , Ferrero S , Forstner R , Freeman S , Goncalves M , Grimbizis G , Guerra A , Guerriero S , Jansen F W , Jurkovic D , Khazali S , Leonardi M , Maciel C , Manganaro L , Mueller M , Nisolle M , Noe G , Reid S , Roman H , Rousset P , Seyer Hansen M , Singh S , Thomas V , Timmerman D , Ulrich U A , Van den Bosch T , Van Schoubroeck D , Wattiez A
Published: May 2024

The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) and International Deep Endometriosis Analysis (IDEA) group, the European Endometriosis League (EEL), the European Society for Gynaecological Endoscopy (ESGE), ESHRE, the International Society for Gynecologic Endoscopy (ISGE), the American Association of Gynecologic Laparoscopists (AAGL) and the European Society of Urogenital Radiology (ESUR) elected an international, multidisciplinary panel of gynecological surgeons, sonographers, and radiologists, including a steering committee, which searched the literature for relevant articles in order to review the literature and provide evidence-based and clinically relevant statements on the use of imaging techniques for non-invasive diagnosis and classification of pelvic deep endometriosis. Preliminary statements were drafted based on review of the relevant literature. Following two rounds of revisions and voting orchestrated by chairs of the participating societies, consensus statements were finalized. A final version of the document was then resubmitted to the society chairs for approval. Twenty statements were drafted, of which 14 reached strong and three moderate agreement after the first voting round. The remaining three statements were discussed by all members of the steering committee and society chairs and rephrased, followed by an additional round of voting. At the conclusion of the process, 14 statements had strong and five statements moderate agreement, with one statement left in equipoise. This consensus work aims to guide clinicians involved in treating women with suspected endometriosis during patient assessment, counselling, and planning of surgical treatment strategies.
Hackflex library preparation enables low-cost metagenomic profiling
Authors: Goldman Samantha L , Sanders Jon G , Sprockett Daniel D , Landers Abigail , Yan Weiwei , Moeller Andrew H
Published: May 2024

Shotgun metagenomic sequencing provides valuable insights into microbial communities, but the high cost of library preparation with standard kits and protocols is a barrier for many. New methods such as Hackflex use diluted commercially available reagents to greatly reduce library preparation costs. However, these methods have not been systematically validated for metagenomic sequencing. Here, we evaluate Hackflex performance by sequencing metagenomic libraries from known mock communities as well as mouse fecal samples prepared by Hackflex, Illumina DNA Prep, and Illumina TruSeq methods. Hackflex successfully recovered all members of the Zymo mock community, performing best for samples with DNA concentrations <1 ng/μL. Furthermore, Hackflex was able to delineate microbiota of individual inbred mice from the same breeding stock at the same mouse facility, and statistical modeling indicated that mouse ID explained a greater fraction of the variance in metagenomic composition than did library preparation method. These results show that Hackflex is suitable for generating inventories of bacterial communities through metagenomic sequencing.
Toward reciprocal feedback between computational design, engineering, and fabrication to co-design coreless filament-wound structures
Authors: Kannenberg Fabian , Zechmeister Christoph , Gil Pérez Marta , Guo Yanan , Yang Xiliu , Forster David , Hügle Sebastian , Mindermann Pascal , Abdelaal Moataz , Balangé Laura , Schwieger Volker , Weiskopf Daniel , Gresser Götz T , Middendorf Peter , Bischoff Manfred , Knippers Jan , Menges Achim
Published: May 2024

Fiber-reinforced composites offer innovative solutions for architectural applications with high strength and low weight. Coreless filament winding extends industrial processes, reduces formwork, and allows for tailoring of fiber layups to specific requirements. A previously developed computational co-design framework for coreless filament winding is extended toward the integration of reciprocal design feedback to maximize design flexibility and inform design decisions throughout the process. A multi-scalar design representation is introduced, representing fiber structures at different levels of detail to generate feedback between computational design, engineering, and fabrication. Design methods for global, component, and material systems are outlined and feedback generation is explained. Structural and fabrication feedback are classified, and their integration is described in detail. This paper demonstrates how reciprocal feedback allows for co-evolution of domains of expertise and extends the existing co-design framework toward design problems. The developed methods are shown in two case studies at a global and component scale.
Carotid artery dissection and non-aneurysmal subarachnoid hemorrhage following carotid endarterectomy
Authors: Kaoutzani Lydia , Garcia Klepper Alfredo , Rahimi Scott Y
Published: May 2024

Stroke continues to be a major public health issue resulting in high mortality and severe long-term disability. Carotid endarterectomy (CEA) plays an important role in the prevention of ischemic stroke. Complications associated with CEA can be life threatening and prompt recognition is crucial. In this report, we present a patient who presented to the hospital with progressive headache, 2 weeks following CEA. He was neurologically intact and hypertensive. Non-contrast head computed tomography (CT) scan showed convexity subarachnoid hemorrhage (SAH). He was found to have a left internal carotid artery dissection. Patients who present to the hospital following CEA with headache and hypertension benefit from a non-contrast head CT scan. The presence of SAH can be a warning sign of cerebral hyperperfusion syndrome. Carotid artery dissection is also a disease entity that can occur in the post-operative period. Prompt recognition and treatment is crucial for the management of these disease entities.
Optimizing aesthetic results in Asian women with giant phyllodes tumors over 10 cm: the periareolar mastopexy approach
Authors: Chen Kun-Han , Hsu Yu-Chen
Published: May 2024

Giant phyllodes tumors, typically exceeding 10 cm in size, are neoplastic lesions with malignant potential. Surgical excision in small-breasted Asian women presents unique challenges where expected poor aesthetic outcomes may delay timely medical intervention. The periareolar mastopexy technique offers a comprehensive solution, enabling complete tumor removal alongside mastopexy to achieve optimal breast contouring. This approach consistently delivers favorable aesthetic outcomes, enhancing symmetry and contour. Additionally, the periareolar approach minimizes visible scarring, thereby enhancing patient satisfaction with the cosmetic outcome. Herein, we present a case report of Asian women with giant phyllodes tumors exceeding 10 cm, successfully managed using the periareolar mastopexy technique, emphasizing the importance of optimizing aesthetic outcomes in these challenging cases.