Inverse ISAsomes in Bio-Compatible Oils—Exploring Formulations in Squalane, Triolein and Olive Oil

In contrast to their more common counterparts in aqueous solutions, inverse ISAsomes (internally self-assembled somes/particles) are formulated as kinetically stabilised dispersions of hydrophilic, lyotropic liquid-crystalline (LC) phases in non-polar oils. This contribution reports on their formation in bio-compatible oils. We found that it is possible to create inverse hexosomes, inverse micellar cubosomes (Fd3m) and an inverse emulsified microemulsion (EME) in excess squalane with a polyethylene glycol alkyl ether as the primary surfactant forming the LC phase and to stabilise them with hydrophobised silica nanoparticles. Furthermore, an emulsified L1-phase and inverse hexosomes were formed in excess triolein with the triblock-copolymer Pluronic® P94 as the primary surfactant. Stabilisation was achieved with a molecular stabiliser of type polyethylene glycol (PEG)-dipolyhydroxystearate. For the inverse hexosomes in triolein, the possibility of a formulation without any additional stabiliser was explored. It was found that a sufficiently strong stabilisation effect was created by the primary surfactant alone. Finally, triolein was replaced with olive oil which also led to the successful formation of inverse hexosomes. As far as we know, there exists no previous contribution about inverse ISAsomes in complex oils such as triolein or plant oils, and the existence of stabiliser-free (i.e., self-stabilising) inverse hexosomes has also not been reported until now

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise.

Aberrant DNA methylation is a hallmark of various human disorders, indicating that the spatial and temporal regulation of methylation readers and modifiers is imperative for development and differentiation. In particular, the cross-regulation between 5-methylcytosine binders (MBD) and modifiers (Tet) has not been investigated. Here, we show that binding of Mecp2 and Mbd2 to DNA protects 5-methylcytosine from Tet1-mediated oxidation. The mechanism is not based on competition for 5-methylcytosine binding but on Mecp2 and Mbd2 directly restricting Tet1 access to DNA. We demonstrate that the efficiency of this process depends on the number of bound MBDs per DNA molecule. Accordingly, we find 5-hydroxymethylcytosine enriched at heterochromatin of Mecp2-deficient neurons of a mouse model for Rett syndrome and Tet1-induced reexpression of silenced major satellite repeats. These data unveil fundamental regulatory mechanisms of Tet enzymes and their potential pathophysiological role in Rett syndrome. Importantly, it suggests that Mecp2 and Mbd2 have an essential physiological role as guardians of the epigenome

Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise

Aberrant DNA methylation is a hallmark of various human disorders, indicating that the spatial and temporal regulation of methylation readers and modifiers is imperative for development and differentiation. In particular, the cross-regulation between 5-methylcytosine binders (MBD) and modifiers (Tet) has not been investigated. Here, we show that binding of Mecp2 and Mbd2 to DNA protects 5-methylcytosine from Tet1-mediated oxidation. The mechanism is not based on competition for 5-methylcytosine binding but on Mecp2 and Mbd2 directly restricting Tet1 access to DNA. We demonstrate that the efficiency of this process depends on the number of bound MBDs per DNA molecule. Accordingly, we find 5-hydroxymethylcytosine enriched at heterochromatin of Mecp2-deficient neurons of a mouse model for Rett syndrome and Tet1-induced reexpression of silenced major satellite repeats. These data unveil fundamental regulatory mechanisms of Tet enzymes and their potential pathophysiological role in Rett syndrome. Importantly, it suggests that Mecp2 and Mbd2 have an essential physiological role as guardians of the epigenome

Oxidized LDL Is Strictly Limited to Hyperthyroidism Irrespective of Fat Feeding in Female Sprague Dawley Rats

Metabolic dysfunctions might play a crucial role in the pathophysiology of thyroid dysfunctions. This study aimed to investigate the impact of a controlled diet (normal versus high fat feeding) on hypothyroid and hyperthyroid Sprague Dawley rats. Female Sprague Dawley rats (n = 66) were grouped into normal diet (n = 30) and high-fat diet (n = 36) groups and subdivided into controls, hypothyroid and hyperthyroid groups, induced through propylthiouracil or triiodothyronine (T3) treatment, respectively. After 12 weeks of treatment metabolic parameters, such as oxidized LDL (oxLDL), malondialdehyde (MDA), 4-hydroxynonenal (HNE), the lipid profile, body weight and food intake parameters were analyzed. Successfully induced thyroid dysfunctions were shown by T3 levels, both under normal and high fat diet. Thyroid dysfunctions were accompanied by changes in calorie intake and body weight as well as in the lipid profile. In detail, hypothyroid rats showed significantly decreased oxLDL levels, whereas hyperthyroid rats showed significantly increased oxLDL levels. These effects were seen under high fat diet and were less pronounced with normal feeding. Taken together, we showed for the first time in female SD rats that only hyper-, but not hypothyroidism, is associated with high atherogenic oxidized LDL irrespective of normal or high-fat diet in Sprague Dawley rats

TF-Prioritizer: a java pipeline to prioritize condition-specific transcription factors

Background: Eukaryotic gene expression is controlled by cis-regulatory elements (CREs), including promoters and enhancers, which are bound by transcription factors (TFs). Differential expression of TFs and their binding affinity at putative CREs determine tissue- and developmental-specific transcriptional activity. Consolidating genomic data sets can offer further insights into the accessibility of CREs, TF activity, and, thus, gene regulation. However, the integration and analysis of multi-modal data sets are hampered by considerable technical challenges. While methods for highlighting differential TF activity from combined chromatin state data (e.g., ChIP-seq, ATAC-seq, or DNase-seq) and RNA-seq data exist, they do not offer convenient usability, have limited support for large-scale data processing, and provide only minimal functionality for visually interpreting results. Results: We developed TF-Prioritizer, an automated pipeline that prioritizes condition-specific TFs from multi-modal data and generates an interactive web report. We demonstrated its potential by identifying known TFs along with their target genes, as well as previously unreported TFs active in lactating mouse mammary glands. Additionally, we studied a variety of ENCODE data sets for cell lines K562 and MCF-7, including twelve histone modification ChIP-seq as well as ATAC-seq and DNase-seq datasets, where we observe and discuss assay-specific differences. Conclusion: TF-Prioritizer accepts ATAC-seq, DNase-seq, or ChIP-seq and RNA-seq data as input and identifies TFs with differential activity, thus offering an understanding of genome-wide gene regulation, potential pathogenesis, and therapeutic targets in biomedical research

The European Trauma Course: Transforming systems through training

The European Trauma Course (ETC) exemplifies an innovative approach to multispecialty trauma education. This initiative was started as a collaborative effort among the European Society for Emergency Medicine, the European Society for Trauma and Emergency Surgery, and the European Society of Anaesthesiology under the auspices of the European Resuscitation Council. With the robust support of these societies, the project has evolved into the independent European Trauma Course Organisation. Over the past 15 years, the ETC has transcended traditional training by integrating team dynamics and non-technical skills into a scenario-based simulation course, helping to shape trauma care practice and education. A distinctive feature of the ETC is its training of doctors and allied healthcare professionals, fostering a collaborative and holistic approach to trauma care. The ETC stands out for its unique team-teaching approach, which has gained widespread recognition as the standard for in-hospital trauma care training not only in Europe but also beyond. Since its inception ETC has expanded geographically from Finland to Sudan and from Brazil to the Emirates, training nearly 20,000 healthcare professionals and shaping trauma care practice and education across 25 countries. Experiencing exponential growth, the ETC continues to evolve, reflecting its unmet demand in trauma team education. This review examines the evolution of the ETC, its innovative team-teaching methodology, national implementation strategies, current status, and future challenges. It highlights its impact on trauma care, team training, and the effect on other life support courses in various countrie