Translational advances of melanocortin drugs: Integrating biology, chemistry and genetics.

Melanocortin receptors have emerged as important targets with a very unusual versatility, as their widespread distribution on multiple tissues (e.g. skin, adrenal glands, brain, immune cells, exocrine glands) together with the variety of physiological processes they control (pigmentation, cortisol release, satiety mechanism, inflammation, secretions), place this family of receptors as genuine therapeutic targets for many disorders. This review focuses in the journey of the development of melanocortin receptors as therapeutic targets from the discovery of their existence in the early 1990 s to the approval of the first few drugs of this class. Two major areas of development characterise the current state of melanocortin drug development: their role in obesity, recently culminated with the approval of setmelanotide, and their potential for the treatment of chronic inflammatory and autoimmune diseases like rheumatoid arthritis, multiple sclerosis or fibrosis. The pro-resolving nature of these drugs offers the advantage of acting by mimicking the way our body naturally resolves inflammation, expecting fewer side effects and a more balanced (i.e. non-immunosuppressive) response from them. Here we also review the approaches followed for the design and development of novel compounds, the importance of the GPCR nature of these receptors in the process of drug development, therapeutic value, current challenges and successes, and the potential for the implementation of precision medicine approaches through the incorporation of genetics advances

Congestive heart failure in rats is associated with increased expression and targeting of aquaporin-2 water channel in collecting duct

We tested whether severe congestive heart failure (CHF), a condition associated with excess free-water retention, is accompanied by altered regulation of the vasopressin-regulated water channel, aquaporin-2 (AQP2), in the renal collecting duct. CHF was induced by left coronary artery ligation. Compared with sham-operated animals, rats with CHF had severe heart failure with elevated left ventricular end-diastolic pressures (LVEDP): 26.9 ± 3.4 vs. 4.1 ± 0.3 mmHg, and reduced plasma sodium concentrations (142.2 ± 1.6 vs. 149.1 ± 1.1 mEq/liter). Quantitative immunoblotting of total kidney membrane fractions revealed a significant increase in AQP2 expression in animals with CHF (267 ± 53%, n=12) relative to sham-operated controls (100 ± 13%, n=14). In contrast, immunoblotting demonstrated a lack of an increase in expression of AQP1 and AQP3 water channel expression, indicating that the effect on AQP2 was selective.Furthermore, postinfarction animals without LVEDP elevation or plasma Na reduction showed no increase in AQP2 expression (121 ± 28% of sham levels, n=6). Immunocytochemistry and immunoelectron microscopy demonstrated very abundant labeling of the apical plasma membrane and relatively little labeling of intracellular vesicles in collecting duct cells from rats with severe CHF, consistent with enhanced trafficking of AQP2 to the apical plasma membrane. The selective increase in AQP2 expression and enhanced plasma membrane targeting provide an explanation for the development of water retention and hyponatremia in severe CHF

seeMotif: exploring and visualizing sequence motifs in 3D structures

Sequence motifs are important in the study of molecular biology. Motif discovery tools efficiently deliver many function related signatures of proteins and largely facilitate sequence annotation. As increasing numbers of motifs are detected experimentally or predicted computationally, characterizing the functional roles of motifs and identifying the potential synergetic relationships between them are important next steps. A good way to investigate novel motifs is to utilize the abundant 3D structures that have also been accumulated at an astounding rate in recent years. This article reports the development of the web service seeMotif, which provides users with an interactive interface for visualizing sequence motifs on protein structures from the Protein Data Bank (PDB). Researchers can quickly see the locations and conformation of multiple motifs among a number of related structures simultaneously. Considering the fact that PDB sequences are usually shorter than those in sequence databases and/or may have missing residues, seeMotif has two complementary approaches for selecting structures and mapping motifs to protein chains in structures. As more and more structures belonging to previously uncharacterized protein families become available, combining sequence and structure information gives good opportunities to facilitate understanding of protein functions in large-scale genome projects. Available at: http://seemotif.csie.ntu.edu.tw,http://seemotif.ee.ncku.edu.tw or http://seemotif.csbb.ntu.edu.tw

Oxalate-Induced Damage to Renal Tubular Cells

Our own studies and those of others have shown that the incidence of calcium oxalate stones and plaques is markedly increased by nephrotoxins. The possible role of oxalate as a nephrotoxin has not been fully appreciated. However, recent studies in experimental animals and in cultured cells support this possibility. The results of these studies led us to hypothesize that hyperoxaluria promotes stone formation in several ways: by providing a substrate for the formation of the most common form of renal stones, calcium oxalate stones, and by inducing damage to renal epithelial cells. Damaged cells in turn would produce an environment favorable for crystal retention and provide membranous debris that promotes crystal nucleation, aggregation and adherence. The present report summarizes evidence for oxalate nephrotoxicity and discusses the potential importance of oxalate toxicity in the pathogenesis of stone disease

Arf4 is required for Mammalian development but dispensable for ciliary assembly

The primary cilium is a sensory organelle, defects in which cause a wide range of human diseases including retinal degeneration, polycystic kidney disease and birth defects. The sensory functions of cilia require specific receptors to be targeted to the ciliary subdomain of the plasma membrane. Arf4 has been proposed to sort cargo destined for the cilium at the Golgi complex and deemed a key regulator of ciliary protein trafficking. In this work, we show that Arf4 binds to the ciliary targeting sequence (CTS) of fibrocystin. Knockdown of Arf4 indicates that it is not absolutely required for trafficking of the fibrocystin CTS to cilia as steady-state CTS levels are unaffected. However, we did observe a delay in delivery of newly synthesized CTS from the Golgi complex to the cilium when Arf4 was reduced. Arf4 mutant mice are embryonic lethal and die at mid-gestation shortly after node formation. Nodal cilia appeared normal and functioned properly to break left-right symmetry in Arf4 mutant embryos. At this stage of development Arf4 expression is highest in the visceral endoderm but we did not detect cilia on these cells. In the visceral endoderm, the lack of Arf4 caused defects in cell structure and apical protein localization. This work suggests that while Arf4 is not required for ciliary assembly, it is important for the efficient transport of fibrocystin to cilia, and also plays critical roles in non-ciliary processes

Genetic link between renal birth defects and congenital heart disease

Structural birth defects in the kidney and urinary tract are observed in 0.5% of live births and are a major cause of end-stage renal disease, but their genetic aetiology is not well understood. Here we analyse 135 lines of mice identified in large-scale mouse mutagenesis screen and show that 29% of mutations causing congenital heart disease (CHD) also cause renal anomalies. The renal anomalies included duplex and multiplex kidneys, renal agenesis, hydronephrosis and cystic kidney disease. To assess the clinical relevance of these findings, we examined patients with CHD and observed a 30% co-occurrence of renal anomalies of a similar spectrum. Together, these findings demonstrate a common shared genetic aetiology for CHD and renal anomalies, indicating that CHD patients are at increased risk for complications from renal anomalies. This collection of mutant mouse models provides a resource for further studies to elucidate the developmental link between renal anomalies and CHD

IWIN: the Isfjorden Weather Information Network

In an effort led by the University Centre in Svalbard (UNIS), with support from the Norwegian Meteorological Institute (MET Norway), the Isfjorden Weather Information Network (IWIN) is under development in the Isfjorden region in central Svalbard. The network substantially expands upon the relatively sparse existing operational network of weather stations and consists of compact and cost-efficient all-in-one weather stations permanently installed at lighthouses around Isfjorden and on board small tourist cruise ships trafficking the fjord from spring to autumn. All data from the network until June 2023, as presented in this paper, can be found at https://doi.org/10.5281/zenodo.8137588 (Frank et al., 2023b). New data become freely available in near-real time via MET Norway's data portals (https://doi.org/10.21343/ebrw-w846, Frank et al., 2023a). The IWIN data are highly valuable for scientific purposes such as atmospheric boundary layer research, the validation and development of numerical weather prediction models, and assimilation in these, as well as the planning and safe conduction of outdoor activities in the region.</p

Understanding parents’ emotional experiences for neonatal education:A narrative, interpretive approach

Aims and objectives: To explore the emotional experiences of parents who have had premature babies to inform and educate neonatal nurses and health professionals in this field. Background: Parents find the neonatal unit a daunting and unfamiliar place leading to anxiety, uncertainty and fear about the future of their baby. Parents have significant emotional needs in relation to assisting them to cope with their neonatal experience. In line with a family-centred approach to neonatal education, it is essential to teach health professionals about the emotional impact of neonatal care based on an appreciation of the parent experience. Design: A narrative-based, interpretive approach was undertaken in line with constructivist learning theory. Methods: Twenty narrative interviews took place, with a total of 23 parents of premature babies. Following core story creation to create coherent stories from the raw transcripts, thematic analysis of the narrative constructs using the principles of Braun and Clarke's, International Journal of Qualitative Studies on Health and Well-Being, 2014, 9, 1, framework was undertaken. The study methods were compliant with the consolidated criteria for reporting qualitative research (COREQ). Findings: Thematic analysis revealed key themes relating to the following: parents’ emotions through the whole neonatal experience, feelings towards the baby, the environment, the staff and the transitions through the different phases of neonatal care. Both negative and positive experiences were reported. Conclusion: Understanding the emotional experience from the parent's perspective, following birth of their premature baby, informs empathic, family-centred teaching and learning within the neonatal education arena. Relevance to clinical practice: Students and health professionals alike can learn what is important in the delivery of care that addresses the emotional needs of parents and families. Educators can use narratives and key messages from parents, both negative and positive, to teach family-centred principles to nurses and health professionals as a core component of a narrative curricula and potentially to enhance empathy

Using Schema Training to Facilitate Students\u27 Understanding of Challenging Engineering Concepts in Heat Transfer and Thermodynamics

Background: Chi and colleagues have argued that some of the most challenging engineering concepts exhibit properties of emergent systems. However, students often lack a mental framework, or schema, for understanding emergence. Slotta and Chi posited that helping students develop a schema for emergent systems, referred to as schema training, would increase the understanding of challenging concepts exhibiting emergent properties. Purpose: We tested the effectiveness of schema training and explored the nature of challenging concepts from thermodynamics and heat transfer. We investigated if schema training could (a) repair misconceptions in advanced engineering students and (b) prevent them in beginning engineering students. Method: We adapted Slotta and Chi\u27s schema training modules and tested their impact in two studies that employed an experimental design. Items from the Thermal and Transport Concept Inventory and expert-developed multiple-choice questions were used to evaluate conceptual understanding of the participants. The language used by students in their open-ended explanations of multiple-choice questions was also coded. Results: In both studies, students in the experimental groups showed larger gains in their understanding of some concepts—specifically in dye diffusion and microfluidics in Study One, and in the final test for thermodynamics in Study Two. But in neither study did students exhibit any gain in conceptual questions about heat transfer. Conclusion: Our studies suggest the importance of examining the nature of the phenomena underlying the concepts being taught because the language used in instruction has implications for how students understand them. Therefore, we suggest that instructors reflect on their own understanding of the concepts