Drejerthomsen1309

The carboxylation status of Osteocalcin (Ocn) not only influences formation and structure in bones but also has important endocrine functions affecting energy metabolism and expenditure. In this study, the role of γ-carboxylation of the glutamate residues in the structure-dynamics-function relationship in Ocn is investigated.

Three forms of Ocn, differentially carboxylated at the Glu-17, 21 and 24 residues, along with a mutated form of Ocn carrying Glu/Ala mutations, are modeled and simulated using molecular dynamics (MD) simulation in the presence of calcium ions.

Characterization of the global conformational dynamics of Ocn, described in terms of the orientational variations within its 3-helical domain, highlights large structural variations in the non-carboxylated osteocalcin (nOcn). The bi-carboxylated Ocn (bOcn) and tri-carboxylated (tOcn) species, in contrast, display relatively rigid tertiary structures, with the dynamics of most regions strongly correlated. check details Radial distribution functions calculatty peptides targeting its cellular receptor GPRC6A, with therapeutic potential for treatment of metabolic disorders.

Modification of Ocn sequence or its carboxylation state may provide the blueprint for developing high-affinity peptides targeting its cellular receptor GPRC6A, with therapeutic potential for treatment of metabolic disorders.

Iron export via the transport protein ferroportin (Fpn) plays a critical role in the regulation of dietary iron absorption and iron recycling in macrophages. Fpn plasma membrane expression is controlled by the hepatic iron-regulated hormone hepcidin in response to high iron availability and inflammation. Hepcidin binds to the central cavity of the Fpn transporter to block iron export either directly or by inducing Fpn internalization and lysosomal degradation. Here, we investigated whether iron deficiency affects Fpn protein turnover.

We ectopically expressed Fpn in HeLa cells and used cycloheximide chase experiments to study basal and hepcidin-induced Fpn degradation under extracellular and intracellular iron deficiency.

We show that iron deficiency does not affect basal Fpn turnover but causes a significant delay in hepcidin-induced degradation when cytosolic iron levels are low. These data have important mechanistic implications supporting the hypothesis that iron export is required for efficient targeting of Fpn by hepcidin. Additionally, we show that Fpn degradation is not involved in protecting cells from intracellular iron deficiency.

We show that iron deficiency does not affect basal Fpn turnover but causes a significant delay in hepcidin-induced degradation when cytosolic iron levels are low. These data have important mechanistic implications supporting the hypothesis that iron export is required for efficient targeting of Fpn by hepcidin. Additionally, we show that Fpn degradation is not involved in protecting cells from intracellular iron deficiency.

Retrograde type A dissection (RTAD) is a rare but life-threatening event following thoracic endovascular aortic repair (TEVAR), and its total endovascular treatment is a huge challenge. This research aimed to evaluate the safety, effectiveness, technical success, and medical outcomes of in situ laser fenestration of aortic arch stent grafts during TEVAR of RTAD.

We retrospectively reviewed the clinical data of 15 patients with RTAD who received in situ laser fenestration of aortic arch stent grafts during TEVAR between Mar 2016 and Dec 2019. All patients were subjected to intraoperative extracorporeal brain perfusion. The preoperative, intraoperative and postoperative medical data were collected and analyzed.

The mean age of the 15 patients was 64±8years, 8 of whom were male. The immediate overall technical success rates, including aortic stent deployment were 100% and primary fenestration success was achieved in 13 (86.7%) patients. The mean postoperative length of stay was 10±4days. Stroke occurred in 1 case. No in-hospital/30-day death nor permanent paraplegia/paresis was observed. The mean follow-up time was 13±5months. Two type Ia endoleaks were found, but no late occlusion and migration of the supra-aortic branch arteries stents during the follow-up were observed.

The in situ laser fenestration of aortic arch stent grafts during TEVAR of RTAD is a potential total endovascular therapy of RTAD for patients unsuitable for direct surgical repair.

The in situ laser fenestration of aortic arch stent grafts during TEVAR of RTAD is a potential total endovascular therapy of RTAD for patients unsuitable for direct surgical repair.

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare lethal autosomal recessive liver disorder caused by loss-of-function variations of the ABCB4 gene, encoding a phosphatidylcholine transporter (ABCB4/MDR3). Currently, no effective treatment exists for PFIC3 outside of liver transplantation.

We have produced and screened chemically and genetically modified mRNA variants encoding human ABCB4 (hABCB4 mRNA) encapsulated in lipid nanoparticles (LNPs). We examined their pharmacological effects in a cell-based model and in a new invivo mouse model resembling human PFIC3 as a result of homozygous disruption of the Abcb4 gene in fibrosis-susceptible BALB/c.Abcb4

mice.

We show that treatment with liver-targeted hABCB4 mRNA resulted in de novo expression of functional hABCB4 protein and restored phospholipid transport in cultured cells and in PFIC3 mouse livers. Importantly, repeated injections of the hABCB4 mRNA effectively rescued the severe disease phenotype in young Abcb4

mice, with rapation of our mRNA construct completely rescues severe liver disease in a genetic model of PFIC3 in mice.Pregnancy demands major cardiovascular, renal and endocrine changes to provide an adequate blood supply for the growing fetus. The renin-angiotensin-aldosterone system plays a key role in this adaptation process. One of its components, prorenin, is released in significant amounts from the ovary and uteroplacental unit. This review describes the sources of prorenin in the periconception period and in pregnancy, including its modulation by in-vitro fertilization protocols, and discusses its potential effects, among others focusing on preeclampsia. It ends with discussing the long-term consequences, even in later life, of inappropriate renin-angiotensin-aldosterone system activity in pregnancy and offers directions for future research. Ultimately, a full understanding of the role of prorenin periconceptionally and during pregnancy will help to develop tools to diagnose and/or prevent reproductive complications.