Computational insights into the aggregation mechanism and amyloidogenic core of aortic amyloid medin polypeptide.

Medin amyloid, prevalent in the vessel walls of 97 % of individuals over 50, contributes to arterial stiffening and cerebrovascular dysfunction, yet our understanding of its aggregation mechanism remains limited. Dividing the full-length 50-amino-acid medin peptide into five 10-residue segments, we conducted individual investigations on each segment's self-assembly dynamics via microsecond-timescale atomistic discrete molecular dynamics (DMD) simulations. Our findings showed that medin1-10 and medin11-20 segments predominantly existed as isolated unstructured monomers, unable to form stable oligomers. Medin31-40 exhibited moderate aggregation, forming dynamic ß-sheet oligomers with frequent association and dissociation. Conversely, medin21-30 and medin41-50 segments demonstrated significant self-assembly capability, readily forming stable ß-sheet-rich oligomers. Residue pairwise contact frequency analysis highlighted the critical roles of residues 22-26 and 43-49 in driving the self-assembly of medin21-30 and medin41-50, acting as the ß-sheet core and facilitating ß-strand formation in other regions within medin monomers, expecting to extend to oligomers and fibrils. Regions containing residues 22-26 and 43-49, with substantial self-assembly abilities and assistance in ß-sheet formation, represent crucial targets for amyloid inhibitor drug design against aortic medial amyloidosis (AMA). In summary, our study not only offers deep insights into the mechanism of medin amyloid formation but also provides crucial theoretical and practical guidance for future treatments of AMA.

Computational insights into the cross-talk between medin and Aß: implications for age-related vascular risk factors in Alzheimer's disease.

The aggregation of medin forming aortic medial amyloid is linked to arterial wall degeneration and cerebrovascular dysfunction. Elevated levels of arteriolar medin are correlated with an increased presence of vascular amyloid-ß (Aß) aggregates, a hallmark of Alzheimer's disease (AD) and vascular dementia. The cross-interaction between medin and Aß results in the formation of heterologous fibrils through co-aggregation and cross-seeding processes both in vitro and in vivo. However, a comprehensive molecular understanding of the cross-interaction between medin and Aß-two intrinsically disordered proteins-is critically lacking. Here, we employed atomistic discrete molecular dynamics simulations to systematically investigate the self-association, co-aggregation and also the phenomenon of cross-seeding between these two proteins. Our results demonstrated that both Aß and medin were aggregation prone and their mixture tended to form ß-sheet-rich hetero-aggregates. The formation of Aß-medin hetero-aggregates did not hinder Aß and medin from recruiting additional Aß and medin peptides to grow into larger ß-sheet-rich aggregates. The ß-barrel oligomer intermediates observed in the self-aggregations of Aß and medin were also present during their co-aggregation. In cross-seeding simulations, preformed Aß fibrils could recruit isolated medin monomers to form elongated ß-sheets. Overall, our comprehensive simulations suggested that the cross-interaction between Aß and medin may contribute to their pathological aggregation, given the inherent amyloidogenic tendencies of both medin and Aß. Targeting medin, therefore, could offer a novel therapeutic approach to preserving brain function during aging and AD by improving vascular health.

Milk Fat Globule Epidermal Growth Factor VIII Fragment Medin in Age-Associated Arterial Adverse Remodeling and Arterial Disease.

Medin, a small 50-amino acid peptide, is an internal cleaved product from the second discoidin domain of milk fat globule epidermal growth factor VIII (MFG-E8) protein. Medin has been reported as the most common amylogenic protein in the upper part of the arterial system, including aortic, temporal, and cerebral arterial walls in the elderly. Medin has a high affinity to elastic fibers and is closely associated with arterial degenerative inflammation, elastic fiber fragmentation, calcification, and amyloidosis. In vitro, treating with the medin peptide promotes the inflammatory phenotypic shift of both endothelial cells and vascular smooth muscle cells. In vitro, ex vivo, and in vivo studies demonstrate that medin enhances the abundance of reactive oxygen species and reactive nitrogen species produced by both endothelial cells and vascular smooth muscle cells and promotes vascular endothelial dysfunction and arterial stiffening. Immunostaining and immunoblotting analyses of human samples indicate that the levels of medin are increased in the pathogenesis of aortic aneurysm/dissection, temporal arteritis, and cerebrovascular dementia. Thus, medin peptide could be targeted as a biomarker diagnostic tool or as a potential molecular approach to curbing the arterial degenerative inflammatory remodeling that accompanies aging and disease.

Cerebrovascular medin is associated with Alzheimer's disease and vascular dementia.

INTRODUCTION: Medin, an aging-associated amyloidogenic protein, induces cerebrovascular dysfunction and inflammation. We investigated the relationship between cerebrovascular medin and Alzheimer's disease (AD) and vascular dementia (VaD). METHODS: Cerebral arteriole medin was quantified from 91 brain donors with no dementia (ND), AD, VaD, or combined AD and VaD. Correlation analyses evaluated the relationship between arteriole medin, and plaques, tangles, or white matter lesions (WML). Receiver operating characteristic and regression analyses assessed whether medin is predictive of AD or VaD versus other cerebrovascular pathologies (circle of Willis [CoW] atherosclerosis and cerebral amyloid angiopathy [CAA]). RESULTS: Arteriole medin was higher in those with AD, VaD, or combined AD/VaD versus ND (P < .05), and correlated with tangle, plaque, and WML, but not CAA or CoW atherosclerosis. Among cerebrovascular pathologies, medin was the strongest predictor of AD diagnosis, whereas CoW atherosclerosis and arteriole medin were predictors of VaD. DISCUSSION: Cerebral arteriole medin is associated with and could be a potential novel risk factor or biomarker for AD and VaD.

Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice.

Medin is the most common amyloid known in humans, as it can be found in blood vessels of the upper body in virtually everybody over 50 years of age. However, it remains unknown whether deposition of Medin plays a causal role in age-related vascular dysfunction. We now report that aggregates of Medin also develop in the aorta and brain vasculature of wild-type mice in an age-dependent manner. Strikingly, genetic deficiency of the Medin precursor protein, MFG-E8, eliminates not only vascular aggregates but also prevents age-associated decline of cerebrovascular function in mice. Given the prevalence of Medin aggregates in the general population and its role in vascular dysfunction with aging, targeting Medin may become a novel approach to sustain healthy aging.

The impact of the epidemic of Heine-Medina disese on the development of rehabilitation in Poland.

The work presents pioneering activities of Polish orthopedists in the interwar period who were the first to propose methods of surgical and physical treatment of the effects of poliomyelitis. It also discusses the activities undertaken by the Ministry of Health and the National Rehabilitation Specialist, prof Wiktor Dega, in the early 1950s in order to fight the effects of the Heine-Medin disease epidemic in Poland. They worked on the creation of a network of rehabilitation centres throughout the country, training of medical personnel, development of uniform procedures that would provide the patient with appropriate treatment in the acute state of the disease and during the following years of its consequences. In addition to treating, it was possible for the sick children to get a profession that would allow them to start working. The authors show that dealing with the effects of Heine-Medin disease had a significant impact on the development of rehabilitation in Poland.

Idiopathic degenerative thoracic aneurysms are associated with increased aortic medial amyloid.

Objective: To explore the relationship of aortic medial amyloid with biochemical and micromechanical properties of the aortic wall in aneurysm patients. Methods: Human aortic tissues removed during aneurysm surgery from tricuspid (idiopathic degenerative aneurysm, DA) and bicuspid valve (BAV) patients were subjected to oscillatory nanoindentation experiments to determine localised mechanical properties of the tissue (shear storage modulus, G´ and shear loss modulus, G˝). Collagen, elastin, matrix metalloproteinase 2 and glycosaminoglycans concentrations were determined, along with relative levels of aortic medial amyloid-related factors (medin, milk fat globule-EGF factor 8, oligomers and fibrils). Measurements were combined with clinical data and statistical analyses performed. Results: The DA cohort can be divided based on their phenotype. One group shared similar characteristics with BAV patients, termed bicuspid like phenotype-tricuspid valve. The second group had high amyloid oligomer species present with a significantly lower G´ (p = .01), indicative of reduced elastic response of the tissue, termed amyloid-rich. Conclusions: We identified a group of DA patients with high amyloid oligomers and altered micromechanical and structural properties of the vessel wall. We propose these findings as a cause for aneurysm formation in these patients. Amyloid is not found in BAV patients, suggesting at least two distinct mechanisms for pathogenesis.

Insights into the Origin of Distinct Medin Fibril Morphologies Induced by Incubation Conditions and Seeding.

Incubation conditions are an important factor to consider when studying protein aggregation in vitro. Here, we employed biophysical methods and atomic force microscopy to show that agitation dramatically alters the morphology of medin, an amyloid protein deposited in the aorta. Agitation reduces the lag time for fibrillation by ~18-fold, suggesting that the rate of fibril formation plays a key role in directing the protein packing arrangement within fibrils. Utilising preformed sonicated fibrils as seeds, we probed the role of seeding on medin fibrillation and revealed three distinct fibril morphologies, with biophysical modelling explaining the salient features of experimental observations. We showed that nucleation pathways to distinct fibril morphologies may be switched on and off depending on the properties of the seeding fibrils and growth conditions. These findings may impact on the development of amyloid-based biomaterials and enhance understanding of seeding as a pathological mechanism.

Amyloidogenic medin induces endothelial dysfunction and vascular inflammation through the receptor for advanced glycation endproducts.

AIMS: Medin is a common amyloidogenic protein in humans that accumulates in arteries with advanced age and has been implicated in vascular degeneration. Medin's effect on endothelial function remains unknown. The aims are to assess medin's effects on human arteriole endothelial function and identify potential mechanisms underlying medin-induced vascular injury. METHODS AND RESULTS: Ex vivo human adipose and leptomeningeal arterioles were exposed (1 h) to medin (0.1, 1, or 5 µM) without or with FPS-ZM1 [100 µM, receptor for advanced glycation endproducts (RAGE)-specific inhibitor] and endothelium-dependent function (acetylcholine dilator response) and endothelium-independent function (dilator response to nitric oxide donor diethylenetriamine NONOate) were compared with baseline control. Human umbilical vein endothelial cells were exposed to medin without or with FPS-ZM1 and oxidative and nitrative stress, cell viability, and pro-inflammatory signaling measures were obtained. Medin caused impaired endothelial function (vs. baseline response: -45.2 ± 5.1 and -35.8 ± 7.9% in adipose and leptomeningeal arterioles, respectively, each P < 0.05). Dilator response to NONOate was not significantly changed. Medin decreased arteriole and endothelial cell nitric oxide production, increased superoxide production, reduced endothelial cell viability, proliferation, and migration. Medin increased gene and protein expression of interleukin-6 and interleukin-8 via activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Medin-induced endothelial dysfunction and oxidative stress were reversed by antioxidant polyethylene glycol superoxide dismutase and by RAGE inhibitor FPS-ZM1. CONCLUSIONS: Medin causes human microvascular endothelial dysfunction through oxidative and nitrative stress and promotes pro-inflammatory signaling in endothelial cells. These effects appear to be mediated via RAGE. The findings represent a potential novel mechanism of vascular injury.

1H, 15N and 13C assignment of the amyloidogenic protein medin using fast-pulsing NMR techniques.

Thirty-one proteins are known to form extracellular fibrillar amyloid in humans. Molecular information about many of these proteins in their monomeric, intermediate or fibrillar form and how they aggregate and interact to form the insoluble fibrils is sparse. This is because amyloid proteins are notoriously difficult to study in their soluble forms, due to their inherent propensity to aggregate. Using recent developments in fast NMR techniques, band-selective excitation short transient and band-selective optimized flip-angle short-transient heteronuclear multiple quantum coherence we have been able to assign a 5 kDa full-length amyloidogenic protein called medin. Medin is the key protein component of the most common form of localised amyloid with a proposed role in aortic aneurysm and dissection. This assignment will now enable the study of the early interactions that could influence initiation and progression of medin aggregation. The chemical shifts have been deposited in the BioMagRes-Bank accession Nos. 25399 and 26576.

Acercamiento a la vida y obra del Doctor Luis de la Caridad Medín Perdomo / An approach to life and work of MD Luis de la Caridad Medin Perdomo

Se profundizó sobre la vida del médico colombino ya fallecido Luis de la Caridad Medín Perdomo con el objetivo de destacar toda su entrega a la medicina. De procedencia humilde, graduado de Doctor en Medicina en diciembre de 1984. Director del Área de Salud del policlínico de Perico. Subdirector Administrativo en el Hospital Territorial Dr Mario Muñoz Monroy, muchos lo recuerdan por sus adecuados métodos de trabajo, por la gran prevalencia de sus condiciones humanas, su preocupación ante el dolor ajeno. Dejó su huella en la docencia de la Filial de Ciencias Médicas Dr Eusebio Hernández Pérez, siendo este su primer director. Uno de los médicos con más altos resultados de jefatura en la provincia. Ocupó responsablemente altos cargos de dirección. Ejerció su profesión dignamente y a conciencia; veló siempre por la salud de sus pacientes consagrando su vida al servicio de la humanidad(AU)

We got deepen through the life of Colon physician Luis de la Caridad Medin Perdomo, already gone, with the aim of highlighting all his commitment to medicine. Low-born, graduated as Medicine Doctor in 1984, Director of the Perico policlinic Health Area, Administrative Sub-director in the Territorial Hospital Dr. Mario Muñoz Monroy, many people recollect him because of his correct work methods, the prevalence of his human conditions, his concern on regard to other people´s grief. He left his imprint in the teaching process of the Medical Sciences Branch Eusebio Guiteras Perez, where he was the first director. Being one of the medicine doctors with higher managing outcomes in the province, he liably occupied high managing posts. He consciously and humanely practiced his profession; he always kept watch over his patient´s health, devoting his life to the service of the human kind(AU)

[Post-polio syndrome - a case report]. / Zespól post-polio - opis przypadku.

Post-polio syndrome occurs 30-40 years after polio virus infection. The main symptoms of PPS are slowly progressive muscle limbs paresis with muscle atrophy, joints pain, paresthesia. In 90% of patients the main symptom is fatigue that leads to physical and mental activity deterioration. The cause of disease remains unknown. Probably it is an effect of motoneurons damage during acute virus polio infection, their overloading and degeneration of remaining ones. In this study we described a case of man who developed PPS 36 years after Heine-Medin disease. The main symptom was intensification of right limb paresis and muscle atrophy. In electromyography there were damage features of muscle clinically affected and unaffected. Changes in lifestyle made possible to continue occupational activity.

Centering ability and dentin removal of rotary systems in curved root canals.

INTRODUCTION: The aim of this study was to compare centering ability and dentin removal of three rotary systems in curved root canals of extracted teeth. MATERIALS AND METHODS: Sixty root canals of mandibular first molars with curvatures ranging between 25-35(o) were divided into three groups of 20 teeth each. Based on pre-instrumentation radiographs that assessed the angle and the radius of canal curvatures, teeth with curvatures were equally spread between the three groups. The root canals were sectioned horizontally at two levels before preparation and then remounted onto the muffle. All root canals were prepared using a low-torque control motor with Mtwo or Medin or Race instruments. Cross sectional images were obtained before and after instrumentation. Cross-sectional area and centering ability were evaluated. The data were analyzed using the one-way ANOVA and Tukey tests. RESULTS: Neither instrument fracture nor permanent deformation occurred during preparations. The best centering ability was obtained by Mtwo instruments compare to Race and Medin instruments. In the coronal and middle sections, Mtwo removed less dentin than Race and Medin; while the difference in the apical section was not significant. CONCLUSION: Under the conditions of this study, the debridement of root canals was more conservative with Mtwo. The canals prepared with these instruments were better centered in all three regions of the root.