This review article presents results of investigations concerning the kinetics of crosslinking photopolymerizations. The main emphasis is given to the propagation and termination rate coefficients ...and to the determination of the mechanism of the termination process. To emphasize the special features of the kinetics of the photocrosslinking process, a comparison with the kinetics of linear polymerizations has been made. Moreover, the paper describes the influence of various factors, both chemical as well as physical (e.g. monomer, structure, system composition, oxygen, temperature) on the chemistry of network formation. The effects of amino, ether and sulfide groups present in additives or introduced within monomer molecules are also discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Molecular chaperones contribute to the maintenance of cellular protein homoeostasis through assisting de novo protein folding and preventing amyloid formation. Chaperones of the Hsp70 family can ...further disaggregate otherwise irreversible aggregate species such as α-synuclein fibrils, which accumulate in Parkinson's disease. However, the mechanisms and kinetics of this key functionality are only partially understood. Here, we combine microfluidic measurements with chemical kinetics to study α-synuclein disaggregation. We show that Hsc70 together with its co-chaperones DnaJB1 and Apg2 can completely reverse α-synuclein aggregation back to its soluble monomeric state. This reaction proceeds through first-order kinetics where monomer units are removed directly from the fibril ends with little contribution from intermediate fibril fragmentation steps. These findings extend our mechanistic understanding of the role of chaperones in the suppression of amyloid proliferation and in aggregate clearance, and inform on possibilities and limitations of this strategy in the development of therapeutics against synucleinopathies.
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•Cross-linking of rigid and elastomeric material with M-POSS gives different results.•M-POSS strongly affects curing kinetics.•Physical factors dominate over H-bonding during ...formation of copolymer structure.•Poly-(HEMA/M-POSS) hybrid polymer shows the antiplasticization effect.•HEMA-based materials exhibit an exceptional behavior.
Hybrid hydrogel materials derived from two types of polymethacrylates: rigid and flexible, crosslinked with methacryloxy-multifunctionalized polyhedral oligomeric silsesquioxane (M-POSS) were obtained in a photo-induced copolymerization process. The base monomers were 2-hydroxyethyl methacrylate (HEMA; forming a rigid polymer) and a mixture of oxyethylene glycol (di)methacrylates (forming an elastomer). Investigations included the kinetics of hybrid materials formation and selected physical and mechanical properties. The obtained results were discussed in terms of effects of H-bonding and viscosity of compositions before curing, additional crosslinking, the presence of POSS cage, M-POSS aggregation and rigidity/flexibility of the base polymer. It was found that physical factors (diffusion, tendency to aggregation) dominate over interactions between reacting molecules (H-bonding) during the formation of the hybrid polymer structure. Disorder in H-bonding in HEMA-based material is responsible for the appearance of the antiplasticization effect manifesting itself by the lowering of the Tg value with simultaneous increase in the Young modulus. Antiplasticization behavior affects also thermal stability of the HEMA-based materials. In general, cross-linking of the rigid and elastomeric material with M-POSS gives quite different results; moreover, the HEMA-based materials show an exceptional behavior. The results presented are important indications in the selection of technological curing parameters in preparation of M-POSS-containing hydrogel materials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Shear forces affect self-assembly processes ranging from crystallization to fiber formation. Here, the effect of mild agitation on amyloid fibril formation was explored for four peptides and ...investigated in detail for A β 42, which is associated with Alzheimer’s disease. To gain mechanistic insights into the effect of mild agitation, nonseeded and seeded aggregation reactions were set up at various peptide concentrations with and without an inhibitor. First, an effect on fibril fragmentation was excluded by comparing the monomer-concentration dependence of aggregation kinetics under idle and agitated conditions. Second, using a secondary nucleation inhibitor, Brichos, the agitation effect on primary nucleation was decoupled from secondary nucleation. Third, an effect on secondary nucleation was established in the absence of inhibitor. Fourth, an effect on elongation was excluded by comparing the seeding potency of fibrils formed under idle or agitated conditions. We find that both primary and secondary nucleation steps are accelerated by gentle agitation. The increased shear forces facilitate both the detachment of newly formed aggregates from catalytic surfaces and the rate at which molecules are transported in the bulk solution to encounter nucleation sites on the fibril and other surfaces. Ultrastructural evidence obtained with cryogenic transmission electron microscopy and free-flow electrophoresis in microfluidics devices imply that agitation speeds up the detachment of nucleated species from the fibril surface. Our findings shed light on the aggregation mechanism and the role of detachment for efficient secondary nucleation. The results inform on how to modulate the relative importance of different microscopic steps in drug discovery and investigations.
Machine learning methods hold the promise to reduce the costs and the failure rates of conventional drug discovery pipelines. This issue is especially pressing for neurodegenerative diseases, where ...the development of disease-modifying drugs has been particularly challenging. To address this problem, we describe here a machine learning approach to identify small molecule inhibitors of α-synuclein aggregation, a process implicated in Parkinson's disease and other synucleinopathies. Because the proliferation of α-synuclein aggregates takes place through autocatalytic secondary nucleation, we aim to identify compounds that bind the catalytic sites on the surface of the aggregates. To achieve this goal, we use structure-based machine learning in an iterative manner to first identify and then progressively optimize secondary nucleation inhibitors. Our results demonstrate that this approach leads to the facile identification of compounds two orders of magnitude more potent than previously reported ones.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Oligomeric assemblies consisting of only a few protein subunits are key species in the cytotoxicity of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Their lifetime in ...solution and abundance, governed by the balance of their sources and sinks, are thus important determinants of disease. While significant advances have been made in elucidating the processes that govern oligomer production, the mechanisms behind their dissociation are still poorly understood. Here, we use chemical kinetic modeling to determine the fate of oligomers formed in vitro and discuss the implications for their abundance in vivo. We discover that oligomeric species formed predominantly on fibril surfaces, a broad class which includes the bulk of oligomers formed by the key Alzheimer’s disease-associated Aβ peptides, also dissociate overwhelmingly on fibril surfaces, not in solution as had previously been assumed. We monitor this “secondary nucleation in reverse” by measuring the dissociation of Aβ42 oligomers in the presence and absence of fibrils via two distinct experimental methods. Our findings imply that drugs that bind fibril surfaces to inhibit oligomer formation may also inhibit their dissociation, with important implications for rational design of therapeutic strategies for Alzheimer’s and other amyloid diseases.
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IJS, KILJ, NUK, PNG, UL, UM
The pathogenesis of hemangiomas still remains poorly understood. Dysregulation of angiogenesis has been proposed to play a central role in hemangioma pathogenesis. The aim of our study was to ...determine the peripheral and local serum levels of VEGF in patients with hemangiomas and vascular malformations.
Material and methods: The study group consisted of 52 children with infantile hemangioma (33 with proliferative lesions, 19 with involuting lesions), 14 children with vascular malformations and 36 healthy children. VEGF serum levels were analyzed by an ELISA assay and the values between the groups were compared.
Results: The serum peripheral VEGF concentrations in children with proliferative hemangiomas were significantly higher than in patients with involuting hemangiomas, vascular malformations and controls. There was no correlation between the measured cytokine level, hemangioma size, and the age of the patients. The local serum VEGF levels in 29 children with hemangiomas were distinctly lower than in the peripheral blood, both in 20 proliferating hemangiomas (
p
<
0.0001) and 9 involuting ones (
p
=
0.007); and the difference between females and males was non-significant (NS
p
=
0.06).
Conclusions: (1) VEGF serum levels vary in the different phases of hemangioma growth and may help to distinguish hemangiomas from vascular malformations; (2) obtained local results may support the intrinsic theory of endothelial cell proliferation in hemangiomas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The third most frequent chronic condition, and the fourth most common cause of death, in Poland is chronic obstructive pulmonary disease (COPD). The diagnosis and treatment of COPD is the ...responsibility of the general practitioner (GP); the GP also serves as gatekeeper, referring patients to the other levels of public health care system when necessary. Undertreatment of COPD can result in a greater frequency of exacerbations and hospitalizations. Elderly patients require special attention due to the increased prevalence of COPD and systemic comorbidities. However, both the occurrence of exacerbations and the quality of life of the patients may be improved by developing and implementing guidelines for practice and ensuring their adherence. This proposal concerns the development of a checklist-based educational program to assist general practitioners in managing COPD patients.
No less than eighty-four general clinics in the Lodz region, Poland (28 clusters in each of three study arms), will be identified, randomized, and included in the trial. The trial will be based on anonymized data in electronic health records within the national public health care system. The educational intervention program will consist of GPs in two intervention arms being provided with a COPD management checklist: those in the first intervention arm with receive the checklist once at the beginning, while those in the second with receive it twice. The third (control) arm receives standard care without the checklist. The study used the International Code of Diseases (ICD)-10 for COPD. The primary aim is to determine the effect of interventions delivered to general practitioners (GPs) in primary health care. These interventions are aimed at decreasing the hospitalization of elderly patients with medical code J-44 (COPD) as the main reason for hospital admission.
The results of this trial will be directly applicable to primary care in Poland and add new data to the growing body of evidence regarding interventions aimed at improving chronic illness care.
This trial has been registered with the Clinical Trials Protocol Registration System. Please see in ClinicalTrial.gov identifier (NCT Number): NCT04301505 . Registered on 10 March 2020.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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