Changes in ESCRT-III filament geometry drive membrane remodelling and fission in silico

BACKGROUND: ESCRT-III is a membrane remodelling filament with the unique ability to cut membranes from the inside of the membrane neck. It is essential for the final stage of cell division, the formation of vesicles, the release of viruses, and membrane repair. Distinct from other cytoskeletal filaments, ESCRT-III filaments do not consume energy themselves, but work in conjunction with another ATP-consuming complex. Despite rapid progress in describing the cell biology of ESCRT-III, we lack an understanding of the physical mechanisms behind its force production and membrane remodelling. // RESULTS: Here we present a minimal coarse-grained model that captures all the experimentally reported cases of ESCRT-III driven membrane sculpting, including the formation of downward and upward cones and tubules. This model suggests that a change in the geometry of membrane bound ESCRT-III filaments-from a flat spiral to a 3D helix-drives membrane deformation. We then show that such repetitive filament geometry transitions can induce the fission of cargo-containing vesicles. // CONCLUSIONS: Our model provides a general physical mechanism that explains the full range of ESCRT-III-dependent membrane remodelling and scission events observed in cells. This mechanism for filament force production is distinct from the mechanisms described for other cytoskeletal elements discovered so far. The mechanistic principles revealed here suggest new ways of manipulating ESCRT-III-driven processes in cells and could be used to guide the engineering of synthetic membrane-sculpting systems

From functional food to medicinal product: Systematic approach in analysis of polyphenolics from propolis and wine

In the last decade we have been working on standardization of propolis extract and determination of active constituents of wine those are rich in polyphenolics and have nutritional as well as therapeutic value. Here we are summarizing our results and providing overview on systematic approach how to analyse natural products rich in flavonoids and phenolic acids

Brachytherapy – Optional Treatment for Choroidal Neovascularization Secondary to Age-Related Macular Degeneration

Age-related macular degeneration (ARMD) presents the main cause of irreversible loss of central vision in older population, due to a progressive neuroretinal damage and damage of retinal pigment epithelium of foveal area. This observation emphasizes the insufficiency of all presently used therapeutic procedures. Therefore, investigation has been conducted at the University Eye Clinic Zagreb for the last three years testing the effects of brachytherapy with direct episcleral application of ruthenium applicators to the posterior pole of the globe. Forty-two patients aged 58–79 were followed for a min. of 12 months. During this period their central visual acuities remained stable. Six patients showed one-line improvement of visual acuity and 8 patients showed no changes. Twenty-one patient lost 1–2 lines of visual acuity and 7 patients lost more than 2 lines. According to this we can conclude that patients treated with brachytherapy showed significantly better results compared to the control subjects, which is very encouraging

Fish and Shellfish Intake and Diabetes in a Costal Population of the Adriatic

Objective: To examine the association between fish and shellfish intake and diabetes in an island population. Design: Cross-sectional. Setting: Two independent population-based field surveys conducted in Hvar Island of the eastern Adriatic coast of Croatia in May 2007 and May 2008. Subjects: A total of 1,379 adults participated. Results: In multivariable logistic regression models, total fish intake was positively associated with diabetes prevalence in the total population (OR Q4 vs Q1 = 1.64; 95% CI = 1.01-2.66; p-trend = 0.09). Oily fish intake also exhibited a positive association with diabetes prevalence in the total population (OR Q4 vs Q1 = 2.22; 95% CI = 1.35-3.64; p-trend = 0.01) and in analyses stratified by body mass index, males and those with a high waist circumference. Conclusions: The study suggests an association between oily fish intake and diabetes in the population of the Hvar Island in Croatia. Longitudinal studies incorporating measures of persistent organic pollutants and local cooking practices are warranted to identify factors in fatty fish that may influence the development or persistence of diabetes

Neuroretinitis associated with cat-scratch disease: a case report

U studenom 2003. godine u Centralnoj prijamnoj ambulanti Klinike za infektivne bolesti »Dr. Fran Mihaljević«, Zagreb liječena je bolesnica s vitritisom i stražnjim uveitisom oba oka te neuroretinitisom lijevog oka, nastalim tijekom bolesti mačjeg ogreba (BMO). Slabljenje vida nastalo je istovremeno s otokom limfnog čvora u aksili, tri tjedna nakon ogreba mačke. Nakon pregleda u jednoj zagrebačkoj klinici za očne bolesti, bolesnica je upućena u našu Kliniku radi etiološke dijagnostike i preporuke za antimikrobno liječenje. Idućeg dana hospitalizirana je na Klinici za očne bolesti. Za vrijeme hospitalizacije liječena je azitromicinom peroralno tijekom pet dana prema preporuci infektologa, uz lokalnu i parenteralnu terapiju kortikosteroidima. Bolest je imala povoljan ishod. Ovo je prvi slučaj neuroretinitisa nastalog tijekom BMO koji je dijagnosticiran u ovoj Klinici, u suradnji s oftalmolozima. Dijagnoza se temeljila na epidemiološkoj anamnezi, regionalnom limfadenitisu s odgovarajućim citološkim nalazom punktata i serološkoj potvrdi protutijela na Bartonellu henselae.In November 2003, a 32-year-old female patient with vitritis and uveitis (pars planitis) of both eyes and neuroretinitis of the left eye, associated with cat-scratch disease (CSD) was treated at the Central Admissions Department of the University Hospital for Infectious Diseases »Dr. Fran Mihaljevic«, Zagreb. Impaired vision occurred simultaneously with axillar lymph node swelling, three weeks after cat scratch. After the patient was examined at the Ophthalmology Clinic in Zagreb, she was referred to our Hospital for etiological diagnostics and recommendation for antimicrobial treatment. The following day the patient was hospitalized at the Ophthalmology Clinic. During hospitalization she was treated with azithromycin p.o. for five days according to recommendation by the infectious disease specialist, with local and parenteral corticosteroid therapy. The disease had favorable outcome. This is the first case of neuroretinitis associated with CSD that was diagnosed in our Hospital in collaboration with colleagues ophthalmologists. The diagnosis was based on epidemiological data, regional lymphadenitis with corresponding cytological finding and serological confirmation of antibodies to Bartonella henselae

Kinetics of spontaneous filament nucleation via oligomers: Insights from theory and simulation

Nucleation processes are at the heart of a large number of phenomena, from cloud formation to protein crystallization. A recently emerging area where nucleation is highly relevant is the initiation of filamentous protein self-assembly, a process that has broad implications in many research areas ranging from medicine to nanotechnology. As such, spontaneous nucleation of protein fibrils has received much attention in recent years with many theoretical and experimental studies focussing on the underlying physical principles. In this paper we make a step forward in this direction and explore the early time behaviour of filamentous protein growth in the context of nucleation theory. We first provide an overview of the thermodynamics and kinetics of spontaneous nucleation of protein filaments in the presence of one relevant degree of freedom, namely the cluster size. In this case, we review how key kinetic observables, such as the reaction order of spontaneous nucleation, are directly related to the physical size of the critical nucleus. We then focus on the increasingly prominent case of filament nucleation that includes a conformational conversion of the nucleating building-block as an additional slow step in the nucleation process. Using computer simulations, we study the concentration dependence of the nucleation rate. We find that, under these circumstances, the reaction order of spontaneous nucleation with respect to the free monomer does no longer relate to the overall physical size of the nucleating aggregate but rather to the portion of the aggregate that actively participates in the conformational conversion. Our results thus provide a novel interpretation of the common kinetic descriptors of protein filament formation, including the reaction order of the nucleation step or the scaling exponent of lag times, and put into perspective current theoretical descriptions of protein aggregation.We acknowledge support from the Human Frontier Science Program and Emmanuel College (A.Š.), St John’s and Peterhouse Colleges (T.C.T.M.), the Swiss National Science Foundation (T.C.T.M.), the Biotechnology and Biological Sciences Research Council (T.P.J.K.), the Frances and Augustus Newman Foundation (T.P.J.K.), the European Research Council (T.C.T.M., T.P.J.K., and D.F.), and the Engineering and Physical Sciences Research Council (D.F.)

Disability reassessment in chronic bronchitis and pulmonary functional criteria

U sklopu reevaluacije gubitka radne sposobnosti 579 osoba s glavnom internističkom dijagnozom specifično je obrađeno 88 muškaraca (dob 52,82 g) s dominantnom bolešću - kronični bronhitis te posljedičnim gubitkom radne sposobnosti. Rearbitraža gubitka radne sposobnosti koju je proveo neformalni arbitrarni tim upućuje na nesklad s obzirom na neispravno donijetu odluku o statusu invalidnosti, posebno s aspekta preostale radne sposobnosti. Kronični opstruktivni bronhitis imalo je 68 muškaraca (dob 52,29 g). U uzorku 68 ispitanika izvršena je kompletna funkcijska obrada uključivši plinsku analizu arterijske krvi, neke izvedene pokazatelje i nespecifičnu reaktivnost dišnih putova. Uzorak ispitanika reevaluiran je prema pokazateljima: pravilna ocjena, neispravna ocjena, preostala radna sposobnost, nezavršeno liječenje. Neparametrijska statistička obrada podataka jednosmjernom Kruskal-Walli-sovom analizom rangova atribuira kao specifične prediktore: dob ispitanika, PC20 FEV1, stanje hiperreaktivnosti i stupanj opstrukcije dišnih putova. U radu se obrazlaže važnost funkcijske obrade u mirovanju, a napose značenje varijable FEV1 u ocjeni gubitka radne sposobnosti osoba s kroničnim opstruktivnim bronhitisom.As part of an investigation to reassess disability which was performed in .579 subjects with an internist\u27s diagnosis, disability was reassessed in 68 males with chronic bronchitis as the main diagnosis. Disability reassessment was carried out by an informal team of physicians consisting of pulmologists and members of a second degree disability board. The aim of the study was to define the differences between disability reevaluation and residual working capacity. In chronic bronchitis, a complete functional pulmonary test was carried out including measurement of the degree of obstruction, several specific parameters, non-specific bronchial reactivity and an analysis of arterial blood gases. Disability was reassessed in accordance with the following parameters: accurate evaluation, inaccurate evaluation, residual working capacity, uncompleted treatment. The one-way Kruskal-Wallis rank analysis of non-parametric data attributed the following predictors as specific: age, PC20, FEV1, the condition of hyperreactive airways and the degree of airway obstruction. The relevance of functional criteria arrest, particularly of FEY1, for assessing the loss of working capacity in persons with chronic obstructive bronchitis is emphasized

Physical mechanisms of ESCRT-III-driven cell division

Living systems propagate by undergoing rounds of cell growth and division. Cell division is at heart a physical process that requires mechanical forces, usually exerted by assemblies of cytoskeletal polymers. Here we developed a physical model for the ESCRT-III-mediated division of archaeal cells, which despite their structural simplicity share machinery and evolutionary origins with eukaryotes. By comparing the dynamics of simulations with data collected from live cell imaging experiments, we propose that this branch of life uses a previously unidentified division mechanism. Active changes in the curvature of elastic cytoskeletal filaments can lead to filament perversions and supercoiling, to drive ring constriction and deform the overlying membrane. Abscission is then completed following filament disassembly. The model was also used to explore how different adenosine triphosphate (ATP)-driven processes that govern the way the structure of the filament is changed likely impact the robustness and symmetry of the resulting division. Comparisons between midcell constriction dynamics in simulations and experiments reveal a good agreement with the process when changes in curvature are implemented at random positions along the filament, supporting this as a possible mechanism of ESCRT-III-dependent division in this system. Beyond archaea, this study pinpoints a general mechanism of cytokinesis based on dynamic coupling between a coiling filament and the membrane

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