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Spontaneous deamidation prompted backbone isomerization of Asn/Asp residues resulting in – most cases – the insertion of an extra methylene group into the backbone poses a threat to the structural integrity of proteins. Here we present a systematical analysis of how temperature, pH, presence of charged residues, but most importantly backbone conformation and dynamics affect isomerization rates as determined by nuclear magnetic resonance in the case of designed peptide-models. We demonstrate that restricted mobility (such as being part of a secondary structural element) may safeguard against isomerization, but this protective factor is most effective in the case of off-pathway folds which can slow the reaction by several magnitudes compared to their on-pathway counterparts. We show that the geometric descriptors of the initial nucleophilic attack of the isomerization can be used to classify local conformation and contribute to the design of stable protein drugs, antibodies or the assessment of the severity of mutations.
The Alma-Ata Declaration was a big step in the development of primary care, defining the main tasks and populations’ expectation. Celebrating the 40th year’s anniversary is a good opportunity to make an analysis. Development of primary care was not parallel in the Eastern and Western part of Europe.
To provide an overview on the societal and economic situation, structural and financial changes of healthcare systems in the former ‘Soviet bloc’ countries, to present an analysis of the primary healthcare (PHC) provision and to find relationships between economic development and epidemiological changes of the respective countries.
Epidemiological data, healthcare expenditures and structure, and financing schemes were compared; systematic literature search was performed.
Visible improvements in population health, in the national economic condition, structural changes in healthcare and more focus to primary care were experienced everywhere. Higher life expectancies with high inter-country variation were observed in the former ‘Soviet bloc’ countries, although it could not be clearly linked to the development of healthcare system. PHC provision improved while structural changes were rarely initiated, often only as a project or model initiation. Single-handed practices are yet predominant. The gate-keeping system is usually weak; there were no effective initiatives to improve the education of nurses and to widen their competences. Migrations of workforce to Western countries become a real threat for the Central-East European countries.
Lack of coordination between practices and interdisciplinary cooperation were recognized as the main barriers for further improvement in the structure.
This article investigates farm investment behaviour and the presence of soft budget constraints in the agricultural sectors of three Central and Eastern European countries – Estonia, Hungary and Slovenia – using individual farm accountancy panel data for the 2007–2015 period. Gross farm investment is positively associated with gross farm investment for the previous year, growth in real sales and public investment subsidies. Mixed results for debt square and cash flow variables imply that the different investment behaviour of farms pertains to different structures of investment sources among the countries under analysis. A particularly significant negative cash flow coefficient implies strong soft budget constraints for Estonian farms, while insignificant cash flow coefficients imply weak soft budget constraints for Hungarian and Slovenian farms.
The proposed methodological framework concerns axiomatic theory fusion (ATF) of non-additive engineering design theories. ATF includes seven steps: (i) semantic discretization of the composite theories, (ii) deriving epistemological entities by logical/semantic analysis, (iii) establishing and representation of relations among all relevant epistemological entities, (iv) combining the inter- theoretical epistemological entities of the component theories, (v) deriving propositions based on the combined set of epistemological entities, (vi) transcription of the epistemological entities and propositions into a textual/visual theory description, and (vii) validation of the resultant theory in application contexts. The proposed framework makes ATF an effective, content independent methodology for fusing component theories, no matter if they are descriptive, explanatory, predictive or controlling in nature. ATF methodology requires professional comprehension and rigor from the researchers. It is necessary to justify the logical correctness and practical validity of the target theory in the specific application context.
Avian malaria parasites can negatively affect many aspects of the life of the passerines. Though these parasites may strongly affect the health and thus migration patterns of the birds also during autumn, previous studies on avian malaria focused mainly on the spring migration and the breeding periods of the birds. We investigated whether the prevalence of blood parasites varies in relation to biometrical traits, body condition and arrival time in the European Robin (Erithacus rubecula) during autumn migration. We found no sex or age related differences in avian malaria prevalence and no relationship between infection status and body size or actual condition of the birds was found either. However, the timing of autumn migration differed marginally between infected and non-infected juveniles, so that parasitized individuals arrived later at the Hungarian stopover site. This is either because avian malaria infections adversely affect the migration timing or migration speed of the birds, or because later arriving individuals come from more distant populations with possibly higher blood parasite prevalence. The possible delay that parasites cause in the arrival time of the birds during autumn migration could affect the whole migratory strategy and the breeding success of the birds in the next season.
In Hungary, since 1990, each government has tried to transform and rationalize the structure of health care. One of the reforms was the Care Managing Organization (CMO) programme introduced in 1999.
The aim of this paper is to describe the regional, environmental, structural and preliminary health related outcomes of the CMO in Bács-Kiskun County (Central-Eastern Hungary).
First, cardiovascular screening programmes were organized for pre-screened and randomly selected populations of a total of 4462 persons. Seven years after completing the programmes, regional mortality data were analysed and compared. Second, nutritional and lifestyle counselling programmes with increased physical activity were organized for 2489 overweight or obese patients from the participating primary care practices. Anthropometric and laboratory data were examined after one and two years.
First, for persons with higher cardiovascular risk, appropriate medical treatment was introduced, and after seven years, their mortality rates proved better than the regional and national data. Second, almost all measured anthropometric parameters improved (body mass index, body weight decrease) after the first year and this trend lasted till the end of the second year.
According to the data of the National Health Insurance Fund, the average savings rate for all CMOs for the fiscal years 1999–2007 was 4.94%. The highest rates of savings were realized in chronic and acute inpatient care and medical devices. In the end of 2008, by which time 14 CMOs had already covered 2.1million people, the programme was discontinued by the government, without a comprehensive evaluation of the experience and outcomes.
To describe the design of the Feel4Diabetes-intervention and the baseline characteristics of the study sample.
School- and community-based intervention with cluster-randomized design, aiming to promote healthy lifestyle and tackle obesity and obesity-related metabolic risk factors for the prevention of type 2 diabetes among families from vulnerable population groups. The intervention was implemented in 2016–2018 and included: (i) the ‘all-families’ component, provided to all children and their families via a school- and community-based intervention; and (ii) an additional component, the ‘high-risk families’ component, provided to high-risk families for diabetes as identified with a discrete manner by the FINDRISC questionnaire, which comprised seven counselling sessions (2016–2017) and a text-messaging intervention (2017–2018) delivered by trained health professionals in out-of-school settings. Although the intervention was adjusted to local needs and contextual circumstances, standardized protocols and procedures were used across all countries for the process, impact, outcome and cost-effectiveness evaluation of the intervention.
Primary schools and municipalities in six European countries.
Families (primary-school children, their parents and grandparents) were recruited from the overall population in low/middle-income countries (Bulgaria, Hungary), from low socio-economic areas in high-income countries (Belgium, Finland) and from countries under austerity measures (Greece, Spain).
The Feel4Diabetes-intervention reached 30 309 families from 236 primary schools. In total, 20 442 families were screened and 12 193 ‘all families’ and 2230 ‘high-risk families’ were measured at baseline.
The Feel4Diabetes-intervention is expected to provide evidence-based results and key learnings that could guide the design and scaling-up of affordable and potentially cost-effective population-based interventions for the prevention of type 2 diabetes.
This special issue is devoted to papers from the meeting on Combinatorics and Probability, held at the Mathematisches Forschungsinstitut in Oberwolfach from the 17th to the 23rd April 2016. The lectures at this meeting focused on the common themes of Combinatorics and Discrete Probability, with many of the problems studied originating in Theoretical Computer Science. The lectures, many of which were given by young participants, stimulated fruitful discussions. The fact that the participants work in different and yet related topics, and the open problems session held during the meeting, encouraged interesting discussions and collaborations.
The Status of the Avant- Garde and Socialist Realism in the Romanian and Hungarian Contexts
Histories of Hungarian literature written in the past two decades tend to describe ‘the episode of socialist realism’ as an imposed deviation or even a gap within the continuity of the Hungarian literary tradition. This idea of ‘interrupted continuity’ seems to be present also in the scholarship on twentieth- century Romanian literature. In his overview of the forerunners and beginnings of postmodernist literature in Romania, Mircea CĂrtĂrescu, who is perhaps the best- known living Romanian novelist, speaks about the ‘frozen’ nature of Romanian culture and society during the 1950s and the 1960s. Researchers of literary history in these countries seem to agree that the possibility to fully reconnect with the tradition (after the partial return in the 1970s to the literary poetics of the interwar period) came only after 1989, with the re- establishment of democratic literary institutions.
These metaphorical references in the post- communist period to ‘interruption’ and ‘freezing’ seem to imply that after a certain historical delay, or after a period during which the culture of these countries followed a wrong path, things should have gone back to the course that had been abandoned in 1948, the year when changes in cultural policies began to produce visible effects in Eastern European countries. However, this approach ignores the fact that during the decades of the ‘deviation’ the structure of Hungarian, Romanian and other neighbouring societies changed considerably. Even if the poetics of some literary works seems to indicate that their authors have liberated themselves from the constraints of socialist realism, either during the ‘neomodernism’ stage of the late 1960s and the 1970s or during the era of postmodernism in the 1980s and the 1990s, the general cultural context was already radically different. There are, of course, just as Mircea CĂrtĂrescu points out, certain similarities between, for example, the texts produced in the 1940s and those written in the 1970s, just as it is true that some of the post- communist cultural, social and political models, particularly those related to nation building or to the political institutions of democracy, seem to correspond to the social logic that defined the society in Romania or Hungary before the wars.
To investigate the presenting symptoms, intra-operative findings and long-term facial nerve function in patients treated for cholesteatoma with associated facial paralysis.
Fifteen patients with facial paralysis due to middle-ear cholesteatoma who underwent tympanomastoidectomy surgery from February 2000 to February 2015 were retrospectively reviewed. After removal of the cholesteatoma, a limited area of the fallopian canal, in which facial nerve oedema or redness was evident, was opened. Incision of the epineural sheath for nerve decompression was not performed.
Pre-operative House–Brackmann grade was grade II in two patients, grade III in four, grade IV in seven, grade V in one and grade VI in one. Facial nerve perineurium damage was observed in two patients with poor prognoses. All patients treated within the first 15 days after paralysis onset showed normal facial function at long-term follow up. Post-operative House–Brackmann grade was grade I in 11 patients, grade II in 1, grade III in 2 and grade VI in 1.
Early surgical treatment is more likely to give good results, and poor outcomes are observed in patients with facial nerve perineurium damage.
This study aimed to evaluate the effect of tumour thickness on other clinicopathological parameters in early stage lower lip squamous cell carcinoma.
Forty-six consecutive patients with lower lip squamous cell carcinoma were included in the study. Demographic, clinical and pathological data were retrospectively collected.
The mean follow-up period for all patients was 32.0 ± 18.9 months. Forty-four tumours were staged as T1 and two were T2. Twelve patients underwent neck dissection. Two patients presented with neck metastasis in the follow-up period. Four patients (8.7 per cent) had local recurrence. Correlation analysis revealed a significant relationship between microscopic tumour thickness and local tumour recurrence (r = 0.328, p = 0.045).
Surgical margin control is important to prevent local recurrence, especially in thicker tumours. In addition, neck metastasis is rare in early stage lower lip squamous cell carcinoma. A ‘wait and see’ policy might be preferred in early stage T1 lower lip squamous cell carcinoma cases.
Poincare's proof of the Descartes–Euler conjecture is referred to above. In his doctoral thesis Lakatos introduced detailed consideration of this proof by a discussion of the arguments for and against the ‘Euclidean’ approach to mathematics. Parts of this discussion were incorporated by Lakatos into chapter 1 (see, e.g., pp. 53–60) and others were rewritten as parts of ‘Infinite Regress and the Foundations of Mathematics’ (Lakatos ). We therefore omit this introductory discussion here.
The advocate of the Euclidean programme – the attempt to supply mathematics with indubitably true axioms couched in perfectly clear terms – has been Epsilon. Epsilon's philosophy is challenged, but the Teacher remarks that the most obvious and direct way to challenge Epsilon is to ask him to produce a proof of the Descartes–Euler conjecture which satisfies Euclidean standards. Epsilon takes up the challenge.
Translation of the conjecture into the ‘perfectly known’ terms of vector algebra. The problem of translation
epsilon: I accept the challenge. I shall prove that all simply-connected polyhedra with simply-connected faces are Eulerian.
teacher: Yes, I stated this theorem in a previous lesson.
epsilon: As I have pointed out, I first have to find the truth in order to prove it. Now I have nothing against using your method of proofs and refutations as a method of discovering the truth, but where you stop, I start. Where you stop improving, I start proving.
alpha: But this long theorem is full of stretchable concepts. I do not think we shall find it difficult to refute it.
epsilon: You will find it impossible to refute it. I shall pin down the meaning of each single term.
teacher: Go on.
epsilon: First I shall use only the clearest possible concepts. Maybe sometime we shall be able to extend our perfect knowledge to cover optical cameras, paper and scissors, rubber balls and pumps, but now we should forget these things. Finality certainly cannot be reached by using all these various tools. Our previous failures, in my view, are rooted in the fact that we used methods which are alien to the simple, naked nature of polyhedra.
The dialogue takes place in an imaginary classroom. The class gets interested in a PROBLEM: is there a relation between the number of vertices V, the number of edges E and the number of faces F of polyhedra – particularly of regular polyhedra – analogous to the trivial relation between the number of vertices and edges of polygons, namely, that there are as many edges as vertices: V = E? This latter relation enables us to classify polygons according to the number of edges (or vertices): triangles, quadrangles, pentagons, etc. An analogous relation would help to classify polyhedra.
After much trial and error they notice that for all regular polyhedra V − E + F = 2. Somebody guesses that this may apply for any polyhedron whatsoever. Others try to falsify this conjecture, try to test it in many different ways – it holds good. The results corroborate the conjecture, and suggest that it could be proved. It is at this point – after the stages problem and conjecture – that we enter the classroom. The teacher is just going to offer a proof.
teacher:In our last lesson we arrived at a conjecture concerning polyhedra, namely, that for all polyhedra V − E + F = 2, where V is the number of vertices, E the number of edges and F the number of faces. We tested it by various methods. But we haven't yet proved it. Has anybody found a proof?
pupil sigma:‘I for one have to admit that I have not yet been able to devise a strict proof of this theorem … As however the truth of it has been established in so many cases, there can be no doubt that it holds good for any solid. Thus the proposition seems to be satisfactorily demonstrated.’ But if you have a proof, please do present it.
The method of proofs and refutations is a very general heuristic pattern of mathematical discovery. However, it seems that it was discovered only in the 1840s and even today seems paradoxical to many people; and certainly it is nowhere properly acknowledged. In this appendix I shall try to sketch the story of a proof-analysis in mathematical analysis and to trace the sources of resistance to the understanding and recognition of it. I first repeat the skeleton of the method of proofs and refutations, a method which I have already illustrated by my case-study of the Cauchy proof of the Descartes–Euler conjecture.
There is a simple pattern of mathematical discovery– or of the growth of informal mathematical theories. It consists of the following stages:
(1) Primitive conjecture.
(2) Proof (a rough thought-experiment or argument, decomposing the primitive conjecture into subconjectures or lemmas).
(3) ‘GlobaL’ counterexamples (counterexamples to the primitive conjecture) emerge.
(4) Proof re-examined: the ‘guilty lemma’ to which the global counterexample is a ‘locaL’ counterexample is spotted. This guilty lemma may have previously remained ‘hidden’ or may have been misidentified. Now it is made explicit, and built into the primitive conjecture as a condition. The theorem – the improved conjecture – supersedes the primitive conjecture with the new proof-generated concept as its paramount new feature.
These four stages constitute the essential kernel of proof-analysis. But there are some further standard stages which frequently occur:
(5) Proofs of other theorems are examined to see if the newly found lemma or the new proof-generated concept occurs in them: this concept may be found lying at cross-roads of different proofs, and thus emerge as of basic importance.
(6) The hitherto accepted consequences of the original and now refuted conjecture are checked.
(7) Counterexamples are turned into new examples – new fields of inquiry open up.
I should now like to consider another case-study. Here the primitive conjecture is that the limit of any convergent series of continuous functions is itself continuous.