Proteomic and metabolomic signature of Dravet Syndrome

Dravet syndrome is a rare, severe form of pediatric epilepsy, accompanied by cognitive, behavioral and motor disturbances. Haploinsufficiency of the Scn1a gene, encoding the function of sodium channels on GABAergic neurons, has been detected in over 80 % of patients. Thus, it is considered the main cause of hyperexcitability. Albeit few drugs have received orphan drug status over the past years, pharmacoresistance remains the biggest challenge in the treatment of Dravet syndrome. Therefore, novel therapeutic strategies are urgently needed. Characterization of a novel, conditional, Scn1a-A1783V knock-in mouse model confirmed an increased seizure susceptibility, behavioral and motor alterations and thus demonstrated excellent face validity for the further investigation of Dravet syndrome. The untargeted proteomic screening displayed more pronounced changes following the onset of spontaneous seizures, dominated by the down-regulation of proteins involved in synaptic and glutamatergic signaling in the hippocampus of Dravet mice. The proteomic data was complemented by metabolome data that detected lower levels of glutamate and GABA in the hippocampus, suggesting a disturbed glutamate/GABA-glutamine cycle and an increased GABA:glutamate ratio. This can later be supported by GABAergic drugs. A comparison of proteomic data to published data from animal models of acquired epilepsies revealed common molecular alterations between genetic and acquired epilepsies comprising proteins linked with synaptic plasticity, astrogliosis and angiogenesis. Metabolomic screening of hippocampal tissue in Dravet mice showed pronounced alterations in energy metabolism and an impact of Dravet genotype on concentrations of several glycolysis and tricarboxylic acid (TCA) cycle intermediates. These changes in energy metabolism may contribute to seizure susceptibility and ictogenesis. Furthermore, they could explain the therapeutic potential of a ketogenic diet, which aims to shift energy metabolism towards a more fat-based energy supply. This diet improved the motor deficits observed in Dravet mice. Overall, the proteome and metabolome analysis in a mouse model of Dravet syndrome demonstrated complex molecular alterations in the hippocampus. Whether these alterations may contribute to hyperexcitability or, instead, represent a compensatory mechanism, will have to be confirmed by further investigations. The proteomic data indicated more complex pathophysiological mechanisms during the course of the disease, which should be considered in the management of Dravet syndrome. However, future studies investigating the functional relevance of the aforementioned molecular changes may confirm our data and provide valuable guidance on the development of novel therapeutic options

On a SHOCKLEY-READ-HALL model for semiconductors

The Shockley-Read-Hall model was introduced in 1952 to describe the statistics of recombination of holes and electrons in semiconductors occurring through the mechanism of trapping and we consider initial-boundary value problems with initial conditions

Fuzzy model of the computer integrated decision support and management system in mineral processing

During the research on the subject of computer integrated systems for decision making and management support in mineral processing based on fuzzy logic, realized at the Department of Applied Computing and System Engineering of the Faculty of Mining and Geology, University of Belgrade, for the needs of doctoral thesis of the first author, and wider demands of the mineral industry, the incompleteness of the developed and contemporary computer integrated systems fuzzy models was noticed. The paper presents an original model with the seven staged hierarchical monitoring-management structure, in which the shortcomings of the models utilized today were eliminated

The model of brand building as a determinant of economy development

Posmatrajući gradove kao nosioce kulturnih, društvenih i političkih promjena, razumijevajući funkcije grada i osnovne elemente grada kao nosioce tih funkcija, brend i brendiranje su koncepcije u službi prepoznavanja i podsticanja privrednog razvoja. Rezultati istraživanja prikazani u ovoj doktorskoj disertaciji su pokazali da izgradnjom modela grada zasnovanog na procesnom pristupu se pruža mogućnost da upravljanje brendom grada (upravljanje procesima - komponentama grada) se ostvare strateški ciljevi grada. Efektivno i efiaksno upravljanje komponentama grada ima presudan uticaj na privredni razvoj grada.Observing cities as the holders of cultural, social and political changes and understanding city functions and basic elements of any city as holders of the aforementioned functions, a brand and branding are concepts for the purpose of recognition and encouragement of economic development. The research results presented in this PhD dissertation have shown that a creation of city model based on the process approach enables the possibility to run the brand of the city. Effective and efficient managing of city components has the crucial effect on the city economic development

Psihosocijalne odrednice zadovoljstva bolničkom skrbi u odraslih bolesnika s uznapredovalim rakom [Psychosocial determinants of the satisfaction with hospital care in adult patients suffering from advanced metastatic cancer]

Direct and indirect relationships between socio-demographic (age, gender, education level, life partner, income and length of treatment), psychological (HADS) variables and satisfaction with hospital care (EORTC INPATSAT32) in adult patients, suffering from advanced cancer, were investigated. Hospitalized participant were recruited at Clinical Hospital Centre Zagreb (N=46; January 2015) and Clinical Hospital Centre ‘Sisters of Mercy’ (N=29; April 2015). Inclusion criteria: 1. advanced stage of disease without metastasis and/or primar malignoma in CNS, 2. receiving treatment without curative intent, 3. ECOG 0 or 1, 4. without acute psychosis, dementia, delirium or psychoorganicum syndrome; 5. ≥ 26 scores on MoCA test. Statistically non significant correlations are found between demographic factors and HADS (p>0,05), but there are statistically significant (p<0,05) negative correlations between HADS and all satisfaction variables. Gender and the income appeared as the significant (p<0,05) moderator variables in the relationship between HADS and the satisfaction with nurses availability and general satisfaction. Emotionally disturbed male respondents are more satisfied with the availability of nurses / technicians and have higher general level of satisfaction with hospital care; emotionally disturbed subjects who have higher income have lower satisfaction availability of nurses / technicians and lower general satisfaction with hospital care

Risk management of machines in open pit mines

Fenomen rizika treba najpre definisati, a da bi se njime upravljalo, potrebno ga je i meriti. Merenje je neophodno da bi se utvrdili ciljevi koji se žele postići i stepen ostvarenja ciljeva. Merenje može biti kvalitativno i kvantitativno, zasnovano na statistici, merenju fizičkih veličina, ili na procenama datim od stručnih lica. U ovom radu je prikazan model upravljanja rizikom mašina koje rade na površinskom kopu, sa posebnim osvrtom na uticaj ljudskog faktora.The phenomenon of risk should first be defined, and in order to be managed it is necessary to be measured. The measurement is necessary to determine the objectives to be achieved and the degree achievement of the objectives. Measurement can be qualitatively and quantitatively, based on statistics, the measurement of physical quantities, and the estimations given by experts. This paper deals with models of risk management of machinery of open coal mines, with special focus on human resource influence

Quality of life in chronic hemodialysis patients and renal transplant

U toku protekle dve decenije razvijeno je nekoliko metoda merenja kvaliteta života, koji su primenjeni kod različitih kategorija zdravih i bolesnih ljudi, uključujući i obolele od hronične bubrežne bolesti (HBB). SZO organizacija svrstava HBB na dvanaesto mesto među vodećim uzrocima smrti u svetu. U terminalnoj fazi HBB neophodno je nadomestiti nedostatak bubrežne funkcije aktivnom terapijom- transplantacijom, peritoneumskom dijalizom ili hemodijalizom. Cilj aktivne terapije jeste nadoknada nedostajuće funkcije bubrega, ali takođe i poboljšanje kvaliteta života Cilj ovog istraživanja bio je da se ispita kvalitet života u populaciji obolelih od hronične bubrežne bolesti koji su na hroničnoj hemodijalizi, i sa transplantiranim bubregom, da se ispita povezanost kvaliteta života sa demografskim, socio-ekonomskim, kliničkim karakteristikama i komorbiditetom u obe ispitivane grupe pacijenata, uporede parametri kvaliteta života u ispitivanim grupama i na osnovu toga donese zaključak o uticaju različitih vidova lečenja na kvalitet života kod obolelih od hronične bubrežne bolesti. Analiza srednjih vrednosti ukupnog 15D skora pokazala je da je kvalitet života statistički značajno bolji kod ispitanika sa transplantiranim bubregom u poređenju sa ispitanicima na hemodijalizi (0,92±0,09 prema 0,78±0,15). Utvrđena je negativna povezanost kvaliteta života sa godinama života radnim statusoom i ICED skorom, a pozitivna sa koncentracijom hemoglobina i kreatinina u hemodijaliziranoj grupi. U grupi transplantiranih pacijenata kvalitet života je negativno korelirao sa godinama života, radnim statusom i ICED skorom. Multivarijantna regresiona analiza pokazala je da su nezavisni prediktorin kvaliteta života pacijenata na hemodijalizi bili: godine života i ICED skor, dok u grupi sa transplantiranim bubregom to su bili: ICED skor, godine života i zaposlenje.During the past two decades sciences developed several methods for measuring quality of life, which are applied in different categories of healthy and sick people, including for patients suffering from chronic kidney disease (CKD). WHO classifies CKD on the twelfth place of the leading causes of death in the world. In the terminal stage CKD is necessary to compensate the lack of renal function with an active therapy - renal transplantation, peritoneal dialysis or hemodialysis. The aim of active treatment is compensation missing kidney function, but also improvment of the quality of life. The aim of this study was to investigate the quality of life in a population of patients with chronic kidney disease who are on hemodialysis, and renal transplantation, to investigate the connection between quality of life with demographic, socio-economic, clinical characteristics and comorbidity in both groups of patients, comparing the parameters of quality of life in the examined groups on the basis of a conclusion about the impact of different forms of treatment on quality of life in patients with CKD. Analysis of the mean values of the total 15D score showed that the quality of life was significantly better in patients with kidney transplantation compared to those on hemodialysis (0.92 ± 0.09 vs. 0.78 ± 0.15). There was a negative correlation between the quality of life with patients age, employment status and ICED, while positive correlation was detected with the hemoglobin concentration and creatinine in hemodialysis group. In the group of patients with kidney transplantation, quality of life was negatively correlated with the patients age, employment status and ICED. Multivariate regression analysis showed that independent predictors of quality of life in hemodialysis patients group were: patients age and ICED score, while in the group of patients with the transplanted kidney it was: ICED score, patients age and employment

Geosystem foundations of environmental governance

Насловом дисертације, теоријским оквиром и предметом истраживања указује се наинтересовање у дисертацији, а то је географски теоријски концепт и сама суштинагеографије као науке (проучавање интеракција друштва и природе), јер управо тајгеографски идентитет одређује и животну средину као појам (феномен). Ако се оживотној средини размишља као о сложеном и вишедимензионалном систему, односноо еколошким проблемима као о мултискаларним и мултисекторским проблемима,претпоставља се да у проучавању датих феномена посебно место има географскомишљење и географска логика.Применом геосистемског приступа методолошки је „елиминисано” одвојено проучавањедруштвених и природних система јер су они у стварности повезани. То полазиштеомогућава да се сагледа функционална, просторна и временска међузависност унутарсистема животне средине. На тим основама (сагледавање интеракција) се мора градитисистем управљања животном средином као незаобилазна стратешка активностусмеравања процеса у животној средини. Из идеје о интеракцијама, односногеосистемском приступу, проистиче интегрални приступ као водећи принцип у решавањумултискаларне и мултисекторске природе еколошких проблема, односно принцип накоме се заснива управљање животном средином.Промена у перцепцији/дефинисању еколошких проблема, од редукционистичког касистемском поимању, са нагласком на интеракцијама, утицала је на прелазак са„владања на управљање”. То је значило отклон од парадигме „заповедај и контролиши”ка флексибилнијим моделима управљања. Интегрални принцип претпостављаинтеграцију политика (секторска интеграција), нивоа управљања (територијалнаинтеграција) и учесника (поделa одговорности између државе и приватног сектора,невладиних организација и др.), као и мера и инструмената у систему управљањаживотном средином, што је приказано у дисертацији.Интердисциплинарност (природна и друштвена компонента), методолошки плурализам,географски концепти (простор, место и животна средина), историјско географскиретроспект, само су нека од обележја географског мишљења која су нашла своју применуу проучавању животне средине.У дисертацији је потврђена улога просторног планирања као веома значајногинструмента за интегрисање циљева заштите животне средине у политикe просторногразвоја.The title of thesis, the theoretical framework and the research subject indicate that the thesisfocuses on the theoretical concept of geography and the essence of geography as a science(the study of interactions between society and nature). This is because the environment as aconcept (phenomenon) is determined by a geographical identity. If the environment isperceived as a complex and multi-dimensional system and ecological problems are interpretedas multiscale and multisectoral issues, it is assumed that a particularly important place in thestudy of these phenomena is occupied by geographical reasoning and a geographical logic.The reliance on a geosystem-based approach "eliminates", methodologically, the study ofsocial and natural systems as unrelated subjects, because they are in fact closely related. Thisapproach enables us to grasp the functional, spatial and temporal interrelationships in theenvironment. It is upon these foundations (understanding of interactions) that anenvironmental governance system must be built as a crucial strategic activity aimed atchannelling various processes in the environment. The integrated approach, as the leadingprinciple in dealing with multiscale and multisectoral nature of environmental problems andthe principle of environmental governance, is derived from the idea of interactions, i.e. from ageosystem-based approach.The changed perception/definition of ecological problems, involving a transition from areductionist to a systemic approach, with an emphasis on interactions, has led to a shift from"government to governance". This implied a departure from the "command and control"paradigm and the adoption of more flexible governance models. The principle of integrationinvolves the integration of policies (cross-sectoral integration), levels of governance (territorialintegration) and stakeholders (sharing responsibilities among the public and private sectors,non-governmental organizations, etc.), as well as environmental governance measures andinstruments, as demonstrated in thesis.Interdisciplinarity (taking into account both natural and social components), methodologicalpluralism, geographical concepts (space, place and environment) and historical andgeographical retrospection, are merely some of the features of geographical reasoning that areapplied in environmental research.The role of spatial planning, as a very important instrument for integrating environmentalprotection goals into spatial development policies, is confirmed in thesis

Rules of Risk Management - Case Study of Open Pit Mine

The issue of human factor risk and rules and regulations in open pit mine is a main focus of this paper in order to develop predictive models of behavior of workers in relation to compliance with the procedures and rules. Presented survey was conducted in open pit coal mine, as high-risk system, involving 476 mineworkers. The survey was in the form of a questionnaire, consisting of 45 questions, aimed to fmd out the opinions of the mining workforce about risk attitude generally as well as about safety rules and regulations