Packaging waste, biodegradable municipal waste, artificial neural networks, model, prediction, waste management

U okviru disertacije, korišćenjem veštačkih neuronskih mreža razvijeni su modeli za predviđanje količina ambalažnog i biorazgradivog komunalnog otpada u Republici Srbiji do kraja 2030. godine. Razvoj modela baziran je na zavisnosti između ukupne potrošnje domaćinstva i generisane količine dva posmatrana toka otpada. Pored toga, na bazi zavisnosti sa bruto domaćim proizvodom (BDP), definisan je i model za projekciju zastupljenosti osnovnih opcija tretmana komunalnog otpada u Republici Srbiji za isti period. Na osnovu dobijenih rezultata, stvorene su polazne osnove za procenu potencijala za reciklažu ambalažnog otpada, kao i za procenu u kojoj meri se može očekivati da određene količine biorazgradivog otpada u narednom periodu ne budu odložene na deponije, što je u skladu sa savremenim principima upravljanja otpadom i postojećim zahtevima EU u ovoj oblasti.By using artificial neural networks, models for prediction of the quantity of packaging and biodegradable municipal waste in the Republic of Serbia by the end of 2030, were developed. Models were based on dependence between total household consumption and generated quantities of two observed waste streams. In addition, based on dependence with the Gross Domestic Product (GDP), a model for the projection of share of different municipal solid waste treatment options in the Republic of Serbia for the same period, was created. Obtained results represent a starting point for assessing the potential for recycling of packaging waste, and determination of biodegradable municipal waste quantities which expected that in the future period will not be disposed at landfills, in accordance with modern principles of waste management and existing EU requirements in this area

Packaging waste, biodegradable municipal waste, artificial neural networks, model, prediction, waste management

U okviru disertacije, korišćenjem veštačkih neuronskih mreža razvijeni su modeli za predviđanje količina ambalažnog i biorazgradivog komunalnog otpada u Republici Srbiji do kraja 2030. godine. Razvoj modela baziran je na zavisnosti između ukupne potrošnje domaćinstva i generisane količine dva posmatrana toka otpada. Pored toga, na bazi zavisnosti sa bruto domaćim proizvodom (BDP), definisan je i model za projekciju zastupljenosti osnovnih opcija tretmana komunalnog otpada u Republici Srbiji za isti period. Na osnovu dobijenih rezultata, stvorene su polazne osnove za procenu potencijala za reciklažu ambalažnog otpada, kao i za procenu u kojoj meri se može očekivati da određene količine biorazgradivog otpada u narednom periodu ne budu odložene na deponije, što je u skladu sa savremenim principima upravljanja otpadom i postojećim zahtevima EU u ovoj oblasti.By using artificial neural networks, models for prediction of the quantity of packaging and biodegradable municipal waste in the Republic of Serbia by the end of 2030, were developed. Models were based on dependence between total household consumption and generated quantities of two observed waste streams. In addition, based on dependence with the Gross Domestic Product (GDP), a model for the projection of share of different municipal solid waste treatment options in the Republic of Serbia for the same period, was created. Obtained results represent a starting point for assessing the potential for recycling of packaging waste, and determination of biodegradable municipal waste quantities which expected that in the future period will not be disposed at landfills, in accordance with modern principles of waste management and existing EU requirements in this area

The influence of modulation of [alpha]5 subunit-containing GABAa receptors on behavioral changes in rats prenatally exposed to the effects of lipopolysaccharide

Epidemiološke studije dovele su u vezu prenatalno izlaganje efektima imune aktivacije izazvane virusnim, bakterijskim ili parazitskim infekcijama sa povećanim rizikom od nastanka neurorazvojnih poremećaja poput shizofrenije. Ova saznanja dovela su do razvoja animalnih modela prenatalne imune aktivacije sa ciljem da se u njima modeluju simptomi i patofiziološki mehanizmi relevantni za određena neurorazvojna oboljenja. Utvrđeno je da primena lipopolisaharida (LPS), imunogene komponente ćelijskog zida gram-negativnih bakterija, gravidnim ženkama glodara izaziva febrilni odgovor i indukciju više citokina, čime utiče na balans pro- i antiinflamatornih medijatora koji je neophodan za pravilan razvoj mozga fetusa. U proučavanju etiologije shizofrenije akcenat je nedavno pomeren ka ispitivanjima poremećaja GABA-ergičkog sistema, a deficiti GABA-ergičke transmisije koji su zabeleženi kod pacijenata obolelih od shizofrenije nađeni su i u modelima prenatalne primene LPS-a gravidnim ženkama pacova. Od posebnog značaja za ispitivanja predstavljena u ovoj disertaciji stoje informacije da se vreme primene LPS-a u našem istraživanju poklapa sa periodom prvobitne ekspresije α5GABAA receptora u fetusnom mozgu pacova, kao i da prenatalna primena LPS-a u tim danima gestacije rezultira smanjenjenjem GABA-ergičke transmisije u hipokampusu potomaka u periodu preadolescencije. Otkrivanje ranih poremećaja u razvoju CNS-a leži u osnovi strategije prevencije razvoja shizofrenije i srodnih poremećaja, koja podrazumeva farmakološko delovanje na neurorazvojne promene u nastanku, pre ispoljavanja prvih simptoma. U ovoj studiji, LPS (serotip O111:B4, Escherichia coli) je primenjivan gravidnim ženkama Wistar pacova 15. i 16. dana gestacije u dozi od 100 μg/kg. Prenatalna inflamacija je detektovana kroz porast nivoa citokina TNF-α u krvi majke i placentalnom tkivu, i povećanje koncentracije IL-6 u krvi majke i amnionskoj tečnosti, dok fetusna neuroinflamacija posredovana ovim citokinima nije potvrđena. Ipak, istovremeno sa porastom koncentracije IL-6 u amnionskoj tečnosti zabeležen je porast nivoa GABA-e i smanjenje nivoa glutamata u fetusnim mozgovima...Epidemiological studies have linked the exposure to the effects of maternal immune activation induced by viral, bacterial or parasitic infections, with the emergence of schizophrenia and several other neurodevelopmental disorders. These findings led to the development of animal models of prenatal immune activation designed to model symptoms and pathological mechanisms relevant to certain neurodevelopmental disorders. It has been shown that administration of lipopolysaccharide (LPS), an immunogen component of the cell wall of gram-negative bacteria, to pregnant rodents causes febrile response and cytokine induction, thus affecting the balance between pro- and anti-inflammatory mediators which is necessary for regular development of the fetal brain. Within the studying of etiology of schizophrenia, a focus of investigation has recently been shifted to abnormalities observed in GABA-ergic system, and deficits of GABA-ergic transmission recorded in schizophrenia patients have also been found in rats tested in models of prenatal LPS administration. Some GABA-related findings are of special interest for investigation presented in this dissertation: the time of LPS administration in our protocol is the very time of primary expression of α5GABAA receptors in rat fetal brain, and prenatal LPS administration the selected days of gestation results in a decrease of GABA-ergic transmission in the hippocampus of preadolescent offspring. The discovery of early disturbances in the development of CNS underlies the strategy for prevention of schizophrenia and related disorders, which implies a pharmacological treatment of neurodevelopmental changes at their occurrence, before the manifestation of first symptoms. In this study, LPS (serotype O111:B4, Escherichia coli) was administered to pregnant Wistar rats at 15th and 16th day of gestation, at the dose of 100 μg/kg. Prenatal inflammation was detected via the elevation of TNF-α concentration in maternal blood and placenta, and IL-6 concentration in maternal blood and amniotic fluid, while fetal neuroinflammation mediated with these cytokines was not confirmed..

A novel positive modulator of α4‐GABAA receptors, XHE-III‐74, reduces ethanol intake in mouse „drinking in the dark” model

Cilj ove studije bio je da se ispita da li akutni tretman ligandom XHe‐III‐74, novim pozitivnim modulatorom α4‐GABAA receptora, može smanjiti unos alkohola u mišijem modelu „pijenja u mraku” (eng. drinking in the dark – DID). Eksperimenti su sprovedeni na odraslim miševima soja C57BL/6. Moguće sedativno dejstvo XHe‐III‐74 (0,5; 2 ili 5 mg/kg, i.p.) ispitano je u testu spontane lokomotorne aktivnosti (SLA). Prvog dana jednog ciklusa DID eksperimenta svaka životinja imala je dvočasovni pristup alkoholu (etanol 20%, v/v). Drugog dana tretman je primenjivan 20 minuta pre pristupa alkoholu, a trećeg dana pacovi nisu tretirani ničim. U svim DID eksperimentima svaka životinja je prošla kroz četiri ciklusa tako da je u svakom primila jednu od tri doze tretmana ili placebo. U prvom DID eksperimentu testirali smo efekat XHe‐III‐74 (0,8; 2 ili 5 mg/kg) na unos vode (n=12, po dozi), dok smo u drugom testirali efekat istih doza na unos alkohola (n=14). Ekekat referetnog leka, naltreksona (1; 4 ili 16 mg/kg) testiran je u trećem eksperimentu. U SLA testu, nijedna od odabranih doza XHe‐III‐74 nije smanjila pređeni put životinje (F3,20=0,48; p=0,703). U prvom DID eksperiementu, tretman XHe‐III‐74 nije uticao na unos vode (F3,33=0,39; p=0,763). Unos alkohola, meren u drugom DID eksperimentu, izmenjen je pod dejstvom XHe‐III‐74 tretmana (F3,39=7,41; p<0,001), gde je doza XHe‐ III‐74 od 5 mg/kg značajno smanjila unos u poređenju sa kontrolom (p<0,001). U trećem eksperimentu, naltrekson je značajno smanjio unos alkohola (F60,3=22.18; p<0,001), i to u sve tri doze: 1 mg/kg (p<0,001); 4 mg/kg (p<0,001) i 16 mg/kg (p<0,001). Uz očekivani izostanak sedativnog dejstva, XHe‐III‐74, pozitivni modulator α4‐ GABAA receptora, ispoljio je evidentan potencijal za smanjenje unosa alkohola u mišijem DID modelu, koji se može porediti sa onim postignutim primenom naltreksona, referentnog leka u terapiji poremećaja unosa alkohola.The present study aimed to investigate whether acute treatment with XHe‐III‐74, a novel positive modulator of α4‐GABAA receptors, may reduce alcohol intake in mouse model of „drinking in the dark” (DID). All experiments were conducted on adult C57BL/6 mice. Potential sedative properties of XHe‐III‐74, (0.5, 2 or 5 mg/kg, i.p.) were assessed using spontaneous locomotor activity (SLA) test. On the 1st day of one DID cycle each animal had 2‐h access to ethanol (20%, v/v), on the 2nd day treatment was given 20 min before the access to ethanol, while on the 3rd day the animal was not treated in any way. In all DID experiments each animal passed through four cycles and respectively receive one of three treatment doses or solvent in each cycle. In Experiment 1 we tested whether XHe‐ III‐74 (0.8, 2 or 5 mg/kg) had any effects on water intake (n=12 per treatment dose), while in Experiment 2, the same doses were used to test potential decrease of ethanol intake (n=14). Effects of the reference drug, naltrexone (1; 4 and 16 mg/kg) were tested in Experiment 3 (n=21). In the SLA test, none of the selected XHe‐III‐74 doses decreased the distance traveled (F3,20=0.48; p=0.703). In DID Experiment 1, XHe‐III‐74 treatment didn’t affect water intake (F33,3=0.39; p=0.763). Ethanol intake, measured in Experiment 2, was affected by XHe‐III‐74 treatment (F39,3=7.41; p<0.001), with 5 mg/kg XHe‐III‐74 significantly reducing the intake relative to control (p<0.001). In Experiment 3, naltrexone significantly affected the intake of ethanol (F60,3=22.18; p<0.001), with all three doses reducing the intake: 1 mg/kg (p<0.001); 4 mg/kg (p<0.001) and 16 mg/kg (p<0.001). With expected lack of sedative actions, XHe‐III‐74, a positive modulator of α4‐ GABAARs, exhibited a clear potential for decreasing ethanol intake in mouse DID model, comparable to that of naltrexone, a reference drug in alcohol use disorder.VII Kongres farmaceuta Srbije sa međunarodnim učešćem: Zajedno stvaramo budućnost farmacije, Beograd, Srbija, 10-14. oktobar 2018

Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide

We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with alpha 5 GABA(A) receptors (alpha 5GABA(A)Rs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of alpha 5GABA(A)Rs in offspring's preadolescence (from postnatal day 22-28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6 h after LPS treatment (100 mu g/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of alpha 5GABA(A)Rs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of alpha 5GABA(A)Rs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero

Pituitary-gonadal, pituitary-adrenocortical hormones and IL-6 levels following long-term magnesium supplementation in male students

Background: Sleep deprivation, malnutrition and lack of physical activity are contemporary stress-related factors present in the student population. Stress activates the HPA and often suppresses the HPG axis, but also influences cytokine synthesis and consequently regulates immune response. Since magnesium deficiency facilitates negative pathophysiological consequences, a reasonable question imposes, wheth er Mg supplementation might correct the adrenal/go nadal hormone balance and immuno-endocrine function. Methods: Fifteen male students were given 2 x 250 mg Mg for four weeks. Serum levels of FSH, LH, testosterone (T), ACTH and cortiso

Magnesium Supplementation Diminishes Peripheral Blood Lymphocyte DNA Oxidative Damage in Athletes and Sedentary Young Man

Sedentary lifestyle is highly associated with increased risk of cardiovascular disease, obesity, and type 2 diabetes. It is known that regular physical activity has positive effects on health; however several studies have shown that acute and strenuous exercise can induce oxidative stress and lead to DNA damage. As magnesium is essential in maintaining DNA integrity, the aim of this study was to determine whether four-week-long magnesium supplementation in students with sedentary lifestyle and rugby players could prevent or diminish impairment of DNA. By using the comet assay, our study demonstrated that the number of peripheral blood lymphocytes (PBL) with basal endogenous DNA damage is significantly higher in rugby players compared to students with sedentary lifestyle. On the other hand, magnesium supplementation significantly decreased the number of cells with high DNA damage, in the presence of exogenous H2O2, in PBL from both students and rugby players, and markedly reduced the number of cells with medium DNA damage in rugby players compared to corresponding control nonsupplemented group. Accordingly, the results of our study suggest that four-week-long magnesium supplementation has marked effects in protecting the DNA from oxidative damage in both rugby players and in young men with sedentary lifestyle

Deciphering ciprofloxacin-induced neurotoxicity: behavioral and molecular profiling of ciprofloxacin treatment in rats

Introduction: Ciprofloxacin is a fluoroquinolone antibiotic commonly used to treat various bacterial infections, with a potential to induce adverse mood effects in patients. Since the molecular mechanism of ciprofloxacin-induced neurotoxicity is poorly understood, we aimed to identify behavioral changes and corresponding neurotransmitter pattern after its prolonged administration in rats. We screened for untoward effects of ciprofloxacin on locomotor activity, despair, anhedonia, object recognition memory, and anxiety, as behavioral domains affected in various psychiatric diseases. Methodology: Three-month old male Sprague-Dawley rats were orally gavaged with ciprofloxacin (20 or 100 mg/kg) or solvent (0.5% methyl cellulose solution) each day for 4 weeks (n=80). One group of animals (n=40) passed the open field (OF), novel object recognition test (NORT), and forced swimming test (FST). Another group (n=40) underwent elevated plus maze (EPM) and sucrose preference test (SPT). After the completion of behavioral battery, the prefrontal cortex and cerebrospinal fluid (CSF) were collected. The neurotransmitters and metabolites of the kynurenine pathway were determined in the prefrontal cortex (PFC) through HPLC-MS/MS. Additionally, levels of interleukin-2 (IL-2) in CSF were quantified with Luminex. Behavioral and molecular parameters were analyzed by one-way ANOVA followed by Dunnett post hoc test in GraphPad Prism 9. Results: In FST, the treatment with high dose of ciprofloxacin decreased the swim time compared to control, which could be related to induction of despair-like behavior (p<0.05). The ciprofloxacin treatment did not affect object memory in NORT. In OF, the distance travelled and the number of rotations were not changed after treatment with ciprofloxacin compared to the control group. Further, animals treated with ciprofloxacin did not show changes in parameters in EPM and SPT. The acetylcholine levels in PFC were increased after ciprofloxacin treatment (p<0.05) in comparison with controls, which could be associated with depressed mood states. In line with that, high dose of ciprofloxacin treatment showed the tendency to decrease and increase levels of GABA and dopamine, respectively, but without reaching the statistical significance (p=0.07 and p=0.06). No changes in kynurenine pathway were observed after the treatment. The IL-2 concentration in CSF was increased after prolonged administration of low dose of ciprofloxacin treatment compared to the control levels (p<0.05), which could imply immunological stimulation of T lymphocytes and potential neuroinflammation. Conclusion: The despair behavior after treatment with high dose of ciprofloxacin was accompanied by increased levels of acetylcholine in PFC. Furthermore, the high dose of ciprofloxacin treatment showed tendency to decrease GABA levels, and increase dopamine levels in PFC, which could be connected to psychiatric adverse effects. Nonetheless, further studies are essential to confirm these neurotransmitter changes. On the other hand, the low dose of ciprofloxacin treatment elicited the increase of IL-2, which could be a marker of neuroinflammation-related neurotoxicity. In the future, efforts should be made to examine the role of IL-2 in the interaction of the immune system and the central nervous system, as its potential significance as a biomarker

Duration of treatment and activation of alpha(1)-containing GABA(A) receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats

Long-term use of benzodiazepine-type drugs may lead to physical dependence, manifested by withdrawal syndrome after abrupt cessation of treatment. The aim of the present study was to investigate the influence of duration of treatment, as well as the role of alpha(1)-containing GABA(A) receptors, in development of physical dependence to diazepam, assessed through the level of anxiety and susceptibility to pentylenetetrazole (PTZ)-induced seizures, 24 h after withdrawal from protracted treatment in rats. Withdrawal of 2 mg/kg diazepam after 28, but not after 14 or 21 days of administration led to an anxiety-like behavior in the elevated plus maze. Antagonism of the diazepam effects at alpha(1)-containing GABA(A) receptors, achieved by daily administration of the neutral modulator beta CCt (5 mg/kg), did not affect the anxiety level during withdrawal. An increased susceptibility to PTZ-induced seizures was observed during diazepam withdrawal after 21 and 28 days of treatment. Daily co-administration of beta CCt further decreased the PTZ-seizure threshold after 21 days of treatment, whilst it prevented the diazepam withdrawal-elicited decrease of the PTZ threshold after 28 days of treatment. In conclusion, the current study suggests that the role of alpha(1)-containing GABA(A) receptors in mediating the development of physical dependence may vary based on the effect being studied and duration of protracted treatment. Moreover, the present data supports previous findings that the lack of activity at alpha(1)-containing GABA(A) receptors is not sufficient to eliminate physical dependence liability of ligands of the benzodiazepine type

Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: The approximated activation of receptor subtypes may explain behavioral effects

Enormous progress in understanding the role of four populations of benzodiazepine-sensitive GABA(A) receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently nonselective modulators. We report on SH-I-048A, a newly synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2 mg/kg diazepam. SH-I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10 mg/kg dose of the novel ligand and 2 mg/kg diazepam; however, SH-I-048A was relatively more active at and as-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24 h after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at al-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the as subunit. The current results encourage further innovative approaches aimed at linking in vitro an in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands