DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW AGENTS TARGETING ESTROGEN RECEPTOR-ALPHA AND -BETA

The two known estrogen receptors, ERa and ERb, are the products of different genes on separate chromosomes. Of these, ERa has been the most extensively studied, and its expression in breast cancer determines the ER+ phenotype. ERb, on the other hand, was discovered only recently and its role in breast cancer pathology remains unclear. ERb inhibits E2-induced proliferation of T47D breast cancer cells in addition to decreasing the expression of cell cycle related genes. Clinical studies have shown a positive correlation between ERâ expression with disease-free survival and overall survival in breast cancer patients. ERb activation with a selective ERb agonist could antagonize the stimulating activity of the ERa in breast cancer cells, and such an ERb agonist could help overcome acquired resistance. Therefore, this work began a search for such agents. A one-pot hydrozirconation-transmetallation-aldimine addition sequence that leads to allylic amides, homoallylic amides and C-cyclopropylalkylamides was significantly accelerated by microwave technology and used for library preparation. The conventional methodology provided a first generation discovery library. A potentially antiestrogenic compound was identified in a transcriptional screening assay from this library, C-cyclopropylalkylamide 26a (O-ethyl-N-{2-[(1S*,2R*)-2-{(R*)[(diphenylphosphinoyl)amino](phenyl)methyl}cyclopropyl]-ethyl}-N-[(4-methylphenyl)sulfonyl]carbamate; a.k.a. CK1-183).Following up on these findings and with the goal to expand the scope of the synthesis methodology, a second generation library of allylic amides and C-cyclopropylalkylamides was prepared. The new library was screened in a fluorescence polarization based homogenous in vitro assay at ERa, and hits were further evaluated in cell-based assays. Three new C-cyclopropylalkylamides, 37c, 37a and 39c, were identified with improved potency over the lead agent 26a against 17b-estradiol (E2) stimulated MCF-7 cells. This second generation library was screened against both ERs. The screening results served to build an SAR model of allylic amides and C-cyclopropylalkylamides at ERa and ERb. A hit from the ERa screen, C-cyclopropylalkylamide 37d (N-(R*)-(((1R*,2R*)-2-butylcyclopropyl)-(4-(phenyl)phenyl)methyl)benzamide), contained a biphenyl core and served as a starting point for the design and synthesis of a third generation of C-cyclopropylalkylamide ER targeting agents. Biphenyl C-cyclopropylalkylamides represent novel structural scaffolds for design and synthesis of ERa and ERb targeting agents and a novel avenue for selective estrogen receptor modulator (SERM) development

MULTI–CRITERIA HOME ENERGY MANAGEMENT SYSTEM SELECTION FOR THE SMART GRID SUPPORT

Home energy management systems (HEMS) are increasingly used as a tool that creates optimal consumption and production schedules for Smart Grids, by considering objectives such as energy costs, environmental concerns, load profiles, and consumer comfort. Multiple criteria selection of optimal HEMS seems to be superior to the traditional cost benefit assessment in measuring intangibles and soft impacts, introducing qualitative aspects in the analysis. This paper proposes an algorithm for the selection of optimal HEMS, using the fuzzy AHP method. This methodological framework provides a multi-criteria approach for estimating the benefits and costs of different HEMS within the Smart Grid uncertain environment. This method allows the decision makers to incorporate unquantifiable, asymmetrical, incomplete, non-obtainable information and partially ignorant facts into a decision model. Four criteria and eleven performances for the optimal solution selection are defined. The method is successful in the evaluation of alternatives in the presence of heterogeneous criteria and uncertain environment. The methodology is illustrated on the choice of HEMS from the power distribution company perspective. It is concluded that the evaluation of weighting factors has a decisive character in the choice of the final one of several alternative variants. Fuzzification of input values can also contribute to a more flexible view of the given problem and analysis of sensitivity to various input parameters

Consumer Responsibility for Food Safety

Nowadays, food safety and quality have a key role in maintaining the health of consumer, as the ultimate link in the food chain. Foodborne diseases can be a problem for every individual, but are particularly important to children, the elderly, and immunocompromised individuals. Although food hygiene experts widely accept many cases of foodborne disease occur as a result of improper food handling and preparation by consumers, the consumers themselves are still not aware of this fact. Correct personal hygiene measures are a well known step facilitating reductions in the risk of these diseases. However, actual implementation of personal hygiene and sanitation behaviors at home remains insufficient. The aim of many studies is to assess consumers’ knowledge of food security and to determine whether that knowledge is applied in practice. Such information can be of great help to professionals who deal with education of consumers about food safety, should help promote the principle among consumers that they themselves have a critical role in reducing the risk of foodborne disease

Koncentracija metala u mišićnom tkivu riba iz različitih ribnjaka

Riba predstavlja važan deo ljudske ishrane, a takođe, riba je dobar pokazatelj kontaminacije životne sredine od strane jednog broja supstanci, uključujući i tragove metala u slatkovodnim sistemima, posebno zbog toga što se ribe, kao tercijelni potrošači, nalaze na vrhu lanca ishrane u vodenom ekosistemu (Noël i sar., 2013). Mnogo pažnje posvećeno je elementima kao što su olovo (Pb), kadmijum (Cd), Živa (Hg) i Arsen (As) i efekti izloženosti ovim elementima su sveobuhvatno istraženi (Castro-González and Méndez-Armenta, 2008; Has-Schön et al., 2008). Zbog svoje toksičnosti, otpornosti i bioakumulacije u vodi i sedimentima, kada se nalaze u visokim koncentracijama, ovi elementi predstavljaju opasnost za sve žive organizme. U pogledu bezbednosti javnog zdravlja, kod riba, prate se koncentracije olova, kadmijuma i žive, gde postoje jasno definisani maksimalni nivoi teških metala u namirnicama koji su određeni od strane Evropske Komisije, br. 1881/2006 (EC, 2006), izmenjena i dopunjena EC 629/2008 (EC, 2008). Za arsen, maksimalni nivo još nije uspostavljen na evropskom nivou, ali se očekuje da će granične vrednosti za arsen biti postavljene u bliskoj budućnosti, kao i metode za određivanje arsena (Noël et al., 2013). Za utvrđivanje koncentracije teških metala u tkivu riba prikupljeno je deset uzoraka dve različite vrste riba - šarana (Cyprinus carpio) i evropske ili severne štuke (Esox lucius). Uzorci su ulovljeni od strane profesionalnih ribara tokom rane jeseni 2013. godine iz četiri različita ribnjaka na području Beograda. Dobijeni rezultati su izraženi kao srednja vrednost ± standardna devijacija. Statistička analiza je urađena je korišćenjem Studentovog t-testa i analizom varijanse (ANOVA) sa višestrukim poređenjem Turkey test za utvrđivanje značajnih razlika između srednjih vrednosti. Primenjen je nivo značajnosti od 0.01 i 0.05. U različitim ribnjacima, koncentracija metala u mišićnom tkivu šarana je varirala u zavisnosti od vrste metala. Između sva četiri poređena ribnjaka nije utvrđena statistički značajna razlika jedino u koncentraciji kadmijuma u mišićnom tkivu. U ostalim slučajevima poređenja utrvđene su statistički značajne razlike (p<0.01). Koncentracija metala u mišićnom tkivu štuke razlikovala se između ribnjaka, zavisno od vrste metala. U svim slučajevima poređenja utvrđene su statistički značajne razlike (p<0.01). Koncentracija olova u mišićnom tkivu štuke u svim poređenim ribnjacima bila je statistički značajno veća (p<0,01) u odnosu na koncentraciju olova u mišićnom tkivu šarana. Koncentracija kadmijuma u mišićnom tkivu štuke bila je statistički značajno veća (p<0,01; p<0,05) od koncentracije kadmijuma u mišićnom tkivu šaran u svim poređenim ribnjacima. Za razliku od koncentracije olova i kadmijuma, koncentracija žive u mišićnom tkivu štuke u poređenim ribnjacima bila je statistički značajno niža (p<0,01) u odnosu na koncentracije žive u mišićnom tkivu šarana. Koncentracija arsena bila je statistički značajno veća (p<0,01) u mišićnom tkivu šarana od koncentracije arsena u mišićnom tkivu štuke. Rezultati koncentracija ispitanih elemenata u mišićnom tkivu riba pokazuju varijacije u opsegu koji se čini tipičan za ribnjake u Srbiji, ali su ove koncentracije niže od onih u rekama sa značajnim antropogenim uticajem

Koncentracija metala u vodi i sedimentu reke Dunav

Voda je osnov opstanka živog sveta koji je u njoj i nastao. Dve trećine zemljine površine je pod vodom. Bez obzira na značaj vode na opstanak živog sveta ljudska vrsta prema vodi nema odgovarajući odnos. O tome govore podaci o zagađenju okeana, mora, vodotokova (reke, potoci) i jezera. Antropogeno zagađenje vode, dakle, poreklom od čoveka, javlja se kao posledica direktnog ili indirektnog ispuštanja zagađivača u vodu, bez adekvatnog postupka sa štetnim i opasnim jedinjenjima. Najčešći zagađivači vode posledica su otpadnih voda i voda koje dolaze sa površina zemlje (naročito obradivih površina). Zagađenost vode je blisko povezana za povećanim potrebama stanovništva za vodenim resursima. Povećane potrebe rastu sa porastom stanovništva, razvoja privrede i tehnologije. Veća potrošnja vode znači i veću količinu otpadnih voda. Dospevanjem u reke otpadne vode menjaju fizička (boja, miris, ukus, providnost), hemijska (sastav) i biološka svojstva (živi svet reka). Naša zemlja nema odgovarajuće propise za procenu kvaliteta sedimenta pa se, zbog toga, koriste standardi kvaliteta prema kanadskom zakonodavstvu, preporuke ICPDR-a (International Commission for the Protection of the Danube River ), a pojedini parametri se procenjuju korišćenjem holandske metodologije. Prema kanadskom zakonodavstvu definisane su dve vrednosti: niža vrednost ISQGs (Interim Sediment Quality Guideline) predstavlja privremene preporuke koje su dobijene teorijskim putem i iznad kojih je moguć uticaj na akvatične organizme, dok je druga, viša, vrednost PEL (Probable Effect Level), vrednost iznad koje je uticaj na akvatične organizme verovatan. Poređenjem sa kanadskim preporukama, sadržaj žive je prekoračen na skoro svim ispitanim lokalitetima, prema ISQG vrednosti. Viša PEL vrednost ukazuje na verovatno prisutne negativne toksične efekte na akvatične organizme i sedimente u dva ispitivana profila u Dunavu (profil A i profil B). Pojava žive u sedimentu je posledica ispuštanja industrijskih otpadnih voda (naročito iz pogona za proizvodnju hlora), upotrebe živinih pesticida za zaštitu semena, upotrebe živinih jedinjenja u upaljačima eksplozivnih sredstava (posledice ratnog konflikta 1999.godine) i upotreba žive u mernim uređajima (u toku razaranja industrijskih postrojenja za vreme konflikta 1999. godine uništen je deo ove merne opreme). Arsen je poznat po negativnim ekotoksičnim efektima, a negov sadržaj u sedimentu reke Dunav nije bio iznad ICPDR vrednosti. Sadržaj drugih teških metala, cinka, bakra, kadmijuma i olova (profil B) je bio u ispod vrednosti propisane ICPDR. Kako se sam proces zagađivanja vode teško može sprečiti, zaštita voda, prvenstveno, je usmerena na smanjenje uticaja, a u najboljem slučaju, potpuno uklanjanjanje uticaja teških metala. To se postiže kroz opšte ekološke (radne akcije, ekološki aktivizam) kao i specifične mere (obrazovanje, sredstva javnog informisanja). Najvažnije je utvrđivanje kvaliteta vode i mogućnosti vodotoka da primi otpadne vode, registovanje svih mogućih zagađivača (njihova lokacije i stepen zagađivanja), obavljanje stalnih kontrola otpadnih voda u blizini vodotokova, prečišćavanje otpadnih voda i izmeštanje industrije na mesta na kojima će zagađivanje biti minimalno

Alergenski proteini u ribi

Riba predstavlja znatan deo ishrane ljudi u svetu. Pre svega, riba je značajan izvor proteina (15-24%) visoke biološke vrednosti, bogata je mineralima, vitaminima, a posebno esencijalnim masnim kiselinama za koje je dokazano da pogoduju u prevenciji mnogobrojnih oboljenja. Zbog velikog značaja polinezasićenih masnih kiselina n-3 klase, u Evropi su date i preporuke o optimalnom dnevnom unosu. Međutim, pored hranljivih svojstava koje ima, riba može biti i izvor različitih bioloških i hemijskih opasnosti. Od bioloških opasnosti posebno su značajni paraziti (Trematodae, Nematodae, Cestodae), bakterije (Salmonella spp, E. coli, Vibrio parahemolyticus, Vibrio vulnificus, Listeria monocytogenes, Clostridium botulinum, Staphyloccocus aureus), virusi (Norwalk virus, Entero virusi, Hepatitis A, Rotavirus) i biotoksini. Najznačajnije hemijske opasnosti su policiklična aromatična jedinjenja, histamin i teški metali (živa, olovo, kadmijum, arsen, gvožđe). Alergije usled konzumiranja pojedinih vrsta namirnica su u porastu poslednjih godina. Veliki pokret oko pravilnog načina ishrane je doveo do toga da ljudi sve češće konzumiraju ribu, proizvode od ribe kao i različite plodove mora. Pored različitih opasnosti koje mogu poticati iz ribe, posebni značaj poslednjih godina se daje ribi kao potencijalnom alergenu. Naime, veliki broj alergija koje se javljaju u svetu pripisuju se alergenima koji potiču iz mesa ribe, pre svega proteinima mesa ribe. Učestalost alergija koje se povezuju za unosom mesa ribe varira u Evropskim zemljama (Norveška 1,5%; 2,3% Turska, 2,3% Grčka; Švedska 1.2-3.2 %). Kao najznačajniji proteinski alergen iz mesa ribe navodi se parvalbumin (ß tip), koji je izolovan kod velikog broja vrsta. Smatra se da su šaran i bakalar najčešći izvori parvalbumina koji se dovodi u vezu sa različitim vidovima alergijskih reakcija. Potencijalni alergeni su takođe kolagen i želatin koji su izolovani iz kože i pojedinih organa riba. Takođe, značajan alergen iz plodova voda je i tropomiozin, arginin kinaza, aldolaza. Pored ovih alergena, značajni alergeni mogu da potiču iz ikre, pojedih vrsta kavijara, a opisani su slučajevi gde su alergijske reakcije povezane sa kolagenom koji se nalazi u ekstracelularnom matriksu proteina. Alergeni koji dovode do različitih alergijskih reakcija, pored proteina mesa ribe, mogu poticati i od gotovih proizvoda od ribe. Tu spadaju različiti panirani proizvodi od ribe koji sadrže celer, gluten i druge dodatke koji mogu biti potencijalni alergeni. Zbog značaja koji imaju na zdravlje ljude, tehnologija je omogućila različite metode za detekciju ovih alergena. Kao neke od njih navode se ELISA (Enzyme-linked immunosorbent assay), RAST (Radioallergosorbent test) i RIE (Rocket Immuno-electrophoresis). Koja će se metoda detekcije primeniti, prvenstveno zavisi od dostupnosti alergena i praga njegove detekcije. Industija mesa je razvojem tehnologije uvela pojedine tehnološke prosece koji imaju mogućnost inaktivacije pojedinih alergena, pre svega proteina mesa ribe. Visoke temperature koje se primenjuju u obradi mesa ribe mogu uticati na ove alergene, tako što će smanjiti alergeni potencijal, dok neki tehnološki postipci nemaju tu mogućnost

Summer undergraduate research: A new pipeline for pain clinical practice and research

BACKGROUND: Most medical schools fail to provide adequate training of clinicians in the treatment of pain. Similarly, despite the fact that over 1/3 of Americans suffer from chronic pain, National Institutes of Health (NIH) funding for pain represents only ~1 % of the NIH budget. These issues may dissuade students from pursing pain in their clinical and research careers. To address these gaps in training and funding, we argue that exposing students to pain science early in their careers, at the undergraduate level, may be an effective method to develop a pipeline for future pain clinicians and scientists. To highlight our argument, we will describe our recent successful implementation of a cross-disciplinary and community-engaged biomedical summer research program. The Pain Undergraduate Research Experience (PURE) summer program involved both off-site and on-site experiences to expose undergraduate students to the range of careers in the pain field from basic science to clinical practice. The objective of the 10-week long PURE program was to evaluate whether a combination of basic science research, clinical practice visits, and patient interactions would increase student understanding of and exposure to the underlying science of pain. METHODS: A pre-post cohort study was used without a comparison group. Entry and exit surveys were used to evaluate students’ perceptions about pain clinical practice and research, student interest in pain, and student confidence about communicating about pain and doing basic science pain research. RESULTS: Students reported significant increases to a number of questions in the survey. Questions were scored on 5 point Likert scales and there was significant increases in student understanding of what life is like with chronic pain (2.6 vs 4.3 post survey), their confidence in explaining pain to a patient (2.8 vs 4.1) or researcher (2.8 vs 4), and their comfort with pain terminology(2.8 vs 3.9). CONCLUSIONS: With the PURE program, we wanted to entice top undergraduates to consider pain as a future area of study, practice, and/or research. We present a model that can be easily implemented at research universities throughout the United States

Characterisation of Bosnia and Herzegovina honeys according to their physico-chemical properties during 2016-2017

This study evaluated the quality of 78 honeys of six different floral types (Acacia, sage [Salvia officinalis L.], linden, chestnut, honeydew and blossom), mainly from Bosnia and Herzegovina. Reducing sugars, sucrose content, moisture, hydroxymethylfurfural (HMF), free acidity, water-insoluble content, diastase activity, electrical conductivity were analysed. The samples of honey, collected during 2016-2017, were analysed using recommended methods. Results show that in 2016 and 2017, a great number of individual honeys sampled were of insufficient quality to satisfy regulatory requirements. Among the overall determined parameters, hydroxymethylfurfural and diastase activities in some honeys were not acceptable according to national and international regulations. A correlation between free acidity and electrical conductivity was found in both acacia and blossom honeys. HMF content and diastase activity was strongly negatively correlated in both acacia and blossom honeys. The quality of the honeys was varied, based on botanical origins, and presumably, handling and storage conditions

Injectable, Reversibly Thermoresponsive Captopril-Laden Hydrogel for the Local Treatment of Sensory Loss in Diabetic Neuropathy

A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release. The ACE inhibitor captopril was encapsulated into a micelle, which was then embedded into a reversibly thermoresponsive pluronics-based hydrogel matrix. Drug-free and captopril-loaded hydrogels demonstrated excellent product stability and sterility. Rheology testing confirmed sol properties with low viscosity at ambient temperature and increased viscosity and gelation at 37 °C. Captopril-loaded hydrogels significantly inhibited Ang II production in comparison to drug-free hydrogels. DPN mice treated with captopril-loaded hydrogels displayed normalized mechanical sensitivity and reduced inflammation, without side-effects associated with systemic exposure. Our data demonstrate the feasibility of repurposing ACE inhibitors as locally delivered anti-inflammatories for the treatment of sensory deficits in DPN. To the best of our knowledge, this is the first example of a locally delivered ACE inhibitor for the treatment of DPN