Evaluating the genotoxic potential of oligonucleotide pharmaceuticals

According to regulatory guidelines, routine genotoxicity tests are not appropriate for biotechnology derived pharmaceuticals, including oligonucleotide based therapeutics, as they are not expected to interact with genomic DNA. However, reports of oligonucleotides capable of binding duplex DNA in a sequence specific manner to form triple-helix (triplex) or displacement-loop (D-loop) structures that in turn cause mutation have raised concern. The European Medicines Agency (EMA) has questioned the capability of antisense oligonucleotide (ASO) therapeutics to form such structures at genomic DNA. Additionally, concern has been expressed regarding the fate of chemically modified ASO degradation products (nucleotide analogues). It is well established that non-canonical antiretroviral nucleoside analogues, employed in antiretroviral therapy, result in gross chromosome aberrations following incorporation into genomic DNA. This study has addressed these concerns by evaluating the genotoxic potential of a triplex forming oligonucleotide (TFO) and a D-loop forming ASO targeting genomic DNA. Furthermore, the incorporation efficiency and genotoxicity of nucleotide analogues derived from ASO degradation was investigated. Data presented here demonstrate a TFO targeting genomic DNA was not capable of inducing mutation above the detection limit of this assay. However, a biologically active ASO molecule induced sequence specific mutation ~4.4 fold above control in a system where RAD51 protein expression was induced. Additionally, DNA polymerase was capable of incorporating various ASO derived nucleotide analogues into a primed DNA template with reduced efficiency. Treatment with phosphorothioate nucleotide analogue, one of the most common chemical modifications used in ASO design, induced mutation ~100 fold above control. To conclude, ASO and their putative degradation products appeared to be capable of off-target mutagenesis providing favourable conditions were met. However, as genotoxicity data has been presented for a single ASO and nucleotide analogue, it seems plausible to suggest this work can provide a foundation to test future ASO therapeutics and putative degradation products

St. Mary's Church in the village of Labova e Kryqit in Gjirokstra Analyses of the Church's Construction Stages, its Age and Some Static Issues

St. Mary's Church, which is situated in the village of Labova e Kryqit (translated as Labova of the Cross in English) and falls under the municipality of Libohova, has brought to the repertoire of the Albanian Medieval Architecture the brilliant demonstration of one of the most wonderful architectonic formulation and such a great iconographic program in terms of its functions, the decoration of the interior and exterior that it might be compared to its equals in the elite of this genre in the Byzantine culture worldwide. The architectonic type of this church is defined as a cross imprinted with the upper volumes of its arms extending up to the level of the roof. Viewed from the perspective of the formulation of the compositional core area which consists of the square structure formed by four columns with three arcades among them to create the cubic base sustaining the tambour of the dome, this type of church provides the best example of a metropolitan style of church and shares similarities with other churches alike. Similar churches are found in the complex of Theotokos Peribleptos in Constantinople, built by the famous emperor Romano III Argjiro, v.1028-1034. Oher similar churches that we can mention are also the church of Teorakos Parnrnakaristos, in Constantinople, dating from the XII century, Monastery of Saint John, in Libos (Fenari Isa Cami) in Constantinople which dates from the X-XII century, Saint George Church in Mangano, 1042-1057, etc.Keywords: St. Mary's Church, the village Labova e Kryqit, Gjirokastra, cupola, arcade, static condition, byzantine architecture; restoration

INTERNATIONAL CIVIL ADMINISTRATION AND STATE BUILDING PROCESS IN KOSOVO

Based on UN Security Council Resolution 1244 adopted on June 10, 1999 Kosovo was put under the international civil administration named UNMIK (UN mission in Kosovo). During the several years UNMIK exercised its powers in Kosovo based on four established pillars. A lots of debates were developed within the academic world about the role of UNMIK in Kosovo, its functions and especially the role it played for the process of the state building in Kosovo. A series of question were raise permanently about whether this mission was only a civil administration or it was a modern type of protectorate. Of course there were also other discussions developed regarding the UNMIK issue in Kosovo. The paper intends to explain the UNMIK mission and its legal basis with the special emphasizes the role it played in the process of Kosovo independence and the state building process. Some claim that UNMIK had a symbolic role in the process of state building whereas it had no role at all in the process of Kosovo independence. Paper analyses the entire process of UNMIK and comes up with findings as well as with the recommendations these types of international administrations should take into the consideration in the future if the need appears

Korupcija, izazov za institucije Kosova / Corruption, the challenge for Kosovo institutions

Tema ovog rada, korupcija, izazov za institucije Kosova, je vrlo široka i aktuelna tema koja obuhvata teorijski i praktični tretman. Korupcija, koja je opisana kao korištenje javne vlasti za pojedine namjene, je vrlo kompleksan pojam. To je odlika raznih društava i država, koja  posljednjih nekoliko godina, smatra se kao vrlo prisutna pojava u zemljama u tranziciji, one  nerazvijene kao i one u razvoju, navodeći kao prepreka za implementaciju demokratije. Korupcija ima tendenciju da raste brže od dinamike implementiranja za njenu neutralizaciju. Sistematski, korupcija je izazvala i nastavlja da izazive mnoge zabrinjavajuće probleme u svim zemljama svijeta, a posebno na Kosovu. Na osnovu izvještaja Transparency International-a, korupcija je jedna od najvećih izazova savremenog svijeta.Važnost proučavanja ovog problema kroz ovu temu ima za cilj prepoznati veličinu, strukturu i dinamiku ovog fenomena; da analizira sveobuhvatan utjecaj općih faktora. Na osnovu identifikacije problema korupcije, lokalnih i međunarodnih izvještaja koji zaključuju visok nivo ove vrste kriminala, pored drugih područja i u sigurnosnim pitanjima, korupcija se vidi kao ozbiljna rana za naše društvo. Obrazloženje ovog rada je logična posljedica fenomena korupcije u Republici Kosovo.Uzroci, posljedice i borba protiv korupcije su uvijek predmet brojnih istraživanja i razgovora među istraživačima, političarima i drugim akterima koji se bave ovim problemima, ne ostavljajući sa strane i segmentia civilnog društva. Ovi problemi predstavljaju predmet proučavanja ovog rada iz moje perspektive sa namerom da bi se pridružio opšte zabrinutosti zbog ove pojave.Tokom ovog studija će se koristiti različite metodologije, kao metodologija analize slučajeva korupcije, metoda komparativne analize, komparativne metode i statističke metode pojave i borbe protiv korupcije na Kosovu za godine 2012-2014.Za borbu i sprečavanje korupcije, društvo i institucije Kosova, pored preventivnih mjera, bi trebala provesti dostignute mjere iz nauke kriminalistike na osnovu savremenih trendova u sigurnostnom menadžmentu. Krajnji cilj ovog rada je utjelovljenje ili praktična primjena njegovih rezultata i statistike u naporima društva da spriječi, ograničuje i eliminira pojavu korupcije na Kosovu.----------------------------The theme of this paper, corruption, the challenge for Kosovo institutions is a very broad and actual topic, which includes both theoretical and the practical handling. Corruption, which is described as the use of public power for individual purposes is a very complex concept. It is a feature of different societies and countries. In recent years it is considered as a very present phenomenon in transition countries, the least developed ones as well as developing countries, stating corruption as an obstacle to the implementation of democracy. Corruption tends to grow faster than the dynamics implemented to neutralize it. Systematically, it has caused and continues to cause many stressing problems in all countries of the world and especially in Kosovo. Based on a report of the Transparency International, corruption is one of the biggest challenges of the contemporary world.The importance of the study of this problem through this topic aims to recognize the size, structure and dynamics of this phenomenon; to analyze comprehensively the impact of general factors. Based on the identification of the problem of corruption, and local and international reports which establish a high level of this type of crime besides other areas in security issues, corruption is seen as a serious wound for our society. Rationality of this paper is the logical consequence of the corruption phenomenon in the Republic of Kosovo.Causes, consequences and fighting against corruption are always subject to numerous studies and discussions among researchers, politicians and other stakeholders dealing with these problems, not leaving out the segments of civil society. These concerns constitute the object of study of this paper from my perspective in order to join the general concern over this phenomenon.During this study, different methodologies will be used, as follows: methodology of the analysis of corruption cases, the method of comparative analysis, comparative methods and statistical methods of presenting and combating corruption in Kosovo for 2012-2014.For combating and preventing corruption, Kosovo society and institutions, in addition to preventive measures, should implement the measures of science of criminology achieved by contemporary trends in safety management. The ultimate goal of this work is the materialization or practical application of its results and statistics in the society efforts to prevent, limit and eliminate the phenomenon of corruption in Kosovo

Experimental Bariatric Surgery in Rats Generates a Cytotoxic Chemical Environment in the Gut Contents

Bariatric surgery, also known as metabolic surgery, is an effective treatment for morbid obesity, which also offers pronounced metabolic effects including the resolution of type 2 diabetes and a decrease in cardiovascular disease and long-term cancer risk. However, the mechanisms of surgical weight loss and the long-term consequences of bariatric surgery remain unclear. Bariatric surgery has been demonstrated to alter the composition of both the microbiome and the metabolic phenotype. We observed a marked shift toward Gammaproteobacteria, particularly Enterobacter hormaechei, following Roux-en-Y gastric bypass (RYGB) surgery in a rat model compared with sham-operated controls. Fecal water from RYGB surgery rats was highly cytotoxic to rodent cells (mouse lymphoma cell line). In contrast, fecal water from sham-operated animals showed no/very low cytotoxicity. This shift in the gross structure of the microbiome correlated with greatly increased cytotoxicity. Urinary phenylacetylglycine and indoxyl sulfate and fecal gamma-aminobutyric acid, putrescine, tyramine, and uracil were found to be inversely correlated with cell survival rate. This profound co-dependent response of mammalian and microbial metabolism to RYGB surgery and the impact on the cytotoxicity of the gut luminal environment suggests that RYGB exerts local and global metabolic effects which may have an influence on long-term cancer risk and cytotoxic load

Doprinos poznavanju faune porodice ljiljaka (Lepidoptera, Sphingidae) u Republici Sjevernoj Makedoniji

Analysis of literature data, data from entomological collections in the Museum of Natural History (SKO), Nikola Nezlobinski Museum in Struga (NNS), the Scientific Tobacco Institute in Prilep (STP) and the Faculty of Agricultural Sciences and Food in Skopje (FASF) and our research,showed that the family Sphingidae is well investigated in the Republic of North Macedonia, and represented by 25 species, or 62.5% of the European fauna. The subfamily Macroglossinae is represented by 10 genera and 17 species, the subfamily Smerinthinae is represented by 4 genera and 4 species and the subfamily Sphinginae is represented by 4 genera and 4 species. Three species are reported for the first time for the fauna of North Macedonia: Hyles gallii (Rottemburg 1775), Hyles nicaea (de Pruner 1798) and Hyloicus pinastri Linnaeus, 1758.Analizom literaturnih podataka, podataka iz zbirki Prirodoslovnog muzeja u Skoplju (SKO), Muzeja Nikola Nezlobinski u Strugi (NNS), Znanstvenog duhanskog instituta u Prilepu (STP), Fakulteta za poljoprivredu i hranu u Skoplju (FASF) te vlastitim terenskim istraživanjima, utvrđeno je da je porodica Sphingidae dobro istražena i da je za područje Republike Sjeverna Makedonija utvrđeno 25 vrsta, 62,5% europske faune. Potporodica Macroglossinae zastupljena je s 10 rodova i 17 vrsta, potporodica Smerinthinae s 4 roda i 4 vrste i potporodica Sphinginae s 3 roda i 4 vrste. Pregledom zbirki tri vrste utvrđene su kao nove za faunu Makedonije: Hyles gallii (Rottemburg 1775), Hyles nicaea (de Pruner 1798) i Hyloicus pinastri Linnaeus, 1758

Mutagenesis by an antisense oligonucleotide and its degradation product.

The European Medicines Agency has expressed concern regarding (1) the potential for antisense oligonucleotide (ASO) therapeutics to induce sequence-specific mutation at genomic DNA and (2) the capability of ASO degradation products (nucleotide analogues) to incorporate into newly synthesized genomic DNA via DNA polymerase and cause mutation if base pairing occurs with reduced fidelity. Treating human lymphoblastoid cells with a biologically active antisense molecule induced sequence-specific mutation within genomic DNA over fourfold, in a system where RAD51 protein expression was induced. This finding has implications for ASO therapeutics with individuals with an induced DNA damage response, such as cancer patients. Furthermore, a phosphorothioate nucleotide analogue potently induced mutation at genomic DNA two orders of magnitude above control. This study shows that a biologically active ASO molecule can induce heritable sequence alterations, and if degraded, its respective analogue may incorporate into genomic DNA with mutagenic consequences. © The Author 2012. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved

ROLE AND OPERATIVE IMPORTANCE OF APPLICATION OF CRIMINAL PROCEDURES DURING THE INVESTIGATION OF ORGANIZED CRIME IN KOSOVO

The application of forensic procedures during the process of investigating organized crime in Kosovo requires a deeper empirical study and broader research of the scientific literature than has been done so far. The failure of many organized crime cases in the courts of Kosovo and the small and acquittal sentences are real indications that the application of criminal proceedings is not properly implemented in practice. The data provided through the empirical research of this paper show that non-compliance with criminal procedures marks a decrease in efficiency and a significant increase in organized crime cases. Through this research we aim to identify possible factors that affect the growth of the phenomenon of crime and the reflection of institutions dealing with the prevention and combating of crime. According to the observation the author suspects that the starting point of criminal proceedings regardless of the degree of probability is extremely important for the fight against crime, especially the fight against modern forms characterized by a high degree of organization, professionalism, specialization and secrecy. This paper reflects the detailed theoretical research of the scientific literature by various local and foreign authors and experts who have written about forensic procedures, research and analysis of theoretical and practical data on the meaning and importance of applying forensic procedures in detection. of organized crime in Kosovo are of particular importance to investigators of organized crime in the future. The effectiveness of forensic procedures in order to detect organized crime in Kosovo should be closely related to criminalistics, criminology and criminal policy, the implementation of forensic procedures should in principle aim to return the basis of suspicion to the highest level of suspicion. This activity begins with the appearance of the basis of suspicion or the highest form of suspicion in the form of orientation and elimination indications. The same activity consists of forensic control and processing. The content and strategy of these activities determine their further course, as well as condition the range of rules of forensic science in a specific case based on the provisions of the Code of Criminal Procedure, as well as other provisions of laws and bylaws. The strategy and tactics of these activities are dictated by the type of criminal offense

Të dhëna të reja mbi arkitekturën e manastirit të Shën Kollit në Mesopotam / New Data on the Architecture of St. Nicholas Monastery at Mesopotam

Gega Reshat. Të dhëna të reja mbi arkitekturën e manastirit të Shën Kollit në Mesopotam / New Data on the Architecture of St. Nicholas Monastery at Mesopotam. In: Iliria, vol. 36, 2012. pp. 297-341