Generalizations and challenges for the spacetime block-diagonalization

Discovery that gravitational field equations may coerce the spacetime metric with isometries to attain a block-diagonal form compatible with these isometries, was one of the gems built into the corpus of black hole uniqueness theorems. We revisit the geometric background of a block-diagonal metric with isometries, foliation defined by Killing vector fields and the corresponding Godbillon-Vey characteristic class. Furthermore, we analyse sufficient conditions for various matter sources, including scalar, nonlinear electromagnetic and Proca fields, that imply the isometry-compatible block-diagonal form of the metric. Finally, we generalize the theorem on the absence of null electromagnetic fields in static spacetimes to an arbitrary number of spacetime dimensions, wide class of gravitational field equations and nonlinear electromagnetic fields.Comment: 22 pages (slightly revised, published version

Black hole thermodynamics in the presence of nonlinear electromagnetic fields

As the interaction between the black holes and highly energetic infalling charged matter receives quantum corrections, the basic laws of black hole mechanics have to be carefully rederived. Using the covariant phase space formalism, we generalize the first law of black hole mechanics, both "equilibrium state" and "physical process" versions, in the presence of nonlinear electrodynamics fields, defined by Lagrangians depending on both quadratic electromagnetic invariants, $F_{ab}F^{ab}$ and $F_{ab}\,{\star F}^{ab}$. Derivation of this law demands a specific treatment of the Lagrangian parameters, similar to embedding of the cosmological constant into thermodynamic context. Furthermore, we discuss the validity of energy conditions, several complementing proofs of the zeroth law of black hole electrodynamics and some aspects of the recently generalized Smarr formula, its (non-)linearity and relation to the first law.Comment: 20 pages (two columns), 2 figures; ver.3: version accepted for publication in Physical Review D (several additional technical comments and references; one paragraph added to the "Discussion"

Lagrangian reverse engineering for regular black holes

Nonlinear extensions of classical Maxwell's electromagnetism are among the prominent candidates for theories admitting regular black hole solutions. A quest for such examples has been fruitful, but mostly unsystematic and littered by the introduction of physically unrealistic Lagrangians. We provide a procedure which admits the reconstruction of a nonlinear electromagnetic Lagrangian, consistent with the Euler--Heisenberg Lagrangian in the weak-field limit, from a given metric representing a regular, magnetically charged black hole.Comment: 8 page

Kolposkopija u dijagnostici premalignih i malignih promjena vrata maternice

Dugotrajna infekcija visokorizičnim tipovima humanog papiloma virusa (HPV-a) glavni je čimbenik nastajanja premalignih i malignih lezija vrata maternice. Učinkovita prevencija i kontrola bolesti zahtijeva poznavanje epidemioloških karakteristika populacije, provođenje metoda probira te otkrivanja bolesti u što ranijem stadiju odnosno predstadiju invazivne bolesti. Dijagnostičke metode koje se koriste u cilju probira uključuju citološke metode – PAPA test, mikrobiološka testiranja, HPV testiranje, HPV genotipizaciju i kolposkopiju. Korištenje novih dijagnostičkih testova zahtijeva preispitivanje uloge svih razina probira odnosno dijagnosticiranja. Usporedom smjernica različitih stručnih društava za probir i dijagnosticiranje premalignih i malignih lezija vrata maternice, kolposkopija je metoda koja određuje daljnji smjer. Cilj je ovog rada propitati važnost i ulogu kolposkopije u dijagnostici i praćenju premalignih i malignih promjena vrata maternice u sinergiji s drugim dijagnostičkim metodama

Comparison of systemic inflammatory and hematology parameters in normal C57BI/6 and genetically diabetic db/db mice during local wound repair

Uvod: Upala je početni odgovor domaćina na ozljedu. Ona nije ograničena samo na mjesto rane, nego izaziva sustavne promjene uključujući raznovrsne fiziološke i biokemijske promjene koje se skupno nazivaju odgovorom akutne faze. Ove se promjene nastavljaju tijekom rješavanja upale i procesa cijeljenja rane. U ovom ispitivanju smo usporedili serumski amiloid A protein (SAA), hematološke parametre (ukupna bijela krvna slika, postotak neutrofila i lim-focita) te koncentracije interferona-gama (IFN-γ) u serumu tijekom cijeljenja neokludirane, ekscizijske kožne rane u punoj debljini kod genetski dijabetičnih db/db miševa i nedijabetičnih C57Bl/6 miševa iz istoga legla. Materijal i metode: Područje rane izazvane „punch" biopsijom (promjera 8 mm) kod svakog je miša analizirano planimetrijski uz računalnu potporu. Trećeg, 6., 9. i 13. dana od ranjavanja SAA i IFN-g mjereni su u plazmi testovima ELISA, a hematološki parametri u punoj krvi na automatskom hematološkom analizatoru Sysmex SF 3000. Rezultati: Šestog i devetog dana jasno je zabilježeno kašnjenje u zatvaranju rane kod db/db miševa u usporedbi sa zdravim miševima. Ukupna bijela krvna slika bila je značajno viša u db/db miševa 9. i 13. dana. Kroz čitavo razdoblje obnove rane, diferencijalni broj neutrofila bio je viši, a broj limfocita niži kod db/db miševa u usporedbi s C57Bl/6 miševima. Vršne koncentracije SAA zabilježene su 3. dana kod C57Bl/6 miševa i db/db miševa (368,7 mg/L odnosno 173,5 mg/L), s težnjom prema nižim vrijednostima kod db/db miševa. Razine IFN-γ bile su značajno više (P < 0,05) 9. i 13. dana kod db/db miševa (75,3 pg/mLodnosno 89,9 pg/mL) u usporedbi s razinama kod C57Bl/6 miševa (66,6 pg/mL odnosno 57,2 pg/mL). Zaljučak: Lokalni proces tkivne regeneracije kod miševa nakon lokalne kožne ozljede uzrokuje sustavne promjene u perifernoj krvi. Niti određivanje koncentracije SAA niti IFN-γ nije se moglo rabiti za motrenje dinamike cijeljenja rane u ovim vremenskim točkama.Introduction: Inflammation is the initial host response to injury. It is not only localized to the wound site but also causes systemic changes, including a variety of physiological and biochemical changes collectively called the acute phase response. These changes continue during the resolution of inflammation and the wound healing process. In this study we compared serum amyloid A protein (SAA), hematological parameters (total white blood cell count, neutrophil and lymphocyte percentage) and interferon-gamma (IFN-γ) concentrations in serum during healing of non-occluded, excisional, full-thickness dermal wounds in genetically diabetic db/db mice and non-diabetic C57Bl/6 littermates. Materials and Methods: Area of a punch biopsy (8 mm in diameter) wound in each mouse was analyzed by computer-assisted planimetry. On days 3,6, 9 and 13 after wounding, SAA and IFN-γ were measured in plasma by ELISA assays and hematological parameters in whole blood by SysmexSF 3000 automatic hematology analyzer. Results: A delay in the closure of wounds in db/db in comparison to normal mice was clearly seen on days 6 and 9. Total white blood cell count was significantly higher on days 9 and 13 in db/db mice. Differential neutrophil counts were higher and lymphocyte counts lower in db/db mice in comparison to C57BL/6 mice throughout the wound repair period. Peak SAA concentrations were seen on day 3 in C57Bl/6 and db/db mice (368.7 mg/L and 173.5 mg/L, respectively), but tended to be lower in db/db mice. IFN-γ levels were significantly higher (P < 0.05) on days 9 and 13 in db/db (75.3 pg/mL and 89.9 pg/mL, respectively) in comparison to those in C57Bl/6 mice (66.6 pg/mL and 57.2 pg/mL, respectively). Conclusion. The local tissue regeneration process in mice after local skin injury causes systemic changes in peripheral blood. Determination of neither SAA nor IFN-γ concentrations could be used to monitor wound healing dynamics at these time points

Design, synthesis, antitrypanosomal activity, DNA/RNA binding and in vitro ADME profiling of novel imidazoline-substituted 2-arylbenzimidazoles

Novel imidazoline benzimidazole derivatives containing diversely substituted phenoxy moieties were synthesized with the aim of evaluating their antitrypanosomal activity, DNA/RNA binding affinity and in vitro ADME properties. The presence of the diethylaminoethyl subunit in 18a-18c led to enhanced antitrypanosomal potency, particularly for 18a and 18c, which contain unsubstituted and methoxy-substituted phenoxy moieties. They were found to be > 2-fold more potent against African trypanosomes than nifurtimox. Fluorescence and CD spectroscopy, thermal denaturation assays and computational analysis indicated a preference of 18a-18c toward AT-rich DNA and their minor groove binding mode. Replacement of the amidine group with less basic and ionisable nitrogen-containing moieties failed to improve membrane permeability of the investigated compounds. Due to structural diversification, the compounds displayed a range of physico-chemical features resulting in variable in vitro ADME properties, leaving space for further optimization of the biological profiles

Ergoregions

Lense-Thirringova precesija općerelativistički je efekt koji nastaje kao posljedica ”povlačenja” prostorvremena oko rotirajućeg tijela. Efekt se opaža i u blizini Zemlje, gdje je eksperimentalno provjeren sondom Gravity Probe B. Ekstremni oblik Lense- Thirringove precesije javlja se u ergopodručjima, dijelovima prostorvremena unutar kojih su svi fizikalni promatrači prisiljeni rotirati zajedno s objektom koji ju uzrokuje. Zbog svojih svojstava, ergopodručja omogućuju ekstrakciju rotacijske energije objekta mehanizmima kao što je Penroseov proces. U ovom je radu opisana geometrija ergopodručja koja se pojavljuju u rješenjima Einsteinove jednadžbe, s posebnim naglaskom na klasu slabo omedenih ergopodručja. Uz to, analizirane su efikasnosti Penroseovog procesa i njegovih inačica u različitim vrstama prostorvremena.Lense-Thirring precession is an effect predicted by general relativity which arises due to the dragging of spacetime near rotating body. This effect can be observed in the vicinity of Earth, where it was experimentally confirmed using the Gravity Probe B satellite. Extreme version of Lense-Thirring precession can be found inside ergoregions, parts of spacetime in which all physical observers must corotate with the object causing the aforementioned effect. Because of its properties, it is possible to extract rotational energy from ergoregions via physical mechanisms such as Penrose process. In this work we will describe the geometry of the ergoregions that appear in the solutions of Einstein’s equation, with special emphasis on a subclass of ergoregions called weakly bounded. Additionally, we analyse the efficiency of Penrose process and its variants in different types of spacetimes

Ergoregions

Lense-Thirringova precesija općerelativistički je efekt koji nastaje kao posljedica ”povlačenja” prostorvremena oko rotirajućeg tijela. Efekt se opaža i u blizini Zemlje, gdje je eksperimentalno provjeren sondom Gravity Probe B. Ekstremni oblik Lense- Thirringove precesije javlja se u ergopodručjima, dijelovima prostorvremena unutar kojih su svi fizikalni promatrači prisiljeni rotirati zajedno s objektom koji ju uzrokuje. Zbog svojih svojstava, ergopodručja omogućuju ekstrakciju rotacijske energije objekta mehanizmima kao što je Penroseov proces. U ovom je radu opisana geometrija ergopodručja koja se pojavljuju u rješenjima Einsteinove jednadžbe, s posebnim naglaskom na klasu slabo omedenih ergopodručja. Uz to, analizirane su efikasnosti Penroseovog procesa i njegovih inačica u različitim vrstama prostorvremena.Lense-Thirring precession is an effect predicted by general relativity which arises due to the dragging of spacetime near rotating body. This effect can be observed in the vicinity of Earth, where it was experimentally confirmed using the Gravity Probe B satellite. Extreme version of Lense-Thirring precession can be found inside ergoregions, parts of spacetime in which all physical observers must corotate with the object causing the aforementioned effect. Because of its properties, it is possible to extract rotational energy from ergoregions via physical mechanisms such as Penrose process. In this work we will describe the geometry of the ergoregions that appear in the solutions of Einstein’s equation, with special emphasis on a subclass of ergoregions called weakly bounded. Additionally, we analyse the efficiency of Penrose process and its variants in different types of spacetimes

ISOLATION AND CHARACTERISATION OF MDCK CELLS WITH LOW EXPRESSION OF mdr1 GENE AND THEIR USE IN MEMBRANE PERMEABILITY SCREENING

U ovoj disertaciji je opisana izolacija klona divljega tipa stanica MDCK s niskom izraženošću gena mdr1 koji kodira P-glikoprotein. Klonovi su izolirani metodom velikog razrjeđivanja, te uspoređeni mjerenjem dvosmjernog transporta prema razini efluksa amprenavira. Klon 79, koji je pokazao najmanji omjer efluksa amprenavira, kao i tri puta manju izraženost mRNA za mdr1 u odnosu na divlji tip (MDCK-WT), odabran je kao klon MDCK s niskim efluksom za daljnje istraživanje. Na standardnom setu spojeva klon 79 pokazao je znatno manji efluks od MDCK-WT, iako je kod nekih spojeva i dalje detektirana ostatna aktivnost P-glikoproteina. Transport 12 makrocikličkih spojeva ispitan je na klonu 79 i nekoliko dodatnih staničnih linija, Caco-2, MDCK-MDR1, MDCK-WT, te MDCK bez ekspresije P-glikoproteina. Nije uočeno značajno poboljšanje permeabilnosti makrolida u staničnim modelima s niskom ili bez izraženosti P-glikoproteina u odnosu na MDCK-MDR1 i MDCK-WT stanični model. Proučen je utjecaj vremenske komponente na permeabilnost makrocikličkih spojeva u staničnom modelu dvosmjernog transporta. Dobiveni rezultati analizirani su multivarijantnim statističkim metodama, te su uspješno razvijeni modeli permeabilnosti i bioraspoloživosti.In this thesis, a clone of wild type MDCK cells with low expression of the mdr1 gene that encodes the efflux pump P-glycoprotein, was isolated using the limiting dilution method. The clones were ranked based on amprenavir efflux level in a bidirectional transport assay. Clone 79 was selected as a low efflux MDCK clone for further investigation since it had the lowest efflux ratio of amprenavir and three fold lower mdr1 mRNA expression in comparison to MDCK wilde type. When profiled using standard compounds, clone 79 had substantially reduced efflux compared to the wild type, although residual P-glycoprotein activity was still observed with some compounds. The transport of 12 macrocyles was tested using clone 79 and several additional cell lines, including Caco-2, MDCK-MDR1, MDCK-WT, and MDCK with no P-glycoprotein expression. No significant improvement in macrolide permeability was observed in cell models with low or no P-glycoprotein expression in comparison to the MDCK-MDR1 and MDCK-WT cells. The influence of the time component on the permeability of macrocyclic compounds in the cellular transport model was further investigated. The obtained results were analyzed by multivariate statistical methods and models of permeability and bioavailability were successfully developed