Existence and approximation of solutions of a system of differential equations of Volterra type

The present paper deals with the nonlinear systems of differential equations of Volterra type regarding the existence, behaviour, approximation and stability of their definite solutions, all solutions in a corresponding region or parametric classes of solutions on an unbounded interval. The approximate solutions with precise error estimates are determined. The theory of qualitative analysis of differential equations and the topological retraction method are used

Kvalitativna procjena eliminacije TCP-a i TAMORF-a iz organizma štakora metodom GC-MS

Nerve agents are highly toxic organophosphorus (OP) compounds. They inhibit acetylcholinesterase (AChE), an enzyme that hydrolyses acetycholine (ACh) in the nervous system. Pathophysiological changes caused by OP poisonings are primarily the consequence of surplus ACh on cholinergic receptors and in the central nervous system. Standard treatment of OP poisoning includes combined administration of carbamates, atropine, oximes and anticonvulsants. In order to improve therapy, new compounds have been synthesised and tested. Tenocyclidine (TCP) and its adamantane derivative 1-[2-(2-thienyl)-2-adamantyl] morpholine (TAMORF) have shown interesting properties against soman poisoning. In this study, we developed a qualitative GC-MS method to measure elimination of TCP and TAMORF through rat urine in order to learn more about the mechanisms through which TCP protects an organism from OP poisoning and to determine the duration of this protective effect. GC-MS showed that six hours after treatment with TCP, rat urine contained only its metabolite 1-thienylcyclohexene, while urine of rats treated with TAMORF contained both TAMORF and its metabolites.Živčani bojni otrovi po strukturi su organofosforni (OP) spojevi, čija je zajednička značajka ireverzibilna inhibicija acetilkolinesteraze (AChE), enzima koji hidrolizira acetilkolin (ACh) u živčanom sustavu. Patofi ziološka zbivanja koja nastaju pri otrovanju OP-spojevima primarno su posljedica akumuliranog ACh na kolinergičkim receptorima i u središnjem živčanom sustavu. Još uvijek nesavršen, standardni tretman liječenja otrovanja OP-spojevima uključuje kombiniranu primjenu estera karbamata, atropina, oksima i antikonvulziva. Kako bi se unaprijedila uobičajena terapija, osobito kod otrovanja somanom, ispituju se antidotski učinci mnogih spojeva. Tenociklidin (TCP) i njegov adamantanski derivat TAMORF pokazali su zanimljiva svojstva pomoćne terapije pri otrovanju somanom. Kako bi se proširile dosadašnje spoznaje o načinu na koji tenociklidini štite organizam od trovanja OP-spojevima te također o trajanju njihova antidotskog učinka, u ovom radu razvijena je GC-MS-metoda za praćenje eliminacije TCP-a i TAMORF-a iz organizma. Rezultati GC-MS-analize pokazali su da šest sati nakon tretiranja štakora TCP-om mokraće sadržavaju metabolit TCP-a 1-tienilcikloheksen, dok šest sati nakon tretiranja štakora TAMORF-om mokraće sadržavaju i TAMORF i njegove metabolite. Drugim riječima, šest sati nakon tretmana TCP se potpuno metabolizira, dok se TAMORF metabolizira djelomično, a djelomično ostaje nepromijenjen

Procjena varijabli stanja sustava s gorivnim člankom i uzlaznim pretvaračem metodom brzog uzorkovanja signala

Estimation of state variables of a peak current mode (PCM) controlled DC-DC boost converter supplied by a PEM fuel cell is described in this paper. Since this system is highly nonlinear and non-minimum phase, its state variables are estimated by using fast output sampling method. Estimated state variables are the converter output voltage and its first derivative, and they are suitable for model reference adaptive control or sliding mode based control techniques. The estimator has been designed in a way that it gives a good estimate of the state variables in the continuous and in the discontinuous conduction mode of the converter, and in the presence of measurement and process noise caused by converter switching-mode operation. Experimental results of estimating the state variables on a 450 W boost converter supplied by the emulator of the PEM fuel cell BCS 64-32 show good results of the estimation, regardless of the conduction mode of the converter, i.e. the operating point determined by its output current.U ovom radu obrađena je procjena varijabli stanja sustava s istomjernim uzlaznim pretvaračem u vršnom strujnom načinu upravljanja napajanim PEM gorivnim člankom. Budući da je taj sustav izrazito nelinearan te neminimalno-fazan, za procjenu njegovih varijabli stanja upotrebljena je metoda brzog uzorkovanja izlaznog signala. Procjenjene varijable stanja su izlazni napon uzlaznog pretvarača te njegova prva derivacija, te su pogodne za adaptivno upravljanje s referentnim modelom i upravljanje temeljeno na kliznim režimima. Procjenitelj je projektiran na način da daje dobru procjenu varijabli stanja u kontinuiranom i diskontinuiranom režimu rada pretvarača, te u uvjetima mjernog i procesnog šuma uzrokovanog sklopnim načinom rada pretvarača. Eksperimentalni rezultati procjene varijabli stanja na uzlaznom pretvaraču snage 450 W napajanim emulatorom gorivnog članka BCS 64-32 pokazuju dobre rezultate procjene, neovisno o režimu rada pretvarača, odnosno radnoj točki određenoj njegovom izlaznom strujom

Odnos strukture i aktivnosti u reaktivaciji tabunom fosforilirane ljudske acetilkolinesteraze bispiridinijevim para-aldoksimima

We investigated interactions of bispyridinium para-aldoximes N,N’-(propano)bis(4-hydroxyiminomethyl) pyridinium bromide (TMB-4), N,N’-(ethano)bis(4-hydroxyiminomethyl)pyridinium methanosulphonate (DMB-4), and N,N’-(methano)bis(4-hydroxyiminomethyl)pyridinium chloride (MMB-4) with human erythrocyte acetylcholinesterase phosphorylated by tabun. We analysed aldoxime conformations to determine the flexibility of aldoxime as an important feature for binding to the acetylcholinesterase active site. Tabun-inhibited human erythrocyte acetylcholinesterase was completely reactivated only by the most flexible bispyridinium aldoxime - TMB-4 with a propylene chain between two rings. Shorter linkers than propylene (methylene or ethylene) as in MMB-4 and DMB-4 did not allow appropriate orientation in the active site, and MMB-4 and DMB-4 were not efficient reactivators of tabun-phosphorylated acetylcholinesterase. Since aldoximes are also reversible inhibitors of native acetylcholinesterase, we determined dissociation constants and their protective index against acetylcholinesterase inactivation by tabun.Proučavali smo interakcije bispiridinijevih para-oksima N,N’-(propano)bis(4-hidroksiiminometil)piridinijeva bromida (TMB-4), N,N’-(etanano)bis(4-hidroksiiminometil)piridinijeva metanosulfonata (DMB-4) i N,N’- (metano)bis(4-hidroksiiminometil)piridinijeva klorida (MMB-4) s ljudskom eritrocitnom acetilkolinesterazom fosforiliranom tabunom. Da bismo odredili fleksibilnosti aldoksima, što je važna osobina kod njihova vezanja u aktivno mjesto acetilkolinesteraze, analizirali smo i konformacijske odlike aldoksima. Ljudska acetilkolinesteraza inhibirana tabunom bila je potpuno reaktivirana samo najfleksibilnijim bispiridinijevim aldoksimom – TMB-4. Aldoksimi MMB-4 i DMB-4 nisu bili efikasni reaktivatori acetilkolinesteraze fosforilirane tabunom jer je kod tih spojeva lanac koji povezuje dva prstena kraći od propilena (metilen u MMB-4 i etilen u DMB-4), što ne dopušta povoljnu orijentaciju tih aldoksima unutar aktivnog mjesta enzima. S obzirom na to da su aldoksimi i reverzibilni inhibitori nativne acetilkolinesteraze, odredili smo njihove disocijacijske konstante, kao i zaštitu acetilkolinesteraze od inhibiranja tabunom reverzibilnim vezanjem aldoksima

New Mediterranean Biodiversity Records (December 2017)

The “New Mediterranean Biodiversity Records” series includes new records of marine species found in the Mediterranean basin and/or information on the spatial distribution of already established species of particular interest. The current article presents information on 20 marine taxa classified per country according to their geographic position in the Mediterranean, from west to east. The new records per ecoregion are as follows: Algeria: the first record of the fish Etrumeus golanii is reported along the Algerian coast. Tunisia: the alien jellyfish Phyllorhiza punctata is reported for the first time in the Gulf of Gabès. Italy: the first record of Siganus rivulatus in the Strait of Sicily and a new record of Katsuwonus pelamis from the central Tyrrhenian Sea are reported. The establishment of the isopod of the genus Mesanthura in the northern Tyrrhenian with some notes on its ecology are also included. Croatia: signs of establishment of the Lessepsian Siganus luridus and the occurrence of the alien mollusc Rapana venosa are reported. Albania: the first record of the elasmobranch Alopias superciliosus and a recent sighting of the rare monk seal Monachus monachus in Albanian waters are given. Greece: signs of the establishment of the fish Parupeneus forsskali and of the ascidian Hermania momus in Hellenic Aegean waters are reported. Turkey: a new record of the fish P. forsskali and of the Acarea of the genus Acaromantis and Simognathus are given, while the first case of Remora australis in association with delphinids and the occurrence of the sea star Coscinasterias tenuispina are reported. Also, the establishment of the two alien species Isognomon legumen and Viriola sp. [cf. corrugata] are presented. Egypt: the fish Bathygobius cyclopterus is reported for the first time in Mediterranean Sea waters. Also, a new record of Pagellus bogaraveo and a first record of Seriola fasciata in Egyptian Mediterranean waters are reported. Lebanon: the first record of Dondice banyulensis is presented

Mehanizam toksičnosti i detoksikacije organofosfornih spojeva s naglaskom na istraživanja u Hrvatskoj

This review comprises studies on the mechanisms of toxicity and detoxication of organophosphorus (OP) compounds done in Croatia in different research areas. One area is the synthesis of antidotes against OP poisoning and their in vivo testing in experimental animals. In vitro studies included in this review focus on the mechanisms of reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), protection of cholinesterases from inhibition by OPs, and reactivation of phosphylated cholinesterases. The third area comprises distribution profiles of BChE and paraoxonase (PON) phenotypes in selected population groups and the detection of OPs and metabolites in humans. Finally, methods are described for the detection of OP compounds in human blood and other media by means of cholinesterase inhibitionPrikazana su istraživanja vođena u Hrvatskoj na različitim područjima mehanizma toksičnosti i detoksikacije organofosfornih (OP) spojeva. Jedno je područje sinteza antidota protiv otrovanja OP spojevima i testiranje in vivo antidota na eksperimentalnim životinjama. Istraživanja in vitro odnose se na mehanizam reverzibilne inhibicije acetilkolinesteraze (AChE) i buturilkolinesteraze (BChE), zaštitu kolinesteraza od inhibicije OP spojevima te reaktivaciju fosfiliranih kolinesteraza. Treće je područje distribucija fenotipova BChE i paraoksonaze (PON) u odabranim populacijama te detekcija OP spojeva i njihovih metabolita u ljudima. Na kraju su opisane metode detekcije OP spojeva u ljudskoj krvi i drugim medijima koje se osnivaju na inhibiciji kolinesteraza

Microneedle Array Design Determines the Induction of Protective Memory CD8+ T Cell Responses Induced by a Recombinant Live Malaria Vaccine in Mice

BACKGROUND: Vaccine delivery into the skin has received renewed interest due to ease of access to the immune system and microvasculature, however the stratum corneum (SC), must be breached for successful vaccination. This has been achieved by removing the SC by abrasion or scarification or by delivering the vaccine intradermally (ID) with traditional needle-and-syringes or with long microneedle devices. Microneedle patch-based transdermal vaccine studies have predominantly focused on antibody induction by inactivated or subunit vaccines. Here, our principal aim is to determine if the design of a microneedle patch affects the CD8(+) T cell responses to a malaria antigen induced by a live vaccine. METHODOLOGY AND FINDINGS: Recombinant modified vaccinia virus Ankara (MVA) expressing a malaria antigen was percutaneously administered to mice using a range of silicon microneedle patches, termed ImmuPatch, that differed in microneedle height, density, patch area and total pore volume. We demonstrate that microneedle arrays that have small total pore volumes induce a significantly greater proportion of central memory T cells that vigorously expand to secondary immunization. Microneedle-mediated vaccine priming induced significantly greater T cell immunity post-boost and equivalent protection against malaria challenge compared to ID vaccination. Notably, unlike ID administration, ImmuPatch-mediated vaccination did not induce inflammatory responses at the site of immunization or in draining lymph nodes. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that the design of microneedle patches significantly influences the magnitude and memory of vaccine-induced CD8(+) T cell responses and can be optimised for the induction of desired immune responses. Furthermore, ImmuPatch-mediated delivery may be of benefit to reducing unwanted vaccine reactogenicity. In addition to the advantages of low cost and lack of pain, the development of optimised microneedle array designs for the induction of T cell responses by live vaccines aids the development of solutions to current obstacles of immunization programmes

Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer

BACKGROUND: The randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone (hazard ratio [HR]=0.75, 95% confidence interval [CI] 0.61-0.93). We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety. RESULTS: Of the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR=0.79, 95% CI 0.59-1.06), combined second- and third-line PFS (HR=0.85, 95% CI 0.68-1.05) or OS (HR=0.96, 95% CI 0.76-1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected. CONCLUSION: In this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS but no improvement in longer-term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life. CLINICALTRIALSGOV: NCT01250379

ClimateFish: A Collaborative Database to Track the Abundance of Selected Coastal Fish Species as Candidate Indicators of Climate Change in the Mediterranean Sea

Under the effects of global warming, many animals and plants are undergoing rapid distribution shifts. These changes can be particularly rapid in marine fishes, and many species have responded markedly to recent increases in sea temperature. ClimateFish is an open-access database, which collates abundance data for 7 Mediterranean indigenous and 8 non-indigenous fishes, proposed as candidate indicators of climate change. These species have been selected by a network of Mediterranean scientists based on their wide distribution, responsiveness to temperature conditions and easy identification. Data are periodically collected according to a standard visual census protocol in four different depth layers. At present, the database collates data on a total number of 101'771 observed individuals belonging to the 15 target species. Counts were realized along 3142 transects carried out in 7 Mediterranean countries between 2009 and 2021. This database, associated with climate data, offers new opportunities to investigate spatiotemporal effects of climate change and to test the effectiveness of each selected indicator. Data are available at https://doi.org/10.17882/86784.The Mediterranean ClimateFish initiative was initially conceived by the international basin wide monitoring program CIESM Tropical Signals (funded by the Albert II of Monaco Foundation) and subsequently supported by the Interreg Med Programme (Projects: MPA-ADAPT, grant number 1MED15_3.2_M2_337 and MPA Engage, grant number 5MED18_3.2_M23_007), 85% co funded by the European Regional Development Fund