3,627 research outputs found
Inhibition of self-replication of protein fibrils
Get PDFProteinski fibrili nastanejo z agregacijo delno zvitih proteinov in so odgovorni ali pomembno vplivajo na mnogo hudih človeških bolezni, kot sta Alzeimerjeva ali diabetes tipa II. Samo-replikacija fibrilov je proces, v katerem obstoječi proteinski fibrili katalizirajo nastanek novih fibrilov na način, da ponudijo vezavno površino, kjer se proteini lažje srečajo in agregirajo. To prispeva k naglem in eksponentnem napredovanju bolezni. V magistrski nalogi predstavimo Monte Carlo simulacije računalniškega modela agregacije, v katerega vpeljemo inhibitorje. To so delci, ki se lahko vežejo na površino fibrilov in tako inhibirajo oziroma upočasnijo proces samo-replikacije. Takšen način inhibicije se izkaže za zelo učinkovit, ampak zaradi odbojne interakcije med delci naletimo tudi na pojav makromolekularnega gnečenja, ki povzroči, da se pri določeni pokritosti površine s proteini hitrost samo-replikacije poveča. Edinstven deskriptor hitrosti replikacije najdemo v povprečni velikosti skupka na površino vezanih proteinov, ki nosi informacijo o celotni porazdelitvi agregacijskih skupkov. Predstavimo teorije, ki uspešno razložijo vse značilnosti opažanega obnašanja. S pomočjo mrežnega modela napovemo, katere interakcije med delci na površini imajo največji inhibicijski potencial.Protein fibrils are formed by a process called amyloid aggregation and are implicated in many debilitating human diseases such as Alzheimer\u27s or Type II Diabetes.
Self-replication of fibrils is a process by which existing protein fibrils catalyse the formation of new fibrils by offering a surface on which proteins can bind, and therefore facilitate aggregation.
This leads to exponential growth of fibril mass and fast propagation of amyloid diseases.
In this thesis, we present simulations of a minimal but fairly complex computational model of aggregation with added inhibitory particles that can bind to the fibril surface.
It turns out the mechanism of inhibition where inhibitors compete with proteins for the surface is very promising. However, we also find a manifestation of a macromolecular crowding effect which actually promotes self-replication at given protein coverage of the fibril surface. We find a unique descriptor for the rate of replication in the average protein aggregate size. We present theories that successfully explain all characteristics of observed simulation behaviour. By employing a lattice model, we predict which inter-particle interactions on the fibril surface have the largest inhibitory potential
aggregation_data
No full textThis data repository underpins the paper, published in PNAS (doi pending) and bioarxiv (doi: https://doi.org/10.1101/2023.07.05.547777)
aggregation_data
No full textThis data repository underpins the paper, published in PNAS (doi pending) and bioarxiv (doi: https://doi.org/10.1101/2023.07.05.547777)
Peljar - samo savjetnik ?
Get PDFThe author argues through an analysis of maritime practice, legal theory and statutory enactments that the pilot is not only an expert adviser but that he takes charge of and conducts a vessel. He distinguishes between conducting and commanding and points out that by recognizing that the pilot conducts a ship no charge in the nowadays widely accepted regime of liability would ensue. He proposes, consequently, a rewording of Article 34 of the Maritime and Internal Waters Navigation Act presently in force in Croatia.Kroz komparativan prikaz pravne teorije i pomorske prakse autor dolazi do zaključka da kvalifikacija pomorskog peljara uključuje mnogo više nego samo davanje stručnih savjeta zapovjedniku. Bitno je za peljara vođenje peljarenog broda, a pojmovi davanja savjeta i vođenja nisu istoznačni, kao što nisu istoznačni ni pojmovi vođenja, upravljanja i zapovijedanja. Autor zatim prikazuje režim odgovornosti peljara i brodara peljarenog broda pa zaključuje da se kvalifikacijom usluge peljara kao usluge vođenja broda ne mora mijenjati danas općeprihvaćeno načelo odgovornosti brodara peljarenog broda za radnje i propuste peljara. Autor zatim sugerira de lege ferenda redefiniciju pojma peljarenja iz Čl. 34. ZPUP-a
"Hosanna uniesiona na samo dno” – ironia w "Odczytaniu popiołów" Jerzego Ficowskiego
No full text“Hosanna uniesiona na samo dno” – irony in Jerzy Ficowski’s “Odczytanie popiołów” The article is an attempt at interpreting selected poems by Ficowski (*** [nie zdołałem ocalić…], List do Marc Chagalla, Postscriptum listu do Marc Chagalla, Pożydowskie and Wniebowzięcie Miriam z ulicy zimą 1942, included in the volume Odczytanie popiołów). The author focuses on irony, which is particularly noticeable in texts referring to the Bible and religion.Key words: Jerzy Ficowski; Odczytanie popiołów; poetry; irony; Extermination; Jews;</jats:p
Costs and benefits of debt and debt service reduction
Get PDFThe author evaluates the costs and benefits of debt and debt service reduction (DDSR) from the point of view of five countries that have concluded Brady deals: Costa Rica, Mexico, the Philippines, Uruguay, and Venezuela. He concludes that, contrary to widely held views, commercial banks have probably benefited from the operations. Commercial bank participation in DDSR is voluntary, so direct financial savings to the country are probably negative at present values. The benefit from DDSR is not that debt is bought at"bargain prices"at the expense of commercial banks. It appears difficult to justify a DDSR operation on purely financial grounds. A more realistic way to look at a DDSR operation is to view it as a"project"that involves a certain financial cost. The return on such a project is how the DDSR operation improves the macroeconomy, or contributes to development. The main purpose of DDSR is to establish a more efficient arrangement between debtor countries and commercial banks, leading to improved conditions for development. A DDSR operation that does not help development is costly and should not be undertaken. The impact of DDSR on development is usually measured by the increase in the growth rate of GDP, but it is too soon to measure that for these five countries. A suitable alternative is to look at the change in investment patterns. A strong policy framework is needed if debt and debt service reduction are to significantly improve development. In Mexico and, to a lesser extent, Venezuela, improved and sustained strong adjustment policies have generated the greatest development benefits. Gains have been less in smaller countries where policies were not as supportive. The author concludes that for a country to benefit from DDSR, it needs significant indirect benefits (such as increased domestic and foreign savings). Direct benefits are likely to be negative because of the commercial banks'financial gains and because DDSR operations are frontloaded. DDSR operations cannot be justified solely by direct benefits and savings in cash flow.Strategic Debt Management,Banks&Banking Reform,Economic Theory&Research,Environmental Economics&Policies,Financial Intermediation
Implementation of asymmetric median tree method for the computation of a consensus phylogenetic tree
Get PDFFilogenetsko drevo prikazuje evolucijska razmerja med taksonomskimi enotami. Danes jih gradimo programsko z uporabo različnih metod in na podlagi različnih virov podatkov (npr., zaporedja DNA ali RNA). To mnogokrat privede do nasprotujočih si evolucijskih hipotez, ki jih nato skušamo združiti v eno samo hipotezo oziroma konsenzno drevo. V diplomskem delu je obravnavana konsenzna metoda asimetričnega srednjega drevesa. Le-ta in še dve aproksimacijski metodi so bile implementirane v odprtokodnem paketu Biopython. Uspešnost metode asimetričnega srednjega drevesa je bila primerjana z uspešnostjo metod za gradnjo striktnega, večinskega in Adamsovega konsenza, na nekaj umetnih in enem dejanskem primeru. Pridobljena drevesa so bila ovrednotena z uporabo Robinson-Fouldsove mere in mere razrešenosti drevesa. Asimetrično srednje drevo je velikokrat najmanj podobno vhodnim drevesom, a hkrati najbolj razrešeno drevo, saj podaja največ informacije o evolucijskih razmerjih med taksonomskimi enotami.A phylogenetic tree displays evolutionary relationships between taxonomical units. Nowadays, they are constructed programmatically by using different methods of inference and relying on various data sources, such as DNA and RNA sequences. The resulting evolutionary hypotheses are often contradictory, and need to be resolved by applying consensus methods. In this thesis, asymmetric median tree method (AMT) for construction of consensus phylogenetic trees is described, and along with two other approximation methods implemented in Biopython. AMT was compared to methods of strict, majority and Adams consensus trees on a number of artificial and one real data set. The comparisons were evaluated using the Robinson-Foulds and the tree resolution metrics. The results show that AMT is often the least similar to the input trees. At the same time, it is the most resolved tree, and therefore it offers the most information about evolutionary history of
taxonomical units
Wiki extension for the Django administration panel
Get PDFZagotovo smo vsi že kdaj obiskali spletno strani in na njej opazili informacijo, ki bi jo lahko izboljšali ali celo popravili. S tem dejanjem bi nadgradili informacijsko vrednost spletne strani tako, da bi obiskovalci za nami od obiska strani odnesli čim več. Takšno funkcionalnost omogoča spletna stran Wikipedia, ki je tudi najbolj znana s takšno funkcionalnostjo. Ta operacija se ime- nuje dodajanje predlogov na že obstoječe vnose v podatkovni bazi. Takšen predlog gre nato v stanje pregleda. V tem stanju so nad pregledom možne tri operacije: spreminjanje, potrditev ali zavrnitev. Zadnji dve operacije lahko izvaja samo administrator spletne strani oziroma lastnik originalnega vnosa. Ureja pa jo lahko kdorkoli.
V diplomski nalogi smo razvili vtičnik za spletne aplikacije, ki so narejene na ogrodju Django. Vtičnik omogoča anonimnemu uporabniku vpogled v vnose v podatkovni bazi. Vnose lahko spremeni, če meni, da jih bo s svojo spremembo izboljšal. Ustvari lahko tudi nove vnose. Originalni vnosi, iz katerih anonimni uporabnik izpelje vnos z popravljeno ali dodatno informacijo, so popolnoma neodvisni in ostanejo nespremenjeni. Vsi novi vnosi so nato vidni skupini administratorjev spletne strani, ki jih lahko potrdijo ali zavrnejo. Pred potrditvijo lahko tudi popravijo vnos.We have all visited a web site and noticed an information that we could improve or add. With this action, we would upgrade the informational value of the site, so other visitors would be presented with better information. This functionality is offered on the well-known Wikipedia website. The operation of adding or improving an existing part of information, is known as input of a proposal. The proposal, new or derived from an existing source, is then put into a review stage. In this stage, there are three valid operations that users can do on the entry: edit, accept or reject. Editing can be done by anyone, while the last two operations can be executed only by the site administrator. This is a very generalized presentation of how wiki entries are generated and handled.
In this diploma thesis, we have developed a plugin for web applications that are built in the Django framework. The plugin enables anonymous user to view entries in the database and perform two operations on them. Create new entry or update an existing one. Original entries stay intact to prevent false information. All the new entries from anonymous users are then visible to administrators of the site. Administrators can approve the requested entry or decline it. Before approving it the administrator can update and fix the information in the entry
Water supply in Upper Bohinj valley and on the mountain huts in the cadastral area of villages
Get PDFNa obravnavanem območju Zgornje Bohinjske doline (Jereka, Bohinjska Češnjica, Srednja vas, Studor in Stara Fužina) in na planinskih postojankah, ki jih naselja katastrsko obsegajo, javne oskrbe s pitno vodo z izjemo naselja Stare Fužine ni. V Bohinjski Češnjici, Srednji vasi in Studoru so prebivalci priključeni na mreže lokalnih vodovodov, ki so v upravljanju vodovodnih zadrug, v Jereki pa so prebivalci odvisni od lastnih virov pitne vode. Dezinficiranje se redno uporablja le na dveh zajetjih in sicer na javnemu zajetju Voje, ki oskrbuje Staro Fužino in zajetju Ribnica, ki oskrbuje Srednjo vas. V nalogi sem s pomočjo obstoječih analiz, anketiranja in terenskega pregleda območij raziskala način oskrbe in mikrobiološko ter fizikalno-kemijsko kakovost pitne vode v naseljih in na planinskih postojankah. Določila sem rabo prostora na napajalnih območjih in sklepala na potencialne onesnaževalce. Raziskava je pokazala, da je kakovost vode v naseljih razmeroma dobra, občasno prihaja do mikrobiološkega onesnaženja, katerega vzrok je pašništvo v zaledju ali neurejenost odpadnih voda. Zaradi neprimerne lege, zgradbe in nezavarovanosti zajetja, voda ni pitna skoraj v polovici obravnavanih planinskih postojank. Ugotovila sem, da so vodovarstvena območja določena samo za zajetje Voje in bi bila nujna določitev še za ostala zajetja, saj so ključnega pomena za ohranjanje kakovosti pitne vode.On the selected area of the Upper Bohinj Valley (Jereka, Bohinjska Češnjica, Srednja vas, Studor and Stara Fužina) and on the mountain huts, which are in the cadastral area of villages, except village Stara Fužina, there is no public water supply. Residents of Bohinjska Češnjica, Srednja vas and Studor are connected to the local water supplies, which are under the management of Water cooperatives. In the village Jereka residents depend on their own sources of drinking water. Disinfection is regularly used only on two water captures, capture Voje which supplies Stara Fužina and capture Ribnica which supplies Srednja vas. In my diploma thesis I selected the existing analyzes, interviewed the holders of water permits and did a field research. So I got the information about the way of supply and the quality of drinking water. I made a map of land use on supply areas and determined the potential polluters. The research showed that the quality of drinking water in villages is relatively good, occasionally it comes to microbiological pollution, which is caused by the grazing in the hinterland or unregulated wastewater. Due to inappropriate position, constructions and insecurity of captures, water is not drinkable in almost half of the mountain huts. As I found out the water protection zones are only specified for capture Voje and it would be necessary to specify them for other captures too, because they are key to maintaining the quality of drinking water
Globoko učenje tkivno specifičnega izražanja genov iz zaporedij DNA
No full textPredicting tissue-specific gene expression is a crucial task in understanding the complex regulatory mechanisms governing gene expression. In this research, we employed three distinct models, two convolutional neural networks (CNNs) and DNABERT, to explore predictive models for tissue-specific gene expression. For the genome, we opted for the publicly available textit{Arabidopsis thaliana}. Our approach involved systematically testing various methodologies, encompassing diverse transcript filtering techniques and an array of input sequences. The integration of multiple models and comprehensive input variations represents a significant step towards enhancing our understanding of tissue-specific gene expression prediction and furthering advancements in bioinformatics and computational biology.
Our findings demonstrate the significance of both sequence data and additional CDS features in predicting gene expression. Combining these features showed only a marginal performance increase. DNABERT struggled with sequence-only inputs but performed comparably to CNN models with augmented CDS features. The Washburn model exhibited the most pronounced tissue-specific performance (R-squared 0.40), followed by DNABERT (R-squared 0.34) and Zrimec (R-squared 0.31). The models faced challenges in predicting both low- and highly-expressed genes but excelled in predicting mid-expressed genes. Additionally, predicting tissue-specific expression closely resembled predicting transcript mean expression, showing a consistent performance ordering across tissues.
We analyzed kernel activations to showcase the model\u27s pattern recognition skills. We cross-referenced these patterns with databases, finding around 650 matches. We used sequence occlusion to pinpoint important areas within the sequences. Our results highlighted the importance of the promoter near the TSS and the 5\u27UTR near the CDS in shaping model performance, especially with shorter occlusions. Additionally, all genomic regions except the terminator proved relevant when occluding their entire regions.
In conclusion, we have demonstrated the model\u27s capability to forecast tissue-specific gene expression and underscored the significance of non-coding genomic regions. While there remains ongoing research in this field, we aspire that our findings contribute to the understanding of tissue-specific gene expression.Predvidevanje tkivno specifične genske ekspresije je ključno za razumevanje kompleksnih regulatornih mehanizmov, ki urejajo izražanje genov. V tem delu smo za raziskovanje napovednih modelov za tkivno specifično gensko ekspresijo uporabili tri različne modele: dve konvolucijski nevronski mreži (angl. convolutional neural network, CNN) in DNABERT. Za genom smo izbrali javno dostopno textit{Arabidopsis thaliana}. Naš postopek je obsegal sistematično testiranje različnih metode, ki zajemajo različne tehnike filtriranja transkriptov in raznolika vhodna zaporedja. Integracija večjega števila modelov in variacije vhodov predstavljajo pomemben korak k izboljšanju razumevanja napovedi tkivno specifične ekspresije genov ter prispevajo k napredku bioinformatike in računske biologije.
Naši rezultati kažejo na pomembnost tako vhodnih zaporedij kot dodatnih značilk kodirajoče regije (CDS) pri napovedovanju izražanja genov. Kombinacija teh vhodnih podatkov je pokazala le zmerno izboljšanje učinkovitosti. DNABERT se je spopadal z vnosom samo vhodnih zaporedij, vendar je dosegel rezultate, primerljive z modeli CNN z dodanimi značilkami CDS. Najizrazitejšo tkivno specifično učinkovitost je pokazal model Washburn (R-kvadrat približno 0,40), sledila sta model DNABERT (R-kvadrat približno 0,34) in model Zrimec (R-kvadrat približno 0,31). Modeli so se soočali z izzivi pri napovedovanju nizko in visoko izraženih genov, izkazali pa so se pri napovedovanju zmerno izraženih genov. Ocena napovedi tkivno specifičnega izražanja genov je podobna oceni napovedi povprečne vrednosti vseh primerov transkripta. Dodatno smo pokazali, da sta oba modela CNN ovrednotila tkiva s primerljivim vrstnim redom.
Da bi prikazali modelove spretnosti prepoznavanja vzorcev, smo analizirali aktivacije konvolucijskih jeder. Te vzorce smo primerjali z referencami v bazah podatkov in našli približno 650 ujemanj. Da bi natančneje določili pomembna območja znotraj zaporedij, smo uporabili zamegljevanje zaporedja. Naši rezultati so poudarili pomen promotorja blizu TSS in 5\u27UTR blizu CDS pri oblikovanju učinkovitosti modela, še posebej pri krajših zameglitvah. Pri zameglitvi celotnih območjih so se vse genomske regije razen terminatorja izkazale za pomembne.
Dokazali smo torej, da je model sposoben napovedati tkivno specifične genske ekspresije, in poudarili pomembnost nekodirajočih genomskih območij. Čeprav na tem področju poteka nenehno raziskovanje, si želimo, da bi naši ugotovitvi prispevali k napredku razumevanja tkivno specifičnega izražanja genov
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