The thesis concentrates on the network infrastructure problems , its proposal in the civil service area and analyses in detail the present condition of surroundings in the chosen organisation which requirements and needs for the suggested network infrastructure result from subsequently . On the base of the analysis it considers the posibility of realising the network infrastructure which consists in the choice of the suitable technology and the proposal of the computer network structure , including the implementation the solution in the given organisation and the specification of the financing resources.

The aim of the diploma thesis is study of modernization of Žilina railway junction. In the railway station is modified passenger station, reduced stabling station and canceled sorting station. In the diploma thesis is proposed new rail line of Košice – Bohumín track and parallel track from Bratislava. Original line speed 40 km / h is increased to 80 km / h.

Práce se zabývá popisem jednotlivých typů zdrojů s důrazem na izolované topologie. Poté je rozebírána nejvhodnější volba pro zdroj na anodické bondování, kde jsou kladeny požadavky na vysoké výstupní napětí s malým proudem. Další část rozebírá problematická místa návrhu a na co je třeba dávat pozor. Poté je proveden vlastní návrh zdroje s popisem optimalizačních kroků. Tento zdroj je odsimulován. Dva rozdílné přístupy k realizaci takového zdroje jsou poté porovnány a nejlepší je vybrán. Je ukázána možnost, jak realizovat bipolární výstup. V poslední části je tento zroj sestaven a proměřeny jeho parametry.

<p>Triple Negative Breast Cancer (TNBC) is the most aggressive type of breast cancer. TNBC patients are resistant to virtually all target therapies and suffer a higher post-chemotherapy relapse with a worse overall survival compared with other types of breast cancers. Therefore, the development of an effective therapy is urgently needed. PKM2 plays a prominent role in mediating<b> </b>tumor glycolysis and PKM2 is often overexpressed in human cancers. However, whether PKM2 mediated glycolysis is necessary for cancer cell growth is questionable. Here, I have found that inhibition of PKM2 does not affect TNBC cell growth due to a metabolic switch from glycolysis to fatty acid oxidation (FAO). We show that PKM2 directly interacts with EZH2 to coordinately mediate epigenetic silencing of SLC16A9, transporter of a key player in FAO, Carnitine. Inhibition of either PKM2 or EZH2 increases levels of SLC16A9 and intracellular Carnitine to promote FAO and thereby sustains cancer cell growth. Direct inhibition of EZH2 using a clinically tested EZH2 inhibitor, GSK126, is able to elicit a previously unidentified vulnerability to a clinically tested FAO inhibitor, Etomoxir. As a result, combined GSK126-Etomoxir treatment synergistically abolishes TNBC xenograft tumor growth in vivo. Together, this study uncovers PKM2-EZH2 mediated metabolic reprogramming that leads to a new drug combination therapy by dual targeting of EZH2 and FAO for effective treatment of TNBC.<b> </b></p> <p> </p> <p>Furthermore, Dendritic Cell (DC) vaccination has shown promise in treating cancer patients. However, the <i>in vitro</i> generation of a fully functional DC remains a big challenge in this field. EZH2 inhibition has shown to be able to create an immunologically ‘hot’ tumors. Nonetheless, the role of EZH2 in regulation of DC function is still unclear. I found that the expression levels of EZH2 and its functional maker, H3K27Me3, are enhanced following maturation from immature DC (iDC) into two functional DCs, α-type 1-polarized-DC (αDC) and gold standard DC (sDC). Moreover, inhibition of EZH2 by GSK126 treatment elicits a dependency of sDC on FAO. These results suggest that EZH2 plays a role in maturation of DC through metabolic reprogramming, which may also provide new DC based immunotherapy of TNBC. </p>

Det anonyma företaget är ett IT-tjänsteföretag som utför IT-tjänster efter kunds behov. De fick för några månader sedan en internetleverantör som kund. De sköter konfigurationen av internetleverantörens routrar och switchar som sen skickas till internetleverantörens företagskunder. Arbetet går ut pa att uppgradera operativsystem på routrar och switchar samt lägga till filer och sedan skicka produkt till internetleverantörens slutkund. Filer och operativsystem skiljer sig åt beroende på vilken typ av router och switch som ska uppgraderas. Arbetssättet idag är ineffektivt och det blir en del fel då man idag arbetar med USB minnen. Målet med detta arbete är att effektivisera deras arbetssätt genom att lagra alla filer på en TFTP server istället för på USB minnen. Ett skript ska skapas med språket VB script som automatiserar konfigurationen av routrar och switchar. Terminal för att kunna kommunicera med router/switch är SecureCrt. Personal på Företaget har sagt att det i snitt tar ca 15 minuter att konfigurera en router manuellt. Man kör endast en åt gången pga. kvalitetssäkring och man måste sitta framför skärmen under hela förloppet då man konfigurerar manuellt. Resultatet av mitt arbete ledde till en effektivisering. Tiden det tar att konfigurera en router hamnar pa samma tid, ca 15 minuter, dock kan man köra flera samtidigt men pga. platsbrist så kan de köra max två åt gången samtidigt som man inte behöver sitta framför skärmen då skriptet sköter all konfiguration. Det blev också säkrare att köra då man slipper leta efter rätt USB minne till motsvarande enhet. / The anonymous company is an IT company that performs IT services according to customer needs. They got an internet provider as a customer about a couple of months ago. They manage the configuration of the ISP's routers and switches, which are then sent to the ISP's corporate customers. The work involves upgrading operating systems on routers and switches as well as adding files and then sending the product to the ISP’s end customer. Files and operating systems differ depending on the type of router and switch to be upgraded. The working method today is inefficient and there can be some errors when working with USB memory sticks today. The goal of this work is to improve and make their operation more effective by storing all files on a TFTP server instead of on USB storage. A script will be created with the language VB script that automates the configuration of routers and switches. The terminal for communicating with the router/switch is SecureCrt. Staff at the company have said that it takes on average about 15 minutes to manually configure a router. You only configure one at a time due to quality assurance and you have to sit in front of the screen throughout the process when configuring manually. The result of my work led to an efficiency improvement. The time it takes to configure a router ends at the same time, about 15 minutes, however, you can run several units simultaneously but because of lack of space, they can run a maximum of two at a time, while not having to sit in front of the screen as the script handles all configuration. It also led to lesser errors as you do not have to look for the correct USB memory for the corresponding device.

The diagnostic technique, polarization and depolarization current (PDC) is useful for insulation testing. It requires applying a DC step voltage to the test sample and measuring the current. To measure fast PDC phenomena a fast step is needed. One way of applying a fast high voltage step is to use power electronic switches. Series connection can be used to increase the voltage limit, but this result in unequal voltage sharing unless equipped with voltage balancing. In this work a high voltage vacuum reed switch is investigated as a simple and low-cost alternative to power electronic switches, handling up to 10 kV with a single device. The switch turn on and off behavior was studied. It was found that the initial turn-on is good, in the range of nanoseconds, but there is a problem with the vacuum recovering its insulating properties at low currents before the contacts fully close. The required output voltage level is therefore obtained only after a further settling time that increases with increased input voltage and is much longer than the initial breakdown, e.g. 20 µs for the case of 4.5 kV input voltage. Other limitations of the fast high voltage PDC were also studied. The output voltage was measured across the test sample without adding an intentional resistor in the circuit. There were large oscillations for 1 µs but these oscillations are damped due to inherent resistance of the connecting leads, series resistance of the capacitors and resistance of the reed switch. A comparison is made between the measured and the simulated results using MATLAB to see the effect of parasitic inductance. A damping resistor was added in the circuit and the output results were again compared. With the addition of the damping resistor, the number of oscillations were reduced and their time scale was limited to 0.1 µs . An analysis is made at the end which describes the limitation occurring in determining the high frequency component of PDC. The current during the step is many orders of magnitude higher than the polarization current even at 1 µs , so measurement of the current and protection of the apparatus is not trivial.

Det finns många olika källor där man kan få information om sårbarheter i routrar och switchar. Mängden information gör det dock svårt att på ett enkelt sätt ta reda på vilka tillverkare som drabbas och vilken typ av sårbarheter man hittar i nätverksutrustning. Därmed är det också svårt att veta hur man ska skydda sin utrustning mot attacker. I detta examensarbete analyseras ett antal befintliga sårbarheter i routrar och switchar. Dessa sårbarheter har valts ut genom att i National Vulnerability Database söka på orden ”router” och ”switch”. Målet med analysen är att svara på frågorna vem, vad och varför när det gäller sårbarheter i routrar och switchar. Examensarbetet beskriver vilka tillverkare som drabbas av sårbarheter, vilka typer av sårbarheter som är vanligast i routrar och switchar och varför sårbarheterna har uppstått. Utifrån detta dras slutsatser om vad man som användare ska göra för att undvika attacker mot sin utrustning. I arbetet beskrivs också hur tillverkarna väljer att hantera de sårbarheter som finns i deras produkter. / There are a lot of different sources to information about vulnerabilities in routers and switches. The amount of information means that there is no easy way to find out which vendors are affected by vulnerabilities and what types of vulnerabilities that are found in network equipment. Thereby it is also hard to know how to protect your equipment against attacks. In this thesis a number of already existing vulnerabilities in router and switches are being analyzed. These vulnerabilities have been chosen by searching the National Vulnerability Database using the words “router” and “switch”. The aim of the analysis is to answer the questions who, what and why when it comes to vulnerabilities in routers and switches. The thesis describes which vendors are exposed to vulnerabilities, what types of vulnerabilities that are most common among routers and switches and why these vulnerabilities have came up. Based on this information, conclusions are drawn regarding what the user should do to avoid vulnerabilities in their equipment. The way the companies deal with vulnerabilities in their products is also described.

<div><div><div><p>The brain dynamically alters its production of flexible behavior: cognitive flexibility increases when demand is high. In task switching experiments, past exposure to a high demand for flexibility in conjunction with specific temporal contexts leads to learned switch readiness such that future exposures to those contexts will cue flexibility. According to a recent proposal (Dreisbach & Fröber, 2019), learned switch readiness following switch demands is supported by a concurrent activation (CA) cognitive mechanism whereby both sets of task rules are kept available in working memory despite only using one at a time. This can be differentiated from a competing candidate mechanism, working memory updating (WMU) thresholds which determine the ease of replacing one task’s rules with another. The WMU mechanism is expected to cause a global increase in flexibility while CA is conceptualized as limited to task-specific associations. To test whether learned switch readiness represents a global or limited change in the cognitive system, I conducted two experiments that both involved learning switch readiness in one context and generalizing it in another. In Experiment 1, I replicated and extended findings that switch probability manipulations can modulate voluntary switch rates (VSR), indicating one type of generalizability. However, in Experiment 2, I found that flexibility learned through switch probability manipulations did not transfer to new tasks when the task rules were changed but contextual cues remained the same, demonstrating a limit: learned switch readiness does not generalize across tasks. These findings together suggest that CA is likely the mechanism behind learned switch readiness.</p></div></div></div>

This communication will demonstrate the existence of a thermodynamic molecular switch in the pairwise, sequence-specific hydrophobic interaction of Ile-Ile, Leu-Ile, Val-Leu, or Ala-Leu over the temperature range of 273-333 K reported by Nemethy and Scheraga in 1962. Based on Chun's development of the Planck-Benzinger methodology, the change in inherent chemical bond energy at 0 K, ΔH°(T0), is 3.0 kcal mol-1 for Ile-Ile, 2.4 for Leu-Ile, 1.8 for Val-Leu, and 1.2 kcal mol-1 for Ala-Leu. The value of ΔH°(T0) decreases as the length of the hydrophobics side chain decreases. It is clear that the strength and stability of the hydrophobic interaction is determined by the packing density of the side chains, with Ala-Leu being the most stable. At , the thermal agitation energy, ∫0T ΔCp°(T)dT, is about five times greater than ΔH°(T0) in each case. Additionally, the thermal agitation energy for the same series, evaluated at , decreases in the same order, that is, as the length of the side chain decreases. This pairwise, sequence-specific hydrophobic interaction is highly similar in its thermodynamic behavior to that of other biological systems, except that the negative Gibbs free energy change minimum at occurs at a considerably higher temperature, 355 K compared to about 300 K. The melting temperature, , is also high, 470K compared to 343 K in a biological system. The implication is that the negative Gibbs free energy minimum at a well-defined >Ts> has it origin in the hydrophobic interactions, which are highly dependent on details of molecular structure. In addition to the four specific dipeptide interactions described, we have shown in our unpublished work the existence of a thermodynamic molecular switch in the interactions of 32 dipeptides wherein a change of sign in ΔCp°(T)reaction leads to a true negative minimum in the Gibbs free energy of reaction, and hence, a maximum in the related Keq. Indeed, all interacting biological systems that we have thus far examined using the Planck-Benzinger approach point to the universality of thermodynamic molecular switches.

Antibiotic resistance is a quickly emerging public health crisis, accounting for more than 700,000 annual global deaths. Global human antibiotic overuse and misuse has significantly expedited the rate at which bacteria become resistant to antibiotics. A renewed focus on discovering new antibiotics is one approach to addressing this crisis. However, it alone cannot solve the problem: historically, the introduction of a new antibiotic has consistently, and at times rapidly, been followed by the appearance and dissemination of resistant bacteria. It is thus crucial to develop strategies to improve how we select and deploy antibiotics so that we can control and prevent the emergence and transmission of antibiotic resistance. Current gold-standard antibiotic susceptibility tests measure bacterial growth, which can take up to 72 hours. However, bacteria exhibit more immediate measurable phenotypes of antibiotic susceptibility, including changes in transcription, after brief antibiotic exposure. In this dissertation I develop a framework for building a paper-based cell-free toehold sensor antibiotic susceptibility test that can detect differential mRNA expression. I also explore how long-term lab evolution experiments can be used to prospectively uncover transcriptional signatures of antibiotic susceptibility. Paper-based cell-free systems provide an opportunity for developing clinically tractable nucleic-acid based diagnostics that are low-cost, rapid, and sensitive. I develop a computational workflow to rapidly and easily design toehold switch sensors, amplification primers, and synthetic RNAs. I develop an experimental workflow, based on existing paper-based cell-free technology, for screening toehold sensors, amplifying bacterial mRNA, and deploying sensors for differential mRNA detection. I combine this work to introduce a paper-based cell-free toehold sensor antibiotic susceptibility test that can detect fluoroquinolone-susceptible E. coli. Next, I describe a methodology for long-term lab evolution and how it can be used to explore the relationship between a phenotype, such as gene expression, and antibiotic resistance acquisition. Using a set of E. coli strains evolved to acquire tetracycline resistance, I explore how each strain's transcriptome changes as resistance increases. Together, this work provides a set of computational and experimental methods that can be used to study the emergence of antibiotic resistance, and improve upon available methods for properly selecting and deploying antibiotics. / 2023-03-17T00:00:00Z