22 research outputs found

    Non-omega-overlapping TRSs are UN

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    This paper solves problem #79 of RTAโ€™s list of open problems [14] โ€” in the positive. If the rules of a TRS do not overlap w.r.t. substitutions of infinite terms then the TRS has unique normal forms. We solve the problem by reducing the problem to one of consistency for โ€œsimilarโ€ constructor term rewriting systems. For this we introduce a new proof technique. We define a relation โ‡“ that is consistent by construction, and which โ€” if transitive โ€” would coincide with the rewrite systemโ€™s equivalence relation =R. We then prove the transitivity of โ‡“ by coalgebraic reasoning. Any concrete proof for instances of this relation only refers to terms of some finite coalgebra, and we then construct an equivalence relation on that coalgebra which coincides with โ‡“

    Confluence of an Extension of Combinatory Logic by Boolean Constants

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    We show confluence of a conditional term rewriting system CL-pc^1, which is an extension of Combinatory Logic by Boolean constants. This solves problem 15 from the RTA list of open problems. The proof has been fully formalized in the Coq proof assistant

    MicroRNAs for Virus Pathogenicity and Host Responses, Identified in SARS-CoV-2 Genomes, May Play Roles in Viral-Host Co-Evolution in Putative Zoonotic Host Species

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    Our recent study identified seven key microRNAs (miR-8066, 5197, 3611, 3934-3p, 1307-3p, 3691-3p, 1468-5p) similar between SARS-CoV-2 and the human genome, pointing at miR-related mechanisms in viral entry and the regulatory effects on host immunity. To identify the putative roles of these miRs in zoonosis, we assessed their conservation, compared with humans, in some key wild and domestic animal carriers of zoonotic viruses, including bat, pangolin, pig, cow, rat, and chicken. Out of the seven miRs under study, miR-3611 was the most strongly conserved across all species; miR-5197 was the most conserved in pangolin, pig, cow, bat, and rat; miR-1307 was most strongly conserved in pangolin, pig, cow, bat, and human; miR-3691-3p in pangolin, cow, and human; miR-3934-3p in pig and cow, followed by pangolin and bat; miR-1468 was most conserved in pangolin, pig, and bat; while miR-8066 was most conserved in pangolin and pig. In humans, miR-3611 and miR-1307 were most conserved, while miR-8066, miR-5197, miR-3334-3p and miR-1468 were least conserved, compared with pangolin, pig, cow, and bat. Furthermore, we identified that changes in the miR-5197 nucleotides between pangolin and human can generate three new miRs, with differing tissue distribution in the brain, lung, intestines, lymph nodes, and muscle, and with different downstream regulatory effects on KEGG pathways. This may be of considerable importance as miR-5197 is localized in the spike protein transcript area of the SARS-CoV-2 genome. Our findings may indicate roles for these miRs in viralโ€“host co-evolution in zoonotic hosts, particularly highlighting pangolin, bat, cow, and pig as putative zoonotic carriers, while highlighting the miRsโ€™ roles in KEGG pathways linked to viral pathogenicity and host responses in humans. This in silico study paves the way for investigations into the roles of miRs in zoonotic disease

    ๊ฐ€์Šคํ„ฐ๋นˆ ๋ฆผ ์”ฐ ์„ฑ๋Šฅ์— ํœ ์ŠคํŽ˜์ด์Šค ์Šค์›”์ด ๋ฏธ์น˜๋Š” ์˜ํ–ฅ ์ธก์ •

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    ํ•™์œ„๋…ผ๋ฌธ (์„์‚ฌ)-- ์„œ์šธ๋Œ€ํ•™๊ต ๋Œ€ํ•™์› : ๊ณต๊ณผ๋Œ€ํ•™ ๊ธฐ๊ณ„ํ•ญ๊ณต๊ณตํ•™๋ถ€, 2019. 2. ์†ก์„ฑ์ง„.๊ฐ€์Šคํ„ฐ๋นˆ ์—”์ง„์€ ๊ฐ€์žฅ ํšจ์œจ์ ์ธ ๋™๋ ฅ์›์œผ๋กœ์„œ ์ œํŠธ ์ถ”์ง„ ๋ฐ ๋ฐœ์ „์„ ์œ„ํ•ด ๋„๋ฆฌ ์‚ฌ์šฉ๋˜์–ด์™”๋‹ค. ์ฒจ๋‹จ ์žฌ๋ฃŒ๊ณตํ•™๊ณผ ์ด์ฐจ ์œ ๋กœ ์‹œ์Šคํ…œ, ๋Œ€๋ฅ˜ ๋ƒ‰๊ฐ, ๋ง‰ ๋ƒ‰๊ฐ ๋“ฑ์˜ ์ง„๋ณดํ•œ ๊ฐ€์Šคํ„ฐ๋นˆ ๋ƒ‰๊ฐ ๊ธฐ์ˆ ์˜ ๋„์ž…์€ ๊ณ ํšจ์œจ, ๊ณ ์ถœ๋ ฅ ๊ฐ€์Šคํ„ฐ๋นˆ ์—”์ง„์˜ ์ง€์†์ ์ธ ๋ฐœ์ „์˜ ์ฃผ์ถง๋Œ์ด ๋˜์—ˆ๋‹ค. ํ˜„๋Œ€์˜ ๊ฐ€์Šคํ„ฐ๋นˆ ์—”์ง„์—์„œ ํ„ฐ๋นˆ์€ 20-30%์˜ ์••์ถ•๊ธฐ ๊ณต๊ธฐ๋ฅผ ๋ƒ‰๊ฐ, ์”ฐ๋ง ๋ฐ ๋ˆ„์„ค ์œ ๋™์œผ๋กœ ์†Œ๋น„ํ•œ๋‹ค. ๋†’์€ ํ„ฐ๋นˆ ์ž…๊ตฌ ์˜จ๋„๊ฐ€ ๋‹ค๋ฅธ ๋ชจ๋“  ์†์‹ค์„ ๋ณด์ƒํ•œ๋‹ค ํ•˜๋”๋ผ๋„, ์ด๋Ÿฌํ•œ ์œ ๋Ÿ‰ ์†์‹ค์€ ์ „ํšจ์œจ์— ์‹ฌ๊ฐํ•œ ๋ถˆ์ด์ต์„ ์ดˆ๋ž˜ํ•œ๋‹ค. ๋”ฐ๋ผ์„œ, ์”ฐ๋ง ์œ ๋Ÿ‰์„ ์ค„์ผ ์ˆ˜ ์žˆ๋Š” ํš๊ธฐ์ ์ธ ์„ค๊ณ„๊ฐ€ ๋†’์€ ์ „ํšจ์œจ์„ ๋‹ฌ์„ฑํ•˜๊ธฐ ์œ„ํ•œ ํ•˜๋‚˜์˜ ์ค‘์š”ํ•œ ์š”์ธ์ด ๋˜์—ˆ๋‹ค. ์Šคํ…Œ์ดํ„ฐ์™€ ๋กœํ„ฐ ๋””์Šคํฌ ์‚ฌ์ด์— ํ˜•์„ฑ๋˜๋Š” ํœ ์ŠคํŽ˜์ด์Šค๋กœ์˜ ์ฃผ์œ ๋กœ ๊ณ ์˜จ ๊ฐ€์Šค ์œ ์ž… ๋ฌธ์ œ๋Š” ์ด์ฐจ ์œ ๋กœ ์‹œ์Šคํ…œ์ด ๋‹น๋ฉดํ•œ ์ค‘์š”ํ•˜๊ณ  ๋ณธ์งˆ์ ์ธ ๋ฌธ์ œ์ด๋‹ค. ์ฃผ์œ ๋กœ์™€ ํœ ์ŠคํŽ˜์ด์Šค ์••๋ ฅ ์ฐจ์ด์— ๊ธฐ์ธํ•˜๋Š” ์ด ํ˜„์ƒ์€, ํ„ฐ๋นˆ ๊ตฌ์„ฑํ’ˆ์— ์—ด ํ”ผ๋กœ์™€ ํฌ๋ฆฝ ๊ฐ™์€ ์‹ฌ๊ฐํ•œ ๊ตฌ์กฐ์  ์•ˆ์ •์„ฑ ๋ฌธ์ œ๋ฅผ ์•ผ๊ธฐํ•œ๋‹ค. ๋•Œ๋ฌธ์—, ๋ฐ˜๊ฒฝ ๋ฐ ์ถ• ๋ฐฉํ–ฅ์œผ๋กœ ๊ฒน์ณ์ง€๋Š” ํ˜•์ƒ์˜ ๋ฆผ ์”ฐ์ด ์Šคํ…Œ์ดํ„ฐ์™€ ๋กœํ„ฐ ๊ตฌ์„ฑํ’ˆ์˜ ์ฃผ๋ณ€์— ์žฅ์ฐฉ๋˜๋ฉฐ ์ถฉ๋ถ„ํ•œ ์”ฐ๋ง ์œ ๋Ÿ‰์ด ์œ ์ž…์„ ์ค„์ด๊ฑฐ๋‚˜ ๋ง‰๊ธฐ ์œ„ํ•ด ํœ ์ŠคํŽ˜์ด์Šค๋กœ ๊ณต๊ธ‰๋œ๋‹ค. ๋ฆผ ์”ฐ๋ง์„ ์œ„ํ•œ ์œ ๋Ÿ‰์„ ์ตœ์†Œํ™”ํ•˜๊ธฐ ์œ„ํ•œ ํšจ๊ณผ์ ์ธ ๋ฐฉ๋ฒ•์— ๋Œ€ํ•œ ๋‹ค์–‘ํ•œ ์—ฐ๊ตฌ๊ฐ€ ์ˆ˜ํ–‰๋˜์—ˆ์œผ๋‚˜, ์œ ์ง€๋ณด์ˆ˜์™€ ๊ตฌ์„ฑํ’ˆ ๋ฌด๊ฒŒ์™€ ๊ฐ™์€ ์‹ค์šฉ์„ฑ ์ธก๋ฉด์˜ ๋ฌธ์ œ๊ฐ€ ์„ฑ๋Šฅ ํ–ฅ์ƒ์˜ ๋ฐœ๋ชฉ์„ ์žก์•˜๋‹ค. ๋ณธ ๋…ผ๋ฌธ์€ ๋ฆผ ์”ฐ๋ง ์„ฑ๋Šฅ์„ ํ–ฅ์ƒ์‹œํ‚ค๊ธฐ ์œ„ํ•œ ํš๊ธฐ์ ์ธ ๋ฐฉ๋ฒ•๋ก ์— ๋Œ€ํ•œ ์‹คํ—˜์  ์—ฐ๊ตฌ๋ฅผ ๋‹ค๋ฃฌ๋‹ค. ๋‹จ์ผ ๋ฐ˜๊ฒฝ ๊ฐ„๊ทน ๋ฆผ ์”ฐ๊ณผ ํ•จ๊ป˜ ํŠน์ˆ˜ํ•˜๊ฒŒ ์„ค๊ณ„๋œ ํœ ์ŠคํŽ˜์ด์Šค ์„ ํšŒ๊ธฐ๊ฐ€ ์”ฐ๋ง ์„ฑ๋Šฅ ํ–ฅ์ƒ์„ ํ‰๊ฐ€ํ•˜๊ธฐ ์œ„ํ•ด ์‚ฌ์šฉ๋˜์—ˆ์œผ๋ฉฐ, ํœ ์ŠคํŽ˜์ด์Šค ๋‚ด ์œ ๋™์˜ ์„ ํšŒ ์„ฑ๋ถ„์„ ์ฆ๊ฐ€์‹œํ‚ด์œผ๋กœ์จ 18.49%์˜ ์”ฐ๋ง ์„ฑ๋Šฅ ํ–ฅ์ƒ์„ ๋‹ฌ์„ฑํ•˜์˜€๋‹ค. ํœ ์ŠคํŽ˜์ด์Šค ๋‚ด์—์„œ ์”ฐ๋ง ํšจ๊ณผ์™€ ์„ ํšŒ๋น„, ๋ฐ˜๊ฒฝ ๋ฐฉํ–ฅ ์†๋„ ๋ถ„ํฌ๋ฅผ ํฌํ•จํ•œ ๋‹ค์–‘ํ•œ ์ธก์ •์ด ์ด๋ฃจ์–ด์กŒ๋‹ค. ๋น„๋ก ๋ฆผ ์”ฐ์„ ํ†ตํ•œ ์œ ์ž…์€ ๋น„์ •์ƒ, 3์ฐจ์› ์œ ๋™์žฅ์— ๊ธฐ์ธํ•˜์ง€๋งŒ, ์‹คํ—˜ ๋ฐ์ดํ„ฐ๋Š” ํœ ์ŠคํŽ˜์ด์Šค ๋‚ด ์œ ๋™์˜ ์œ ์ฒด์—ญํ•™์  ํ†ต์ฐฐ๋ ฅ์„ ์ œ๊ณตํ•œ๋‹ค. ์ด๋Ÿฌํ•œ ์‹คํ—˜์  ์ธก์ •์€ ํ–ฅํ›„ ์—”์ง„ ์„ค๊ณ„์˜ ๋ฐ์ดํ„ฐ๋ฒ ์ด์Šค๋ฅผ ํ™•์žฅํ•˜๋Š”๋ฐ ๊ธฐ์—ฌํ•  ๊ฒƒ์œผ๋กœ ๊ธฐ๋Œ€๋œ๋‹ค. ๊ณต๋ ฅ ์„ฑ๋Šฅ์‹œํ—˜๊ณผ ์ด์ฐจ ์œ ๋กœ ์‹œ์Šคํ…œ ์—ฐ๊ตฌ๋ฅผ ์œ„ํ•ด 1๋‹จ ์ถ•๋ฅ˜ ํ„ฐ๋นˆ ์‹œํ—˜ ์žฅ๋น„๊ฐ€ ์ƒˆ๋กœ์ด ์„ค๊ณ„๋˜์—ˆ๋‹ค. ์‹œํ—˜ ์žฅ๋น„์˜ ํ˜•์ƒ๊ณผ ์œ ๋™ ์กฐ๊ฑด์€ ์‹ค์ œ ์—”์ง„์„ ๋ฌด์ฐจ์› ์ƒ์‚ฌํ•จ์œผ๋กœ์จ ์—”์ง„์˜ ์ฃผ์œ ๋กœ ๋ฐ ํœ ์ŠคํŽ˜์ด์Šค ์œ ๋™์„ ๋ชจ์‚ฌํ•  ์ˆ˜ ์žˆ๋„๋ก ์„ค๊ณ„๋˜์—ˆ๋‹ค. ์„ค๊ณ„ ํ•ญ๋ชฉ์€ ๋™๋ ฅ์› ๊ตฌ์„ฑ, ์‹œํ—˜๋ถ€ ์„ค๊ณ„, ์žฌ์งˆ ์„ ์ •, ๊ตฌ์กฐ ํ•ด์„, ๊ณต์ฐจ ๊ด€๋ฆฌ ๋ฐ ๋ฐธ๋Ÿฐ์‹ฑ, ๊ณ„์ธก ์žฅ๋น„ ๊ตฌ์„ฑ์„ ํฌํ•จํ•œ๋‹ค. ์šด์ „ ์กฐ๊ฑด์€ ํƒ€๊ธฐ๊ด€ ์‹œํ—˜ ์„ค๋น„์˜ ์‚ฌ์–‘๊ณผ ์ผ์น˜ํ•˜๋Š” ๊ฒฝํ–ฅ์„ ๋ณด์—ฌ์ฃผ์—ˆ์œผ๋ฉฐ, ์„ค๊ณ„๋œ ์‹œํ—˜ ์žฅ๋น„๋Š” ๊ณ ์••ํ„ฐ๋นˆ๋‹จ์— ๋„๋ฆฌ ์ด์šฉ๋˜๋Š” ์ด์ค‘ ๋ฐ˜๊ฒฝ ๊ฐ„๊ทน ๋ฆผ ์”ฐ๋กœ ๊ฒ€์ฆ๋˜์—ˆ๋‹ค. ํฌ๊ด„์ ์ธ ๊ณ„์ธก์žฅ๋น„ ๊ตฌ์„ฑ์€ ์ฃผ์œ ๋กœ์™€ ํœ ์ŠคํŽ˜์ด์Šค ๋‚ด์—์„œ ๋‹ค์–‘ํ•œ ์ธก์ •์„ ๊ฐ€๋Šฅ์ผ€ํ•œ๋‹ค. ๋˜ํ•œ, ์‹œํ—˜ ์žฅ๋น„์— ์ ์šฉ๋œ ์„ค๊ณ„ ํŠน์„ฑ๋“ค์„ ํ†ตํ•ด ๋‹ค์–‘ํ•œ ์‹œํ—˜ ํ™˜๊ฒฝ์„ ์กฐ์„ฑํ•  ์ˆ˜ ์žˆ๋‹ค.As the most adaptable source of power, the gas turbine engines have been widely used for jet propulsion, marine and industrial application. Introduction of advanced gas turbine cooling technologiessecondary air system, internal convective cooling, external surface film cooling with cutting edge metallurgy, formed one of the major pillars supporting the continuous development of high efficiency, high power output gas turbine engines. In modern gas turbine engines, the turbine alone may use 20 to 30% of the compressor air for cooling, sealing and leakage flows, which presents a severe penalty on the overall efficiency even the turbine inlet temperature is sufficiently high for the gains to outweigh the losses. Therefore, the novel design to minimize the sealing flow demand will be a key factor to achieve the better overall efficiency of the engines. The hot mainstream gas ingress into the wheel-space, formed between the stator and rotor disks, is one of the most important and intrinsic problems of the secondary air system faced. Principally governed by the pressure difference between mainstream annulus and wheel-space, the turbine components experience serious structural integrity problems such as thermal fatigue and unwanted creep. The rim seals, with the combinations of radial and axial overlapping geometries, are installed at the endwall platform between stator and rotor components. Inevitably, sufficient sealing flow is introduced into wheel-space to reduce or isolate the ingress. The efficient methods to minimize the sealing flow demand for rim sealing purpose have been studied, however, following practical problems in the aspect of maintenance and weight of components caught up with further improvement. This thesis presents an experimental investigation of novel methodology to improve rim sealing performance. By adding swirl flow component inside the wheel-space, 18.49% reduction in sealing flow demand was achieved. The single radial-clearance rim seal with specially designed blades, called ``wheel-space swirler'', are used to evaluate the sealing performance improvement. The extensive range of measurements including sealing effectiveness, swirl ratio and radial velocity distribution inside the wheel-space had been conducted. Although the ingress through the rim seal is a consequence of an unsteady, three-dimensional flow field, the experimental data gave insights into the fluid dynamics for wheel-space flow. These experimental measurements are expected to provide the wider database that can be used for future engine design. The design of single-stage axial turbine research facility, available on both aerodynamic performance and secondary air system studies, is described. It was designed to fulfil engine representative flows both in mainstream and wheel-space, by downscaling the full size engine. The on-design operating conditions are shown to be in the trend of other gas turbine research facilities. The research facility was validated with the double radial-clearance rim seal which has been widely used in high pressure turbine stage. Comprehensive instrumentations allow the detailed measurements both in the mainstream and wheel-space. The design features applied on the research facility enable versatile test configurations.Abstract Contents List of Tables List of Figures Nomenclature Chapter 1 Introduction 1.1 Gas Turbine Engines 1.2 Secondary Air System 1.3 Hot Gas Ingestion 1.4 Thesis Aims 1.5 Thesis Outline Chapter 2 Literature Review 2.1 Wheel-space Flow Structure 2.2 Hot Gas Ingestion 2.2.1 Experiments on Various Rim Seal Congurations 2.2.2 Analytical Models 2.3 Mainstream and Sealing Flow Interactions Chapter 3 Design of a Single-stage Axial Turbine Research Facility 3.1 Overview 3.2 Flow Path Configurations 3.3 Powertrain and Carriage System 3.4 Test Section Configuration 3.4.1 Stage Design 3.4.2 Wheel-space Geometries 3.5 Material Selections 3.6 Structural Analysis 3.7 Machining and Assembly Features 3.7.1 Tolerance and Surface Roughness Control 3.7.2 Balancing and Bearing Selection 3.8 Instrumentations 3.8.1 Mainstream Annulus and Secondary Flow Line 3.8.2 Wheel-space 3.8.3 Data Acquisition System 3.9 Sensor Calibrations and Uncertainty Analysis Chapter 4 Experimental Measurements on Double Rim Seal For Facility Validation 4.1 Test Configurations for Double Rim Seal 4.2 Sealing Effectiveness 4.3 Pressure and Velocity Measurements 4.3.1 Mainstream Pressure Asymmetries 4.3.2 Swirl Ratio Chapter 5 Study of Wheel-space Swirl Effects on Single Rim Seal Performance 5.1 Test Configurations for Single Rim Seal 5.2 Wheel-space Swirler Design 5.3 Sealing Effectiveness 5.4 Pressure and Velocity Measurements 5.4.1 Mainstream Pressure Asymmetries 5.4.2 Swirl Ratio and Wheel-space Pressure 5.4.3 Wheel-space Radial Velocity Chapter 6 Conclusion 6.1 Design of the Experimental Facility 6.2 Facility Validation 6.3 Wheel-space Swirl Effects on Sealing Performance 6.4 Proposal for Modified Orifice Model 6.5 Practical Implications 6.6 Scaling to Engine Conditions 6.7 Future Works Bibliography Appendix A Owen's Orifice Model ๊ตญ๋ฌธ์ดˆ๋กMaste

    Daily Eastern News: September 28, 1988

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    https://thekeep.eiu.edu/den_1988_sep/1017/thumbnail.jp

    Daily Eastern News: September 28, 1988

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    https://thekeep.eiu.edu/den_1988_sep/1017/thumbnail.jp

    Daily Eastern News: September 28, 1988

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    https://thekeep.eiu.edu/den_1988_sep/1017/thumbnail.jp

    Tools and Algorithms for the Construction and Analysis of Systems

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    This open access two-volume set constitutes the proceedings of the 26th International Conference on Tools and Algorithms for the Construction and Analysis of Systems, TACAS 2020, which took place in Dublin, Ireland, in April 2020, and was held as Part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2020. The total of 60 regular papers presented in these volumes was carefully reviewed and selected from 155 submissions. The papers are organized in topical sections as follows: Part I: Program verification; SAT and SMT; Timed and Dynamical Systems; Verifying Concurrent Systems; Probabilistic Systems; Model Checking and Reachability; and Timed and Probabilistic Systems. Part II: Bisimulation; Verification and Efficiency; Logic and Proof; Tools and Case Studies; Games and Automata; and SV-COMP 2020

    Regulatory Mechanisms of Bacterial Stress Responses

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    Bacterial growth and survival critically hinges on the ability to rapidly adapt to ever-changing environmental conditions. Elaborated stress response systems allow bacteria to sensitively detect and adequately respond to fluctuations in environmental conditions, such as pH, temperature, osmolarity, or the concentrations of nutrients and harmful substances. Often, bacterial stress responses towards a specific stressor involve multiple interconnected mechanisms - controlled by a sophisticated network involving signal-transduction cascades, metabolic pathways and gene expression regulation. In this thesis, bacterial stress responses towards two different environmental stressors are analysed; mainly focussing on the regulatory mechanisms that give rise to the overall cellular response. The first part of this thesis addresses the heme stress response in Corynebacterium glutamucim. Heme is an essential cofactor and alternative iron source for almost all bacterial species but can cause severe toxicity when present in elevated concentrations. Consequently, heme homeostasis needs to be tightly controlled. Therefore, one important challenge is to understand how bacteria regulate heme stress responses to both benefit from heme while simultaneously eliminating the associated toxicity. It is shown that C. glutamicum induces a heme detoxification mechanism (mediated via the heme exporter HrtBA) and a heme utilization mechanism (mediated via the heme ogygenase HmuO) in a temporal hierarchy, with prioritisation of detoxification over utilization. A combined approach of experimental reporter profiling and computational modelling reveals how differential biochemical properties of the two two-component systems that sense heme in C. glutamicum - ChrSA and HrrSA - and an additional regulator (the global iron-regulator DtxR) control this hierarchical expression of the two stress response modules. This analysis sheds light on the multi-layered heme stress response that contributes to overall heme homeostasis in C. glutamicum and adds on to the understanding of bacterial strategies to deal with the Janus-faced nature of heme. The second part of this thesis focusses on bacterial response strategies towards cell wall antibiotics, which play a key role in bacterial antibiotic resistance. To combat resistance evolution, it is important to understand how cell wall antibiotics affect bacterial cell wall biosynthesis and how bacteria orchestrate stress response mechanisms to protect themselves from cell wall damage. The first question is addressed through a comprehensive mathematical model describing the bacterial cell wall synthetic pathway - the lipid II cycle - and its systems-level behaviour under antibiotic treatment. It is found that the lipid II cycle features a highly asymmetric distribution of pathway intermediates and that the efficacy of antibiotics in vivo scales directly with the abundance of targeted pathway intermediates: The lower the relative abundance of a lipid II intermediate within the lipid II cycle, the lower the in vivo efficacy of an antibiotic targeting this intermediate. This leads to the formulation of a novel principle of โ€˜minimal target exposureโ€™ as an intrinsic bacterial resistance mechanism and it is demonstrated that cooperativity in drug-target binding can mitigate the associated resistance. The development of new drugs to counteract antibiotic resistance clearly benefit from these insights. The second question is then addresses by an experimental-based expansion of the model, which allows the analysis of the interplay between multiple stress response mechanisms that protect against a single antibiotic - focussing here on the well-studied response of Bacillus subtilis towards the cell wall antibiotic bacitracin. This study reveals that the properties of the lipid II cycle itself control the interaction between the primary bacitracin stress response determinant BceAB mediating bacitracin detoxification, and the secondary determinant BcrC, which contributes to cell wall homeostasis under bacitracin treatment. By elucidating regulatory mechanisms of the multi-layered response towards bacitracin, this analysis contributes to an advanced understanding of bacterial antibiotic resistance
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