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Serum response factor (SRF) controls gene transcription in vascular smooth muscle cells (VSMCs) and regulates VSMC phenotypic switch from a contractile to a synthetic state, which plays a key role in the pathogenesis of cardiovascular diseases (CVD). SRF activity is regulated by its associated cofactors. However, it is not known how post-translational SUMOylation regulates the SRF activity in CVD. Here, we show that Senp1 deficiency in VSMCs increased SUMOylated SRF and the SRF-ELK complex, leading to augmented vascular remodeling and neointimal formation in mice. Mechanistically, SENP1 deficiency in VSMCs increased SRF SUMOylation at lysine 143, which reduced its lysosomal localization concomitant with increased nuclear accumulation. SUMOylation of SRF switched its binding with the contractile phenotype-responsive cofactor myocardin to binding with the synthetic phenotype-responsive cofactor phosphorylated ELK1. Both SUMOylated SRF and phosphor-ELK1 were increased in VSMCs from coronary arteries of CVD patients. Importantly, preventing the shift from SRF-myocardin to SRF-ELK complex by AZD6244 inhibited the excessive proliferative, migratory, and synthetic phenotypes, attenuating neointimal formation in Senp 1-deficient mice. Therefore, targeting the SRF complex may have a therapeutic potential for the treatment of CVD., Competing Interests: COMPETING INTERESTS STATEMENT The authors declare no competing interests.

Purpose Several healthcare quality assessment tools measure the processes and outcomes of the care system. The actual physical infrastructure (buildings and organizational) aspects are, however, rarely considered. The purpose of this paper is to describe the process of validation and weighting of an evidence-informed framework for the quality assessment of hospital facilities from social, environmental and organizational perspectives to complement other assessments. Design/methodology/approach Sustainable High-quality Healthcare version 2 (SustHealth v2) is the updated version of an existing framework composed of three domains (social, environmental and organizational quality). To validate and establish a relevant weighting, interviews were conducted with 15 professionals within the field of healthcare planning, design, research and management. The study has been conducted through semi-structured interviews and the application of the Simon Roy Figueras (SRF) procedure for the elicitation of weights criteria. The data collected have been processed through the DecSpace web platform. Findings Among the three domains, the organizational qualities appear to be the most important (W = 49%), followed by the environmental (W = 29%) and social aspects (W = 22%). Relevant indicators such as future-proofing, wayfinding and users’ space control emerged as the most important within each macro-area. Those results are confirmed by the outcome of the interviews that highlight user/patient-centeredness, wayfinding strategies and space functionality as the most important concepts to foster in existing healthcare facilities improvement. Practical implications The study highlights important structural and organizational aspects that hospital managers and planners can consider when dealing with healthcare facilities’ quality improvement. Originality/value The use of the SRF multicriteria method is novel in this context when used to weight an assessment tool with a focus on hospital built environment.

Pericytic tumors comprise a histologic continuum of neoplasms with perivascular myoid differentiation, which includes glomus tumors, myopericytoma, myofibroma, and angioleiomyoma. Despite their morphologic overlap, recent data suggest a dichotomy in their genetic signatures, including recurrent NOTCH gene fusions in glomus tumors and PDGFRB mutations in myofibromas and myopericytomas. Moreover, SRF-RELA fusions have been described in a subset of cellular variants of myofibroma and myopericytoma showing myogenic differentiation. Triggered by an index case of an unclassified cellular myoid tumor showing a novel SRF-ICA1L fusion we have investigated our files for cases showing similar histology and screened them using a combined approach of targeted RNA sequencing and fluorescence in situ hybridization. A fusion between SRF exon 4 and ICA1L exon 10 or 11 was identified in a total of 4 spindle cell tumors with similar clinicopathologic features. Clinically, the tumors were deep-seated and originated in the trunk or proximal lower extremity of adult patients (age range: 23 to 55 y). Histologically, the tumors were composed of cellular fascicles of monomorphic eosinophilic spindle cells showing increased mitotic activity, harboring densely hyalinized stroma, often with focal areas of necrosis. All 4 tumors had similar immunoprofiles with positivity for smooth muscle actin, calponin, and smooth muscle myosin heavy chain. Tumors were negative for desmin and caldesmon, markers often seen in SRF-RELA-positive tumors with similar morphology. Follow-up information was available in 3 patients. Two patients had no evidence of disease, 2 and 5 years after surgical resection. One patient, a 35-year-old male patient with a 19 cm deep-seated tumor with brisk mitotic activity (>20 mitoses in 10 HPF), developed lung metastases 7 years after initial diagnosis. In summary, we report a series of 4 cellular myoid tumors with novel SRF-ICA1L gene fusions, characterized by bland spindle cell fascicular growth, expression of specific smooth muscle markers, elevated mitotic activity, marked stromal hyalinization, focal coagulative necrosis, and potential for malignant behavior. Given the morphologic overlap with related cellular myopericytic tumors with SRF-RELA fusions, it is likely that SRF-ICA1L fusions define a similar subset of neoplasms composed of immature smooth muscle cells.

At the electron accelerator for beams with high brilliance and low emittance (ELBE), the second version of a superconducting radio-frequency (SRF) photoinjector was brought into operation in 2014. After a period of commissioning, a gradual transfer to routine operation took place in 2017 and 2018, so that more than 3000h of user beam have already been generated since 2019. During this time, a total of 20 cathodes (2 Cu, 12 Mg, 6 Cs₂Te) were used, but no serious cavity degradation was observed. In this paper, we summarize the operational experience of the last 6 years of SRF gun operation, with special emphasis on the main RF properties of the cavity. This includes the evolution of QvsE, dark current, multipacting, but also mechanical properties such as Lorentz force detuning, helium pressure sensitivity as well as microphonics. The latter is closely connected to an active compensation by a so-called low-level RF feedback loop, which is also briefly presented., Proceedings of the 20th International Conference on RF Superconductivity, SRF2021, East Lansing, MI, USA

CEA is committed to delivering a Medium Energy Beam Transfer line and a superconducting linac (SCL) for SARAF accelerator in order to accelerate 5 mA beam of either protons from 1.3 MeV to 35 MeV or deuterons from 2.6 MeV to 40 MeV. The SCL consists in four cryomodules. The first two identical cryomodules host 6 half-wave resonator (HWR) low beta cavities (β= 0.09) at 176 MHz. The last two identical cryomodules will host 7 HWR high-beta cavities (β = 0.18) at 176 MHz. The low-beta prototypes was qualified in 2019. Low-beta series manufacturing is on-going. The high-beta prototype was first tested in 2019 but failed. A new prototype was tested in the end of 2020. This contribution will present the results of the tests for low- and high-beta SARAF cavities, series and prototypes., Proceedings of the 20th International Conference on RF Superconductivity, SRF2021, East Lansing, MI, USA

In cells, proteins encoded by the same gene do not all behave uniformly but engage in functional subpopulations induced by spatial or temporal segregation. While conventional microscopy has limitations in revealing such spatial and temporal diversity, single-molecule tracking (SMT) microscopy circumvented this problem and allows for high-resolution imaging and quantification of dynamic single-molecule properties. Particularly in the nucleus, SMT has identified specific DNA residence times of transcription factors (TFs), DNA-bound TF fractions and positions of transcriptional hot-spots upon cell stimulation. By contrast to cell stimulation, SMT has not been employed to follow dynamic TF changes along stages of cell differentiation. Herein, we analysed the serum response factor (SRF), a TF involved in the differentiation of many cell types to study nuclear single-molecule dynamics in neuronal differentiation. Our data in living mouse hippocampal neurons show dynamic changes in SRF DNA residence time and SRF DNA-bound fraction between the stages of adhesion, neurite growth and neurite differentiation in axon and dendrites. Using TALM (tracking and localization microscopy), we identified nuclear positions of SRF clusters and observed changes in their numbers and size during differentiation. Furthermore, we show that the SRF cofactor MRTF-A (myocardin-related TF or MKL1) responds to cell activation by enhancing the long-bound DNA fraction. Finally, a first SMT colocalization study of two proteins was performed in living cells showing enhanced SRF/MRTF-A colocalization upon stimulation. In summary, SMT revealed modulation of dynamic TF properties during cell stimulation and differentiation., publishedVersion

The Proton Improvement Plan II (PIP-II) that will be installed at Fermilab is the first U.S. accelerator project that will have significant contributions from international partners. CEA joined the international collaboration in 2018, and is responsible of the 650 MHz low-beta section made of 9 cryomodules, with the design of the cryostat (i.e the cryomodule without the cavities, the power couplers and the frequency tuning systems) and the manufacturing of its components, the assembly and tests of the pre-production cryomodule and the 9 series ones. This paper will present the design of the 650 MHz low-beta cryomodule., Proceedings of the 20th International Conference on RF Superconductivity, SRF2021, East Lansing, MI, USA

The preparation of SRF cavities includes a lengthy, costly, and safety issued electrochemical polishing (EP or BCP) step to remove the damaged layer coming from the cavity fabrication. We have shown that most of the damage layer is originated from the rolling process during the preparation of the sheet material, while subsequent deep drawing tends to leave only µm thick damage layer. We propose a 2-steps mechanical process that allows us to easily get rid of the thick damage layer on the sheets before cavity forming. The process has been established on samples and extended to large disks ready for 1.3 GHz half-cell forming. The polished sheets will be then sent to KEK for half-cell forming and subsequent surface and material analysis before proceeding to half-cell welding. Former studies on the sample demonstrated that damages induced by forming can successfully be removed by recrystallization and less than 10 µm final chemistry., Proceedings of the 20th International Conference on RF Superconductivity, SRF2021, East Lansing, MI, USA

The sustainable next generation particle accelerators require innovative solutions to overcome the current technological challenges set by existing bulk niobium superconducting radio-frequency (SRF) cavities. Thin film-based multilayer structures in the form of superconductor-insulator-superconductor (SIS) may be the long-sought-after breakthrough for higher performance SRF cavities by enhancing both accelerating gradients and quality factors. In order to understand better the underlying mechanisms of SIS structures to be coated onto (S)RF cavities, we study various material properties with the resultant superconducting properties of high-power im-pulse magnetron sputtering (HiPIMS)-coated S(I)S structures of Nb-(AlN)-NbN with different thicknesses which are designed to be coated mainly on OFHC copper (Cu) samples for more efficient SRF cavities. This contribution presents materials properties of the aforementioned HiPIMS-coated S(I)S structures as well as the superconducting and RF behaviours of these multilayers which are assessed comparatively via DC and AC magnetization techniques., Proceedings of the 31st International Linear Accelerator Conference, LINAC2022, Liverpool, UK

We investigate whether the bank crisis management framework of the European banking union can effectively bar the detrimental influence of national interests in cross-border bank failures. We find that both the internal governance structure and decision making procedure of the Single Resolution Board (SRB) and the interplay between the SRB and national resolution authorities in the implementation of supranationally devised resolution schemes provide inroads that allow opposing national interests to obstruct supranational resolution. We also show that the Single Resolution Fund (SRG), even after the ratification of the reform of the European Stability Mechanism (ESM) and the introduction of the SRF backstop facility, is inapt to overcome these frictions. We propose a full supranationalization of resolution decision making. This would allow European authorities in charge of bank crisis management to operate autonomously and achieve socially optimal outcomes beyond national borders.

Solid recovered fuels (SRF) can provide another treatment option to the solid waste management (SWM) sector. However, in developing countries, to date, this system approach has not found considerable application. In Bolivia, SRF is not deemed within the national regulation and the final disposal in open dumping areas is still a reality. This research article provides the first attempt in evaluating the SRF characteristics and its potentialities in Bolivia, taking La Paz as a case study. Laboratory analysis of the rejects produced after selective collection and sorting has been conducted, focusing on non-hazardous and non-recyclable waste fractions. The international standards related to EN 15359:2011 for the classification of the SRF were employed, assessing the most feasible mix of materials to provide the highest classification of SRF in terms of low calorific value (LCV), chlorine, and mercury concentration. Results reported that the SRF made of 80% plastics (85% PE and 15% PP) and 20% cellulosic (blend 2), as well as 30% plastics (50% PP and 50% PE) and 70% cellulosic (blend 1), can be considered an alternative fuel in Bolivia. On balance, it has been estimated that the use of non-recyclable plastics and cardboard from municipal solid waste can provide, on average, about 0.9-2.7 billion MJ of energy for cement kilns, solving about 1.4-5.3% of the SWM issues and covering about 8-23.4% of the energy demand for cement production in Bolivia. These results are novel for the scientific literature for estimating the potentialities of SRF in Latin America.

The prototype High Beta 650 MHz cryomodule (pHB650 CM) has been designed by an integrated design team, consisting of Fermilab (USA), CEA (France), STFC UKRI (UK), and RRCAT (India). The manufacturing and assembly of this prototype cryomodule is being done at Fermilab, whereas the production cryomodules will be manufactured and assembled by STFC-UKRI. As the first PIP-II cryomodule for which standardization was applied, the design, manufacturing and assembly of this cryomodule led to significant lessons being learnt and experiences gathered. These were incorporated into the design of the pre-production Single Spoke Resonator Type 2 cryomodule (ppSSR2 CM) and the pre-production Low Beta 650 MHz cryomodule (ppLB650 CM). This paper presents the pHB650 CM lessons learned and experiences gathered from the design to the lower coldmass assembly and how this cryomodule has a positive impact on all the next Proton Improvement Plan-II (PIP-II) cryomodules due to the standardization set up among SSR and 650 cryomodules., Proceedings of the 31st International Linear Accelerator Conference, LINAC2022, Liverpool, UK

We present here a description of field emission (FE) measurements set-up developed for elliptical cryomodules test activities at Lund Test Stand 2. A test campaign of field emission measurements has been developed and optimized during cryomodules tests. The scintillator detectors (and their respective shields), chosen for these measurements, have been characterized and optimized. The field emission application has been developed and integrated in the cryomodules tests operator interface. The Initial test results are presented and commented., Proceedings of the 13th International Particle Accelerator Conference, IPAC2022, Bangkok, Thailand

"Bulk niobium (Nb) has been the material of choice for superconducting RF (SRF) cavities but for further improvement in cavity RF performance, one may have to turn to films of Nb and to other superconducting materials deposited on copper as thermal and mechanical support. Other materials known as A15, such as Nb₃Sn or V₃Si and B1 such as NbTiN and NbN are much easier to synthesise in thin films rather than being made as bulk cavity. The potential benefits of using materials other than Nb would be a higher Tc, a potentially higher critical held Hc, leading to potentially significant cryogenics cost reduction if the cavity operation temperature is 4.2 K or higher. We report on optimising deposition parameters and effect of substrate treatment prior to deposition for successful synthesising of Nb and the alternative superconducting thin film with high superconducting properties (Tc and Hsh) on flat substrates and QPR samples in single layer. The DC and RF SC properties have been tested using PPMS and QPR measurements. This work is part of the H2020 ARIES collaboration. We further report on preparation of RF cavities employing these alternative material for future cavity production.", Proceedings of the 20th International Conference on RF Superconductivity, SRF2021, East Lansing, MI, USA

The Serum Response Factor (SRF) is a transcription factor that regulates the expression of a wide set of genes involved in cell proliferation, migration, cytoskeletal organization and myogenesis. Accumulating evidence suggests that SRF may play a role in carcinogenesis and tumor progression in various neoplasms, where it is often involved in different fusion events. Here we investigated SRF rearrangements in soft tissue tumors, along with a gene expression profile analysis to gain insight into the oncogenic mechanism driven by SRF fusion. Whole transcriptome analysis of cell lines transiently overexpressing the SRF::E2F1 chimeric transcript uncovered the specific gene expression profile driven by the aberrant gene fusion, including overexpression of SRF-dependent target genes and of signatures related to myogenic commitment, inflammation and immune activation. This result was confirmed by the analysis of two cases of myoepitheliomas harboring SRF::E2F1 fusion with respect to EWSR1-fusion positive tumors. The recognition of the specific gene signature driven by SRF rearrangement in soft tissue tumors could aid the molecular classification of this rare tumor entity and support therapeutic decisions.

Now that bulk Nb technology has reached it full maturity, improving SRF technology demands that new materials need to be developed. For reasons explained in the talk, all next generation SRF materials will be in the form of thin films. The IFAST project has the ambition to coordinate European activities on that topic, not only throughout its own program (that will be presented here), but also by keeping in touch with all actors worldwide, with the hope of developing a more efficient collaborative actions, in a limited funding context. In this talk, we will present the challenges presented by the development of new thin films materials, each developed for tailored applications and the main research direction proposed by the thin film community., Proceedings of the 65th ICFA Advanced Beam Dynamics Workshop on High Luminosity Circular e+e- Colliders, eeFACT2022, Frascati, Italy

Proceedings of the 31st International Linear Accelerator Conference, LINAC2022, Liverpool, UK 31st International Linear Accelerator Conference, LINAC2022, Liverpool, UK, 28 Aug 2022 - 2 Sep 2022; [Geneva] : JACoW Publishing, Geneva, Switzerland 785-788 (2022). doi:10.18429/JACoW-LINAC2022-THPOPA21, LCLS-II is an X-Ray Free Electron Laser (XFEL) com-missioned in 2022, being the first Continuous Wave (CW) hard XFEL in the world to come into operation. To accelerate the electron beam to an energy of 4 GeV, 280 TESLA type superconducting RF (SRF) cavities are used. A quality factor $(𝑄_𝐿 )$ of $4×10^7$ is used to drive the cavities at a power level of a few kilowatts. For this $𝑄_𝐿$ , the RF cavity bandwidth is 32 Hz. Therefore, keeping the cavity resonance frequency within such bandwidth is imperative to avoid a significant increase in the required drive power. In superconducting accelerators, resonance frequency variations are produced by mechanical microphonic vibrations of the cavities. One source of microphonic noise is rotary machinery such as vacuum pumps or HVAC equipment. A possible method to reject these disturbances is to use Narrowband Active Noise Control (NANC) techniques. Such a technique was already tested at DESY/CMTB [1] and Cornell/CBETA [2].This proceeding presents the implementation of a NANC controller adapted to the LCLS-II Low Level RF (LLRF) control system. Tests showing the rejection of LCLS-II microphonic disturbances are also presented., Published by JACoW Publishing, Geneva, Switzerland, [Geneva]

[Ebook] International Linear Accelerator Conference 2022, 28 August-2 September 2022 : proceedings / McIntosh, Peter ; Burt, Graeme ; Apsimon, Robert ; Schaa, Volker RW , [Geneva] : JACoW Publishing, [2022], 31st International Linear Accelerator Conference, LINAC2022, Liverpool, Germany, 28 Aug 2022 - 2 Sep 2022; Geneva, Switzerland : JACoW Publishing 76-79 (2022). doi:10.18429/JACoW-LINAC2022-MOPOPA02, The European X-Ray Free-Electron Laser (EuXFEL) is to-date the largest X-ray research facility around the world which spans over 3.4 km. EuXFEL is currently being operated in a pulsed mode with a repetition rate of 10Hz. One upgrade scenario consists of operating the EuXFEL also in a Continuous-Wave (CW) mode of operation to improve the quality of experiments. This upgrade brings new challenges and requires new algorithms to deal with controlling a stable accelerating field inside the Superconducting Radiofrequency (SRF) accelerating cavities and keeping them on resonance in this new mode of operation. The purpose of this research work is to identify the mechanical dynamics of the cavities which will facilitate the development of the resonance controller for the CW upgrade. To this extent, experiments were conducted at a test bench. For the first time, in this work, two different types of spectrally rich excitation signals: multi-sine and stepped-sine are used to excite the mechanical dynamics of the cavities using the piezo actuator. After the analysis of experimental data, mechanical modes are successfully identified and will be used to design the controller., Published by JACoW Publishing, Geneva, Switzerland

During the last 10 years, a constant improvement of single-molecule live-cell imaging techniques and single-molecule protein labeling enabled the possibility to study dynamic processes of TFs. Here, highly interesting results have been uncovered, increasing the understanding of TF binding behavior and mRNA bursting. In a previous study also, single-molecule tracking of SRF in a fibroblast cell line was performed, and the established method was adapted to primary hippocampal neurons. By lentiviral transfection of these neurons with Halo-mSRF, it was shown that the SRF bound and long bound fraction was significantly elevated upon stimulation with the growth factor BDNF. Together with the Halo-mSRF αI-helix mutant version, it was shown that the elevation of SRF long bound fraction was diminished upon BDNF stimulation which indicates that the interaction of SRF and MRTF is a fundamental part of SRF mediated gene expression. Along the differentiation stages of primary hippocampal neurons, this thesis uncovered changes in SRF long bound fraction and the DNA residence times. Interestingly, the highest long bound fraction and DNA residence times were identified in neurons in differentiation stage 1. Additional qPCR experiments of neuronal cells in different stages with and without Halo-mSRF overexpression underlined the results discovered in the single-molecule tracking experiments. Interestingly, the IEGs were highly upregulated in stage 1 neurons, whereas no changes were observed in the case of the cytoskeletal genes, which was counterintuitive at first. One reason could be that the gene expression of cytoskeletal genes was upregulated earlier than the first measurement was taken. Due to technical reasons (cell attachment and sufficient Halo-mSRF expression level), the first measurements were taken 5 h after plating. To further investigate this hypothesis, experiments with a genetically modified mouse line would be an option to measure the cells at an earlier time point. Additionally, TALM measurements uncovered changes in Halo-mSRF clusters along the stages of differentiation. Here, changes were detected regarding the cluster number and the cluster size, showing that the cluster size was reduced with increasing nuclear volume, whereas the cluster number was increased. The question of whether these clusters represent transcriptional hot spots was not addressed in this study but represents a highly interesting hypothesis that should be the target of future projects. To target these questions, additional experiments, e.g., single-molecule FISH analysis or the colocalization of SRF with the RNA-polymerase II, can be performed. Additionally, further investigation of SRF target promotor site localizations during neuronal differentiation could gain more explanations about the observed SRF cluster properties in the different stages of differentiation. To address this, the specific binding sites could be labeled using TALEN-based approaches or deactivated Cas9 molecule (dCas9) systems. Nevertheless, it would also be highly interesting to investigate changes in SRF binding dynamics during axonal injury and the followed regeneration process, which also could be a potential further project. Using UV-Laser ablation, single axons could be injured with high precision, and the SRF binding dynamics could be determined beforehand and during the regeneration processes. Taken together, this study provides more data on SRF binding dynamics upon BDNF stimulation which are in line with previous findings. Additionally, changes in SRF long bound fraction and DNA residence time were uncovered along the differentiation stages of primary neurons, indicating that SRF binding behavior differs along the neuronal differentiation.

Solid waste materials that cannot be reused or recycled are increasingly used to produce Solid Recovered Fuels (SRF). They can be transformed by thermochemical processes such as gasification, thus producing a synthesis gas that can be used in cogeneration (heat and electricity) or for the synthesis of liquid or gaseous fuels. SRF constitute a raw material of interest, that has been largely less studied than biomass in gasification. The objective of the thesis is to investigate the pyrolysis and gasification of SRF, in relation with their physical and chemical characteristics, under controlled operating conditions. For this purpose, a new laboratory-scale experimental device was developed. An experimental characterization and CFD calculations provided a complete description of the temperature profiles for the sample and the gas inside the reactor. Several model materials (wood, cardboard, polyethylene terephthalate, polyethylene and polypropylene), often found in SRF, were studied separately, in an inert atmosphere and in the presence of air as an oxidizing agent. The yield and distribution of reaction products (char, gas species, tar) were determined. Pyrolysis of wood/plastic mixtures showed an increased conversion of carbon to gaseous products in comparison with what would be expected with no interaction. Based on the experimental pyrolysis results for the individual model materials, a correlation was developed to predict the product yields as a function of the feedstock C, H and O contents., Certains déchets solides qui ne peuvent être ni réutilisés ni recyclés sont de plus en plus utilisés dans la production de Combustibles Solides de Récupération (CSR). Ils peuvent être valorisés par des procédés thermochimiques comme la gazéification, produisant ainsi un gaz de synthèse utilisable en cogénération (chaleur et électricité) ou pour la synthèse de carburants liquides ou gazeux. Les CSR constituent une matière première d'intérêt, qui a cependant été largement moins étudiée que la biomasse en gazéification. L'objectif de la thèse est d'étudier la pyrolyse et la gazéification de CSR, en lien avec leurs caractéristiques physiques et chimiques, dans des conditions opératoires contrôlées. Pour cela, un nouveau dispositif expérimental à l'échelle du laboratoire a été développé. Une caractérisation expérimentale et des calculs CFD ont fourni une description complète des profils de température pour l'échantillon et le gaz à l'intérieur du réacteur. Plusieurs matériaux modèles (bois, carton, polyéthylène téréphtalate, polyéthylène et polypropylène), souvent présents dans les CSR, ont été étudiés séparément, en atmosphère inerte et en présence d'air en tant qu'agent oxydant. Le rendement et la distribution des produits de réaction (résidu carboné, espèces gazeuses, goudrons) ont été déterminés. La pyrolyse des mélanges bois/plastique a montré une conversion accrue du carbone en produits gazeux en comparaison à ce qui aurait été attendu sans interaction. En se basant sur les résultats expérimentaux de pyrolyse pour les matériaux modèles, une corrélation a été développée dans le but de prévoir les rendements de pyrolyse à partir des fractions massiques en C, H et O des ressources.

Emitiranjem stakleničkih plinova njihova koncentracija u atmosferi raste što uzrokuje efekt staklenika, odnosno klimatske promjene koje imaju sve veći utjecaj na život ljudi. U ovom radu prikazana je analiza mjera za smanjenje emisija stakleničkih plinova u odabranom industrijskom postrojenju korištenjem alternativnih goriva. Kao industrijsko postrojenje odabrana je energetski intenzivna cementna industrija koja emitira velike količine stakleničkog plina CO2. U prvome dijelu rada opisana je cementna industrija te procesi koji se odvijaju kako bi se iz sirovine dobio konačan proizvod – cement, te su pritom opisani izvori štetnih i stakleničkih plinova i načini na koji se oni nastoje smanjiti. Opisane su i mogućnosti smanjenja emisija koje se temelje na poboljšanju energetske učinkovitosti i mogućnosti smanjenja emisija uporabom alternativnih goriva s naglaskom na gorivo iz otpada RDF/SRF. Drugi dio rada sadrži proračun potencijala smanjenje stakleničkih plinova u cementnoj industriji uporabom RDF/SRF goriva čiji su sastav i svojstva određeni na temelju komunalnog otpada Republike Hrvatske. Prikazan je izračun udjela biorazgradive komponente, emisijskog faktora i ogrjevne vrijednost alternativnog RDF/SRF goriva. Potencijal smanjenja stakleničkih plinova prikazan je na 3 scenarija u kojemu su različiti udjeli potrebnog konvencionalnog goriva zamijenjeni RDF/SRF gorivom te je izrađena ekonomska analiza potencijalnih ušteda na troškovima goriva i troškovima dozvola za emitiranje u sklopu EU ETS sustava. By emitting greenhouse gases, their concentration in the atmosphere increases, which causes the greenhouse effect and climate change, which has an increasing impact on people's lives. This paper presents an analysis of measures to reduce greenhouse gas emissions in a selected industrial plant using alternative fuels. The energy-intensive cement industry, which emits large amounts of greenhouse gas CO2, was chosen as the industrial plant. The first part of the paper describes the cement industry and the processes that take place to obtain the final product from the raw material – cement and describes the sources of air pollutants and greenhouse gases and the ways in which they are reduced. Possibilities of reducing emissions based on improving energy efficiency and possibilities of reducing emissions using alternative fuels with an emphasis on RDF/SRF waste fuels are also described. The second part of the paper contains a calculation of the potential of reducing greenhouse gases in the cement industry using RDF/SRF fuels whose composition and properties are determined based on municipal waste of the Republic of Croatia. The calculations of the share of biodegradable component, emission factor and calorific value of alternative RDF/SRF fuel are presented. The potential reduction of greenhouse gases is shown in 3 scenarios in which different shares of the required conventional fuel are replaced by RDF/SRF fuel and economic analysis of potential savings on fuel costs and emission allowance costs within the EU ETS system is made.

The performance of the Nb bulk cavities has now reached the theoretical limits imposed by the material. It is necessary to look at other superconducting materials, among which the most promising is Nb3Sn. The deposition of Nb3Sn on copper cavities is interesting for the higher thermal conductivity of copper compared to common Nb substrates. The better heat exchange would allow the use of cryocoolers reducing cryogenic costs and the risk of thermal quench [1]. Magnetron sputtering technology allows the deposition of Nb3Sn on substrates different than Nb, however the coating of substrates with complex geometry (such as elliptical cavities) may require target with non-planar shape, difficult to realize with classic powder sintering techniques. In this work, the possibility of using the Liquid Tin Diffusion (LTD) technique to produce sputtering targets is explored. The LTD technique is a wire fabrication technology, already developed in the past at LNL for SRF applications [2], that allows the deposition of very thick and uniform coating on Nb substrates even with complex geometry [3]. Improvements in LTD process, proof of concept of a single use LTD target production, and characterization of the Nb3Sn film coated by DC magnetron sputtering with these innovative targets are reported in this thesis work.

Background The study examined the efficacy of eplerenone in the management of chronic central serous chorioretinopathy (CSCR) with the aim of short-term observations. The study also aimed at observing changes in optical coherence tomography (OCT) parameters and visual acuity. Methodology This retrospective study was conducted at Layton Rahmatulla Benevolent Trust (LRBT) Eye Hospital from September 2019 to October 2020. A thorough ocular examination, color fundus photographs, fluorescein angiography, and macular OCT were performed on all patients. We administered one tablet of 50 mg eplerenone on day one and further advised the use of the same dose for 30 days. After the administration of the tablet, the patients were further analyzed on weeks one, two, and four. On every visit, we examined ophthalmic conditions by visual acuity, slit lamp, and dilated fundus examinations along with macular OCT and measured blood pressure. At follow-up, we measured the levels of serum creatinine at weeks one and four. Student's t-test and chi-square test were used for normal distribution and nominal variables. A p-value < 0.05 was considered statistically significant in all the analyses. Results A total of 15 patients were selected for this research, but unfortunately, two of them withdrew amid the study. For the remaining 13 patients, the mean duration of observing symptoms was three months and three weeks. At one-month follow-up, the mean subretinal fluid (SRF) height (94.18 μm) decreased, but we did not find any statistical significance between the SRF height at one-month follow-up and baseline (113.15 μm). In four patients, the SRF height increased up to 3-30 μm after four months of treatment. In our study, we found some negative consequences of eplerenone therapy in terms of hypertension, cramps, nausea, and migraine. Conclusion We concluded that short-term eplerenone treatment assists in the reduction of the choroidal thickness (CT) and central macular thickness (CMT) among patients with central serous chorioretinopathy. However, eplerenone treatment failed to decrease subretinal fluid height and does not bring any significant improvement in the visual acuity of patients. Some mild adverse effects of the treatment include hypertension, abdominal cramps, nausea, and migraine.

Background: Soluble epoxide hydrolase inhibitors (sEHis) inhibit the degradation of epoxyeicosatrienoic acids (EETs) in cells, and EETs have antiarrhythmic effects. Our previous experiments confirmed that t-AUCB, a preparation of sEHis, inhibited ischemic arrhythmia by negatively regulating microRNA-1 (miR-1), but its specific mechanism remained unclear.Aim: This study aimed to examine the role of serum response factor (SRF) and the PI3K/Akt/GSK3β pathway in t-AUCB-mediated regulation of miR-1 and the interaction between them.Methods/Results: We used SRF small interfering RNA (siSRF), SRF small hairpin (shSRF) RNA sequence adenovirus, PI3K/Akt/GSK3β pathway inhibitors, t-AUCB, and 14,15-EEZE (a preparation of EETs antagonists) to treat mouse cardiomyocytes overexpressing miR-1 and mice with myocardial infarction (MI). We found that silencing SRF attenuated the effects on miR-1 and its target genes KCNJ2 and GJA1 in the presence of t-AUCB, and inhibition of the PI3K/Akt/GSK3β pathway antagonized the effects of t-AUCB on miR-1, KCNJ2, and GJA1, which were associated with PI3Kα, Akt, and Gsk3β but not PI3Kβ or PI3Kγ. Moreover, the PI3K/Akt/GSK3β pathway was involved in the regulation of SRF by t-AUCB, and silencing SRF inhibited the t-AUCB-induced increases in Akt and Gsk3β phosphorylation.Conclusions: Both the SRF and the PI3K/Akt/GSK3β pathway are involved in the t-AUCB-mediated regulation of miR-1, and these factors interact with each other.

Mit weltweit über 1,5 Millionen Todesfällen pro Jahr ist das Bronchialkarzinom ein häufig auftretendes und gleichzeitig aggressives Malignom. Eine späte Diagnose und limitierte Therapiemöglichkeiten sind die Hauptursachen dafür, dass die Prognose, trotz neuer Therapieansätze, oft immer noch schlecht ist. Auch beim seltener auftretenden Pleuramesotheliom ist die Prognose schlecht mit limitierten Therapiemöglichkeiten. Dies sind wichtige Gründe, warum bei beiden Krankheitsbildern dringend neue Therapien benötigt werden. Ein Ansatz könnte eine RNA-Interferenz vermittelte Hemmung bestimmter, für die Tumorzelle wichtiger Proteine darstellen. So gibt es bereits Studien, die siRNA als Therapie gegen verschiedene Krankheitsbilder aus diversen medizinischen Fachbereichen testen. In dieser Arbeit wurden mit SRF-siRNA, Survivin-siRNA, HIF1α-siRNA, HIF2α-siRNA, E2F1-siRNA und STAT3-siRNA siRNAs appliziert, die die Bildung von Proteinen inhibieren, welche an der Zellproliferation und Wachstum beteiligt sind. Insgesamt zeigten die Untersuchungen der Genexpression und der Zellzahl ein unterschiedliches Verhalten der verschiedenen Zelllinien auf die Transfektion mit den siRNAs, selbst wenn der gleiche histologische Subtyp vorlag. Die Großzellige Bronchialkarzinomzelllinie NCI-H640 reagierte auf den siRNA vermittelten Knockdown mit der größten Reduktion der Zellzahl. Der Knockdown von Survivin reduzierte die Zellzahl bei allen Zelllinien am wirksamsten. Als langfristiges Ziel steht die Behandlung von Patienten mit siRNA, die an einem Bronchialkarzinom oder einem MPM leiden. Dafür müssen die Effekte einer Therapie mittels RNAi in vivo geprüft werden. Unsere in vitro Ergebnisse legen allerdings nah, dass mit der richtigen siRNA in der idealen Konzentration, große Effekte erzielt werden könnten. In allem suggeriert diese Arbeit, dass eine personalisierte, multimodale Therapie zur Verbesserung des Überlebens unerlässlich ist. So könnte der Einsatz von siRNA vor allem Patienten in fortgeschrittenen Stadien oder mit chemoresistenten Tumoren als alternative adjuvante oder neoadjuvante Therapie, z.B. in Form einer isolierten Lungenperfusion, von großem Nutzen sein.

Myocardin-related transcription factors (MRTFs: myocardin/MYOCD, MRTF-A/MRTFA, and MRTF-B/MRTFB) are co-factors of serum response factor (SRF) that activate the smooth muscle cell (SMC) gene program and that play roles in cardiovascular development and mechanobiology. Gain and loss of function experiments have defined the SMC gene program under control of MRTFs, yet full understanding of their impact is lacking. In the present study, we tested the hypothesis that the muscarinic M3 receptor (CHRM3) is regulated by MRTFs together with SRF. Forced expression of MYOCD (8d) in human coronary artery (SMC) followed by RNA-sequencing showed increased levels of M2, M3, and M5 receptors (CHRM2: 2-fold, CHRM3: 16-fold, and CHRM5: 2-fold). The effect of MYOCD on M3 was confirmed by RT-qPCR using both coronary artery and urinary bladder SMCs, and correlation analyses using human transcriptomic datasets suggested that M3 may also be regulated by MRTF-B. Head-to-head comparisons of MYOCD, MRTF-A and MRTF-B, argued that while all MRTFs are effective, MRTF-B is the most powerful transactivator of CHRM3, causing a 600-fold increase at 120h. Accordingly, MRTF-B conferred responsiveness to the muscarinic agonist carbachol in Ca2+ imaging experiments. M3 was suppressed on treatment with the MRTF-SRF inhibitor CCG-1423 using SMCs transduced with either MRTF-A or MRTF-B and using intact mouse esophagus in culture (by 92±2%). Moreover, silencing of SRF with a short hairpin reduced CHRM3 (by >60%) in parallel with α-actin (ACTA2). Tamoxifen inducible knockout of Srf in smooth muscle reduced Srf (by 54±4%) and Chrm3 (by 41±6%) in the urinary bladder at 10days, but Srf was much less reduced or unchanged in aorta, ileum, colon, trachea, and esophagus. Longer induction (21d) further accentuated the reduction of Chrm3 in the bladder and ileum, but no change was seen in the aorta. Single cell RNA-sequencing revealed that Mrtfb dominates in ECs, while Myocd dominates in SMCs, raising the possibility that Chrm3 may be driven by Mrtfb-Srf in the endothelium and by Myocd-Srf in SMCs. These findings define a novel transcriptional control mechanism for muscarinic M3 receptors in human cells, and in mice, that could be targeted for therapy.

Simple Summary Hepatocellular carcinoma (HCC) ranks second among the leading causes of cancer-related death. Since current therapeutic options are very limited, a deeper understanding of the molecular mechanisms underlying the tumor onset and progression of HCC holds great potential for improved therapeutic options. Although it has been shown that deleted in liver cancer 1 (DLC1) acts as a tumor suppressor whose allele is lost in 50% of liver cancers, alterations in gene expression initiated by DLC1 loss have not yet been the primary focus of liver cancer research. To identify novel gene targets that allow for a personalized medicine approach for HCC therapy, we performed gene expression profiling for HepG2 cells stably expressing DLC1shRNA. We provide evidence that TSPAN5 is required for HCC growth, migration and invasion, and dissected the underlying molecular mechanisms involving myocardin-related transcription factors. Thus, TSPAN5 represents a novel therapeutic target for the treatment of HCC characterized by DLC1 loss. Abstract Human hepatocellular carcinoma (HCC) is among the most lethal and common cancers in the human population, and new molecular targets for therapeutic intervention are urgently needed. Deleted in liver cancer 1 (DLC1) was originally identified as a tumor suppressor gene in human HCC. DLC1 is a Rho-GTPase-activating protein (RhoGAP) which accelerates the return of RhoGTPases to an inactive state. We recently described that the restoration of DLC1 expression induces cellular senescence. However, this principle is not amenable to direct therapeutic targeting. We therefore performed gene expression profiling for HepG2 cells depleted of DLC1 to identify druggable gene targets mediating the effects of DLC1 on senescence induction. This approach revealed that versican (VCAN), tetraspanin 5 (TSPAN5) and N-cadherin (CDH2) were strongly upregulated upon DLC1 depletion in HCC cells, but only TSPAN5 affected the proliferation of HCC cells and human HCC. The depletion of TSPAN5 induced oncogene-induced senescence (OIS), mediated by the p16INK4a/pRb pathways. Mechanistically, silencing TSPAN5 reduced actin polymerization and thereby myocardin-related transcription factor A- filamin A (MRTF-A-FLNA) complex formation, resulting in decreased expression of MRTF/SRF-dependent target genes and senescence induction in vitro and in vivo. Our results identify TSPAN5 as a novel druggable target for HCC.