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Proliferative vitreoretinopathy (PVR) is an abnormal intraocular scarring process that can complicate cases of rhegmatogenous retinal detachment (RRD). Although previous studies have examined the relevance of microRNAs (miRNAs) in ophthalmic diseases, only a few studies have evaluated the expression profiles of microRNAs in subretinal fluid. We hypothesized that the expression profiles of specific miRNAs may change in response to RRD, in the subretinal fluid that is directly in contact with photoreceptors and the retinal pigment epithelium (RPE). We looked for a potential correlation between the expression of specific miRNAs in eyes with RRD and known clinical risk factors of PVR. A total of 24 patients (59 ± 11 years) who underwent scleral buckling procedure were enrolled in this prospective study. Twenty-four undiluted subretinal fluid samples were collected, RNA was isolated and qRT-PCR was performed to analyze the expression of 12 miRNAs. We found the existence of a positive association between the expression of miR-21 (p = 0.017, r = 0.515) and miR-34 (p = 0.030, r = 0.624) and the duration of symptoms related to retinal detachment. Moreover, the expression of miR-146a tended to decrease in patients who developed PVR. Subretinal fluid constitutes an intriguing biological matrix to evaluate the role of miRNAs leading to the development of PVR.

The elevated expression of the hyaluronan-mediated motility receptor (HMMR) is known to be highly associated with tumor progression in prostate cancer, but the molecular mechanisms underlying the regulation of HMMR expression remain unclear. Here, we report that mammalian target of rapamycin (mTOR) is a key regulator of HMMR expression, for which its kinase activity is required. Pharmacological inhibitors of mTOR, such as rapamycin and Torin2, markedly suppressed the mRNA level as well as the protein level of HMMR in LNCaP and PC-3 cells. Our data demonstrate that such regulation occurs at the transcription level. HMMR promoter reporter assays revealed that the transcription factor SRF is responsible for the mTOR-mediated transcriptional regulation of HMMR gene. Consistently, the suppression of HMMR expression by Torin2 was noticeably reversed by the overexpression of SRF. Moreover, our findings suggest that the SRF binding sites responsible for the transcriptional regulation of HMMR through the mTOR-SRF axis are located in HMMR promoter sequences carrying the first intron, downstream of the translational start site. Furthermore, the upregulation of HMMR by DHT was abolished by stimulation with rapamycin, prior to DHT treatment, suggesting that mTOR activity is required for the induction of HMMR expression by androgen. Collectively, our study provides new mechanistic insights into the role of mTOR/SRF/AR signaling in HMMR regulation in prostate cancer cells.

Nb3Sn Target Synthesis via LTD. diffusion-fundamentals.org 34 (2022) 4, pp 1-12

CEA, KEK and Marui Galvanizing Company have been collaborating to apply the Vertical Electropolishing (VEP) process of elliptical SRF cavities to a 704MHz single-cell ESS-type cavity, using a rotating so called and patented "Ninja" cathode. First presented results* were promising with a gradient of 27MV/m achieved, without any heat treatment applied. The performance has been pushed further since. The cavity has undergone a heat treatment at 650°C during 10h, followed by a final VEP sequence and a baking at 120°C during 48h hours. The achieved gradient at 2K was 44MV/m (power limitation), and the quality factor Q₀ exceeding 5·10¹⁰ up to 10 MV/m. The superiority of VEP compared to standard "BCP" chemical treatment is demonstrated and we intend now to scale the process to 5-Cell β=0.86 ESS cavity. We also intend to push further the performance by applying "2-step baking" (75°C and 120°C) proposed by FNAL, which was successfully applied at CEA Saclay on 1300MHz single-cell resonators with gradients above 50MV/m achieved after VEP bulk treatment., Proceedings of the 31st International Linear Accelerator Conference, LINAC2022, Liverpool, UK

The Bubbling Circulating Fluidized-Bed (BCFB) gasifier described in this paper is based on a combination of the two fluidized-bed reactor types: a bubbling and a circulating fluidized-bed. The BCFB gasifier was originally developed in the early 2000s and designed for air-blown gasification of waste-derived feedstocks that have very high volatile matter content resulting in high tar concentration in the raw product gas. In an ongoing EU project FlexSNG, the BCFB gasification technology is now adapted for the co-production of biochar and synthesis-quality gas, using steam and oxygen as fluidizing gases. In this paper, the pilot-scale development of the BCFB gasifier in air-blown operation with wood residues and a waste-derived feedstock is firstly presented. Then, the use of this gasifier design for the co-production of biochar and synthesis gas is described and the results from preliminary process simulations are presented. Estimated process performances are shown for two operation modes. In the maximized synthesis gas mode, the gasifier is operated at 900 °C resulting in a similar performance to a conventional CFB gasifier. In co-production operation mode, the bottom section of the BCFB gasifier acts as the carbonization zone producing good-quality biochar, which is recovered from the bottom of the gasifier.

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 will deliver 10 low-beta cryomodules as In-Kind Contribution to the PIP-II project, with cavities supplied by LASA-INFN and power couplers and tuning systems supplied by Fermilab. This paper presents the CEA scope of work that includes the design, manufacturing, assembly and tests of the cryomodules and the upgrade of the existing infrastructures to the PIP-II requirements., Proceedings of the 13th International Particle Accelerator Conference, IPAC2022, Bangkok, Thailand

In a clinical study of autologous cell–based therapy using dermal sheath cup (DSC) cells, the treatment of hair loss showed improvements. However, the outcomes were variable. Here, correlations between marker gene expression in DSC cells and treatment outcomes were assessed to predict therapeutic efficacy. Overall, 32 DSC cell lines were used to evaluate correlations between marker gene expression and treatment outcomes. Correlations between vascular pericyte and preadipocyte marker expression and treatment outcomes were inconsistent. As smooth muscle cell markers, MYOCD correlated negatively with treatment outcomes and SRF consistently demonstrated an inverse correlation. Additionally, CALD1 correlated negatively and ACTA2 correlated inversely with treatment outcomes. DSC cell lines were divided into good and moderate/poor responders to further investigate the correlations. SRF and CALD1 were lower in a good responder compared with a moderate responder. Next, DSC cells were differentiated toward dermal papilla cells. Dermal papilla markers SOX2 and LEF1 before differentiation had moderate positive and inverse correlations with the treatment outcome, respectively. SOX2 after differentiation more consistently demonstrated a positive correlation. Significant downregulation of smooth muscle–related genes was also observed after differentiation. These findings revealed putative markers for preclinical evaluation of DSC cells to improve hair loss.

Skeletal muscle hypertrophy can be induced by hormones and growth factors acting directly as positive regulators of muscle growth or indirectly by neutralizing negative regulators, and by mechanical signals mediating the effect of resistance exercise. Muscle growth during hypertrophy is controlled at the translational level, through the stimulation of protein synthesis, and at the transcriptional level, through the activation of ribosomal RNAs and muscle-specific genes. mTORC1 has a central role in the regulation of both protein synthesis and ribosomal biogenesis. Several transcription factors and co-activators, including MEF2, SRF, PGC-1α4, and YAP promote the growth of the myofibers. Satellite cell proliferation and fusion is involved in some but not all muscle hypertrophy models.

This study was conducted to evaluate four hybrid poplar comparison tests along a groundwater availability gradient in Western Slovakia. The weather fluctuation during the 3-year study period was described with indices, such as the Forestry Aridity Index (FAI) or the hydrothermal coefficient (HTC). The soil chemical and physical parameters were determined from soil samples from the two upper horizons. The nutrient status and supply of the trees were categorized based on leaf elemental analysis. Altogether, 21 different clones from 6 genomic groups were compared. The survival (SRV), diameter at breast height (DBH), and height of the trees (H) had been measured annually since the plantations were established, and from these measurements, mean annual height increment (MAHI) values were derived. These weather, edaphic, and clonal factors were evaluated and compared. Significant effects of the site (edaphic factors) were found as the primary source of variance and clonal differences as secondary sources of variance among the growth of trees. The interaction of site × clone effects was not significant. The results showed that for short rotation forestry (SRF), the site parameters—especially groundwater availability—are key factors.

Current estimates of the actual productivity of heavy construction machinery at a construction site are not supported by an appropriate and widely used methodology. Recently, for the purpose of estimating the actual productivity of heavy construction machinery, vision-based technologies are used. This paper emphasizes the importance of estimating actual productivity and presents a way (i.e. a research framework) to achieve it. Therefore, the aim of this paper is to propose a simple research framework (SRF) for quick and practical estimates of excavator actual productivity and cycle time at a construction site. The excavator actual productivity refers to the maximum possible productivity in real construction site conditions. The SRF includes the use of a video camera and the analysis of recorded videos using an advanced computer program. In cases of continuous application of SRF, a clear and transparent base for monitoring and control of earthworks can be obtained at an observed construction site.

Over the last decade, the interstitial alloying of niobium has proven to be essential for enabling superconducting radiofrequency (SRF) cavities to operate more efficiently at high accelerating gradients. The discovery of "nitrogen doping" was the first readily accessible avenue of interstitial alloying in which researchers saw an increase in cavity performance. However, the serendipitous nature of the discovery led to additional research to fundamentally understand the physics behind the increase in cavity performance. This knowledge gap is bridged by materials characterization. Secondary ion mass spectrometry (SIMS) is a characterization technique which has become a staple of SRF cavity characterization that details elemental concentration profiles as a function of depth into the niobium surface with submicron resolution. SIMS has been widely used by the semiconductor industry for decades but has found less application in other fields due to the difficulty to produce reproducible data for polycrystalline materials. Much effort has been given to reduce the uncertainty of SIMS results to as low as 1% - 2% for single crystals. However, less attention has been given to polycrystalline materials with uncertainty values reported between 40% - 50% The sources of uncertainty were found to be deterministic in nature and therefore could be mitigated to produce reliable results. This dissertation documents the efforts to reduce SIMS method uncertainty which has been further used to solve mysteries regarding the characterization of SRF cavities which include predictive modeling of oxygen diffusion as well as the identification of contaminants resulting from cavity furnace treatments. Doctor of Philosophy Particle accelerators find many uses in society in which their complexity depends on their intended purpose. These purposes vary from projecting an image as in cathode ray tube (CRT) TVs, to creating high energy x-rays for life saving cancer treatments, to researching the very fundamental principles of science and physics. The later uses particle accelerators which are very large, spanning multiple miles, and run at extremely high energies. To keep operational costs reasonable, these instruments need to run as efficiently as possible. Therefore, superconducting radiofrequency (SRF) niobium cavities are used and are responsible for propulsion of charged particles. Although, niobium SRF cavities can pass incredibly high currents with very little surface resistance, these high-end particle accelerators push the operational boundaries of efficiency. To improve the efficiency of these cavities, an optimal concentration of impurities, such as oxygen and nitrogen, are added to the niobium surface. The addition of an impurity level that is too high or too low causes the resistance to increase which translates to higher operational costs. Therefore, it is important to accurately determine the concentration of impurities within the niobium and with high depth resolution. Secondary ion mass spectrometry is a characterization method that uses a primary ion beam to impact the surface of a material to remove atoms at the very surface. The ejected atoms are then ionized into a secondary beam which can then be detected to determine the concentration and to identify the species which was removed. Historically, this instrument has yielded results with 40% - 50% uncertainty for polycrystalline metals, such as niobium, which do not sputter evenly. With SRF cavity performance depending on accurate quantitation of impurities, a more robust method is needed. Therefore, this dissertation identifies issues which cause high uncertainties for polycrystalline materials and in addition offers mitigation strategies to reduce uncertainty to below 10%. These methods were then applied to solve real problems aimed to improve the production of niobium SRF cavities.

Myocardin-related transcription factor A (MRTF-A), a coactivator of serum response factor (SRF), regulates the expression of many cytoskeletal genes in response to cytoplasmic and nuclear actin dynamics. Here we describe a novel mechanism to regulate MRTF-A activity within the nucleus by showing that lamina-associated polypeptide 2α (Lap2α), the nucleoplasmic isoform of Lap2, is a direct binding partner of MRTF-A, and required for the efficient expression of MRTF-A/SRF target genes. Mechanistically, Lap2α is not required for MRTF-A nuclear localization, unlike most other MRTF-A regulators, but is required for efficient recruitment of MRTF-A to its target genes. This regulatory step takes place prior to MRTF-A chromatin binding, because Lap2α neither interacts with, nor specifically influences active histone marks on MRTF-A/SRF target genes. Phenotypically, Lap2α is required for serum-induced cell migration, and deregulated MRTF-A activity may also contribute to muscle and proliferation phenotypes associated with loss of Lap2α. Our studies therefore add another regulatory layer to the control of MRTF-A-SRF-mediated gene expression, and broaden the role of Lap2α in transcriptional regulation.

SRSF3, an important member of the serine/arginine-rich protein (SRp) family, is highly expressed in various tumors and plays an important role in tumor cell proliferation, migration and invasion. However, it is still unclear whether SRSF3 is involved in tumor angiogenesis. In this study, we first revealed that SRSF3 regulated the expression of numerous genes related to angiogenesis, including proangiogenic SRF. Then, we confirmed that SRSF3 was highly expressed in colorectal cancer (CRC) and was positively correlated with SRF. Mechanistic studies revealed that SRSF3 directly bound to the “CAUC” motif in exon 6 of SRF and induced the exclusion of introns. Knockdown of SRSF3 significantly reduced the secretion of VEGF from CRC cells. Conditioned medium from SRSF3-knockdown CRC cells significantly inhibited the migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs). In addition, SRF silencing inhibited angiogenesis, while SRF overexpression reversed the antiangiogenic effects of SRSF3 knockdown on tube formation. These findings indicate that SRSF3 is involved in the splicing of SRF and thereby regulates the angiogenesis of CRC, which offers novel insight into antiangiogenic therapy in CRC.

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.

Serum response factor (SRF) is an essential transcription factor that influences many cellular processes including cell proliferation, migration, and differentiation. SRF directly regulates and is required for immediate early gene (IEG) and actin cytoskeleton-related gene expression. SRF coordinates these competing transcription programs through discrete sets of cofactors, the ternary complex factors (TCFs) and myocardin-related transcription factors (MRTFs). The relative contribution of these two programs to in vivo SRF activity and mutant phenotypes is not fully understood. To study how SRF utilizes its cofactors during development, we generated a knock-in SrfaI allele in mice harboring point mutations that disrupt SRF-MRTF-DNA complex formation but leave SRF-TCF activity unaffected. Homozygous SrfaI/aI mutants die at E10.5 with notable cardiovascular phenotypes, and neural crest conditional mutants succumb at birth to defects of the cardiac outflow tract but display none of the craniofacial phenotypes associated with complete loss of SRF in that lineage. Our studies further support an important role for MRTF mediating SRF function in cardiac neural crest and suggest new mechanisms by which SRF regulates transcription during development.

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.

The BEAmline for Tomography at SESAME (BEATS) will operate an X-ray��tomography station providing service to scientists from archaeology, cultural heritage, medicine, biology, material science and engineering, geology and environmental sciences*. BEATS will have a length of 45 m with a 3-pole-wiggler source (3 T peak magnetic field at 11 mm gap). Filtered white and monochromatic beam (8 keV to 50 keV, dE/E: 2% to 3% using a double-multilayer-monochromator) modalities will be available. In this work we present the beamline optical design, verified with simulation tools included in OASYS**. The calculated flux through 1 mm�� at the sample position will be as high as 8.5��10��� Ph/s/mm�� in 0.1% of the source bandwidth, for a maximum usable beam size of 70��15 mm��. Beam transverse coherence will be limited to below 1 ��m by the horizontal size of the X-ray source (~2 mm FWHM). For phase contrast applications requiring enhanced coherence, front end slits can be closed to 0.5 mm horizontally, with a reduction of the available beam size and photon flux. The BEATS beamline will fulfill the needs of the tomography community of SESAME., Proceedings of the 11th Mechanical Engineering Design of Synchrotron Radiation Equipment and Instrumentation, MEDSI2020, Chicago, IL, USA

This paper presents the design of a new linear fast shutter for topography and tomography. A prototype will be assembled and tested at the BM05 beamline at ESRF, and another unit will be installed in the future BEATS beamline at SESAME. The application of the shutter in X-ray diffraction topography allows performance of long exposure cycles of monochromatic beam on crystal samples while preventing irradiation of the detector during readout. It can be also used during sample alignment and acquisition of X-ray tomography scans. Particularly for white-beam tomography, which uses a very high photon flux, minimizing exposure is critical to protect the sample and detector from radiation damage. This highlights the importance of obtaining a short and uniform exposure time over the beam aperture. To fulfill this objective, a new shutter based on the synchronization of two tantalum blades driven by linear brushless DC motors is under development. This versatile design can be used with both monochromatic and white-beam, and it can achieve exposure times ranging from 50 ms to 60 s for a beam size of H 80 mm x V 20 mm. The linear motors allow for a much smoother operation, preventing vibration issues reported with the old shutter. In addition, the use of linear motors rather than solenoids allows an unlimited exposure time, where the previous version used solenoids that could overheat if kept open for too long. A test bench has been constructed for the characterization of the sequence produced by the linear motors, and exposure times of 50 ms with a maximum error of 1 ms have been measured. This article describes the main features of the shutter prototype and its associated motion control system, and the results of the measurements with the motor test bench are discussed as well., Proceedings of the 11th Mechanical Engineering Design of Synchrotron Radiation Equipment and Instrumentation, MEDSI2020, Chicago, IL, USA

Elk-1 is a transcription factor that binds together with a dimer of the serum response factor (SRF) to the serum-response element (SRE), a genetic element that connects cellular stimulation with gene transcription. Elk-1 plays an important role in the regulation of cellular proliferation and apoptosis, thymocyte development, glucose homeostasis and brain function. The biological function of Elk-1 relies essentially on the interaction with other proteins. Elk-1 binds to SRF and generates a functional ternary complex that is required to activate SRE-mediated gene transcription. Elk-1 is kept in an inactive state under basal conditions via binding of a SUMO-histone deacetylase complex. Phosphorylation by extracellular signal-regulated protein kinase, c-Jun N-terminal protein kinase or p38 upregulates the transcriptional activity of Elk-1, mediated by binding to the mediator of RNA polymerase II transcription (Mediator) and the transcriptional coactivator p300. Strong and extended phosphorylation of Elk-1 attenuates Mediator and p300 recruitment and allows the binding of the mSin3A-histone deacetylase corepressor complex. The subsequent dephosphorylation of Elk-1, catalyzed by the protein phosphatase calcineurin, facilitates the re-SUMOylation of Elk-1, transforming Elk-1 back to a transcriptionally inactive state. Thus, numerous protein–protein interactions control the activation cycle of Elk-1 and are essential for its biological function.

Tighter specifications in synchrotron instrumentation development force the design engineers more and more often to choose a mechatronics design approach. This includes actively controlled systems that need to be properly designed. The new Nano Active Stabilization System (NASS) for the ESRF beamline ID31 was designed with such an approach. We chose a multi-body design modelling approach for the development of the NASS end-station. Significance of such models depend strongly on its input and consideration of the right stiffness of the system���s components and subsystems. For that matter, we considered sub-components in the multi-body model as reduced order flexible bodies representing the component���s modal behaviour with reduced mass and stiffness matrices obtained from finite element analysis (FEA) models. These matrices were created from FEA models via modal reduction techniques, more specifically the component mode synthesis (CMS). This makes this design approach a combined multibody-FEA technique. We validated the technique with a test bench that confirmed the good modelling capabilities using reduced order flexible body models obtained from FEA for an amplified piezoelectric actuator (APA)., Proceedings of the 11th Mechanical Engineering Design of Synchrotron Radiation Equipment and Instrumentation, MEDSI2020, Chicago, IL, USA

Reducing the size of ambient magnetic flux trapping during cooldown in superconducting radio-frequency niobium cavities is essential to reaching the lowest power dissipation as required for continuous wave application. Here, it is suggested that applying an alternating magnetic field superimposed to the external DC field can potentially reduce the size of trapped flux by supporting flux line movement. This hypothesis is tested for the first time systematically on a buffered chemically polished (BCP) niobium sample before and after high temperature annealing, a procedure which is known to reduce flux pinning. External low-frequency (Hz-range) magnetic fields were applied to the samples during their superconducting transition and the effect of varying their amplitude, frequency and offset was investigated. A few results can be highlighted: The influence of the frequency and magnitude of the AC fields on the flux trapping in the untreated Nb sample cannot be neglected. The trapped flux seems to be homogeneously distributed, unlike the flux trapping in, e.g., lead (Pb), which is a type I superconductor. After annealing, the Nb sample shows practically no dependency of flux trapping on external AC fields. The trapped magnetic flux was measured by polarized neutron imaging, and calculations of trapped fields show good agreement with experimental results.

Studying flux expulsion during superconducting cavities test increases the need for exhaustive magnetometric cartography. The use of Anistropic Magneto Resistance (AMR) sensors, much cheaper than commercial fluxgates, allows the use of tens of sensors simultaneously. Such sensors are developed and sold for room temperature application but are resistant to cryogenic temperatures. However, they need proper calibration, which is more difficult at cryogenic temperature. Actually, this calibration uses the flip of the magnetization of the anisotropic ferromagnetic element, which coercitive field is increased at low temperature. We will present the development of method and software carried out at CEA for the use of such sensors, as well as the preliminary design of a rotating magnetometric device destined to elliptical cavities., Proceedings of the 20th International Conference on RF Superconductivity, SRF2021, East Lansing, MI, USA

An international collaboration of research teams from CEA (France), CERN (Switzerland), INFN/LNL (Italy), HZB and USI (Germany), IEE (Slovakia), RTU (Latvia) and STFC/DL (UK), are working together on better understanding of how to improve the properties of superconducting thin films (ScTF) for RF cavities. The collaboration has been formed as WP15 in the H2020 ARIES project funded by EC. The systematic study of ScTF covers: Cu substrate polishing with different techniques (EP, SUBU, EP+SUBU, tumbling, laser), Nb, NbN, Nb₃Sn and SIS film deposition and characterisation, Laser post deposition treatments, DC magnetisation characterisation, application of all obtained knowledge on polishing, deposition and characterisation, Laser post deposition treatments, DC magnetisation characterisation, application to the QPR samples for testing the films at RF conditions. The preparation, deposition and characterisation of each sample involves 3-5 partners enhancing the capability of each other and resulting in a more complete analysis of each film. The talk will give an overview of the collaborative research and will be an introduction to the detailed talks given by the team members., Proceedings of the 20th International Conference on RF Superconductivity, SRF2021, East Lansing, MI, USA

The Proton Improvement Plan II (PIP-II) is the first U.S. accelerator project that will have significant contributions from international partners. The prototype High Beta 650 MHz cryomodule (pHB650 CM) is designed by an integrated design team, consisting of Fermilab (USA), CEA (France), UKRI-STFC (UK), and RRCAT (India). The manufacturing assembly of this prototype cryomodule will be done at Fermilab, whereas the production cryomodules will be manufactured and/or assembled by UKRI-STFC, RRCAT, or Fermilab. Similar to the prototype Single Spoke Resonator 1 cryomodule (pSSR1 CM), this cryomodule is based on a strong-back at room temperature supporting the coldmass. The pSSR1 CM led to significant lessons being learnt on the design, procurement, and assembly processes. These lessons were incorporated into the design and processes for the pHB650 CM. Amongst many challenges faced, the main challenges of the pHB650 CM design were to make the cryomodule compatible to overseas transportation and to design components that can be procured in USA, Europe, and India., Proceedings of the 20th International Conference on RF Superconductivity, SRF2021, East Lansing, MI, USA