Successful cooling of a pixel tracker using gaseous helium: studies with a mock-up and a detector prototype

We report the successful operation of a functional pixel detector with gaseous helium cooling. Using an accurate mock-up beforehand, the cooling was validated. We use a miniature turbo compressor to propel the helium at $2\,g/s$ under ambient pressure conditions with gas temperatures above $0^{\circ}C$. Our earlier results based on computational fluid dynamics simulations and a much simpler mock-up are confirmed. With this, we paved the path to cool pixel detectors in experimental particle physics at heat densities up to $400\, mW/cm^2$ using helium. This enables cooling of detectors with very low mass requirements, minimising the effects of multiple Coulomb scattering effectively. The concept presented here is not limited to pixel detector applications and can be used to cool any surface with comparable heat-densities, only limited by shaping the helium gas flow

Immune profiling in multiple sclerosis: a single-center study of 65 cytokines, chemokines, and related molecules in cerebrospinal fluid and serum

IntroductionThe understanding of the pathophysiology of multiple sclerosis (MS) has evolved alongside the characterization of cytokines and chemokines in cerebrospinal fluid (CSF) and serum. However, the complex interplay of pro- and anti-inflammatory cytokines and chemokines in different body fluids in people with MS (pwMS) and their association with disease progression is still not well understood and needs further investigation. Therefore, the aim of this study was to profile a total of 65 cytokines, chemokines, and related molecules in paired serum and CSF samples of pwMS at disease onset.MethodsMultiplex bead-based assays were performed and baseline routine laboratory diagnostics, magnetic resonance imaging (MRI), and clinical characteristics were assessed. Of 44 participants included, 40 had a relapsing–remitting disease course and four a primary progressive MS.ResultsThere were 29 cytokines and chemokines that were significantly higher in CSF and 15 in serum. Statistically significant associations with moderate effect sizes were found for 34 of 65 analytes with sex, age, CSF, and MRI parameters and disease progression.DiscussionIn conclusion, this study provides data on the distribution of 65 different cytokines, chemokines, and related molecules in CSF and serum in newly diagnosed pwMS

MuPix & ATLASpix: Architectures and Results

High Voltage Monolithic Active Pixel Sensors (HV-MAPS) are based ona commercial High Voltage CMOS process and collect charge by driftinside a reversely biased diode. HV-MAPS represent a promising technology for future pixel tracking detectors. Two recent developments are presented. The MuPix has a continuous readout and is being developed for the Mu3e experiment whereas the ATLASPix is being developed for LHC applications with a triggered readout. Both variants have a fully monolithic design including state machines, clock circuitries and serial drivers. Several prototypes and design variants were characterised in the lab and in testbeam campaigns to measure efficiencies, noise, time resolution and radiation tolerance. Results from recent MuPix and ATLASPix prototypes are presented and prospects for future improvements are discussed.High Voltage Monolithic Active Pixel Sensors (HV-MAPS) are based on a commercial High Voltage CMOS process and collect charge by drift inside a reversely biased diode. HV-MAPS represent a promising technology for future pixel tracking detectors. Two recent developments are presented. The MuPix has a continuous readout and is being developed for the Mu3e experiment whereas the ATLASPix is being developed for LHC applications with a triggered readout. Both variants have a fully monolithic design including state machines, clock circuitries and serial drivers. Several prototypes and design variants were characterised in the lab and in testbeam campaigns to measure efficiencies, noise, time resolution and radiation tolerance. Results from recent MuPix and ATLASPix prototypes are presented and prospects for future improvements are discussed

Induction of anti-tumor immunity by vaccination with dendritic cells pulsed with anti-CD44 IgG opsonized tumor cells

Due to the pivotal role that dendritic cells (DC) play in eliciting and maintaining functional anti-tumor T cell responses, these APC have been exploited against tumors. DC express several receptors for the Fc portion of IgG (Fcγ receptors) that mediate the internalization of antigen-IgG complexes and promote efficient MHC class I and II restricted antigen presentation. In this study, the efficacy of vaccination with DC pulsed with apoptotic B16 melanoma cells opsonized with an anti-CD44 IgG (B16-CD44) was explored. Immature bone marrow derived DC grown in vitro with IL-4 and GM-CSF were pulsed with B16-CD44. After 48 h of pulsing, maturation of DC was demonstrated by production of IL-12 and upregulation of CD80 and CD40 expression. To test the efficacy of vaccination with DC+B16-CD44, mice were vaccinated subcutaneously Lymphocytes from mice vaccinated with DC+B16-CD44 produced IFN-γ in response to B16 melanoma lysates as well as an MHC class I restricted B16 melanoma-associated peptide, indicating B16 specific CD8 T cell activation. Upon challenge with viable B16 cells, all mice vaccinated with DC alone developed tumor compared to 40% of mice vaccinated with DC+B16-CD44; 60% of the latter mice remained tumor free for at least 8 months. In addition, established lung tumors and distant metastases were significantly reduced in mice treated with DC+B16-CD44. Lastly, delayed growth of established subcutaneous tumors was induced by combination therapy with anti-CD44 antibodies followed by DC injection. This study demonstrates the efficacy of targeting tumor antigens to DC via Fcγ receptors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45862/1/262_2005_Article_104.pd

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

The Mu3e vertex detector - construction, cooling, and first prototype operation

The Mu3e experiment searches for the charged lepton flavor violating decay µ -> eee with an aimed single event sensitivity of 2*10^-15 in phase I. To achieve this goal, the highest momentum resolution possible is approached, which is mainly affected by multiple Coulomb scattering. This results in extremely tight constraints on the material budget to the level of 0.1 % radiation length per layer for the tracking detector. The Mu3e pixel detector is based on High-Voltage Monolithic Active Pixel Sensors (HV-MAPS) developed for this project, the MuPix, which can be thinned to 50 µm. The electrical services and the support are realized by ultra-thin (around 80 µm) structured aluminum-polyimide laminates. Furthermore, the detector is cooled by gaseous helium, a novelty for particle detectors. This thesis covers the construction of detector mock-ups in preparation for the final production of the Mu3e vertex detector, the studies of the helium cooling system, and the operation of a first functional prototype of the Mu3e vertex detector. The mock-up construction demonstrated that an excellent longitudinal chip placement precision of σ = 4 µm and a lateral precision of σ = 3 µm is achieved with a manual approach. An average glue thickness of only (5.3 ± 1.7) µm for the joint between chips and laminates is realized. The helium cooling system is verified to be sufficient to cool the Mu3e vertex detector. To prove this, the thermal-mechanical mock-ups were heated actively and cooled by the helium cooling system. For a heat dissipation of 350 mW/cm², all chip temperatures are found to be below 70°C for an inlet helium temperature of 0°C. The temperature change during heating up and cooling down can be described by a time constant of about 2 s to 3 s. A first functional vertex detector prototype has been operated under Mu3e-like conditions. The communication with the vertex detector and the readout of its hits is performed by the Mu3e DAQ, which is proven to be functional. The hits from different portions of the detector are correlated, and the results are in agreement with the expectation for all the target geometries that have been used. The conceptual detector design and the functionality of the novel detector cooling system are validated, which paves the way for the detector production in 2022

Increased peripheral inflammatory responses in myelin oligodendrocyte glycoprotein associated disease and aquaporin-4 antibody positive neuromyelitis optica spectrum disorder

Autoantibody-associated demyelinating diseases of the central nervous system such as myelin oligodendrocyte glycoprotein-antibody associated disease (MOGAD) and aquaporin 4-antibody positive neuromyelitis optica spectrum disorders (AQP4+ NMOSD) are rare diseases but can cause severe disability. In both diseases, associated neuroinflammation is accompanied by blood and cerebrospinal fluid cytokine and chemokine signatures, which were shown to be distinct from those observed in patients with multiple sclerosis (MS). In this study, we aimed to confirm and extend these findings by analyzing a larger number of serum cytokines, chemokines and related molecules in patients with MOGAD or AQP4+ NMOSD in comparison to MS, to better understand the pathophysiology and to identify biomarkers potentially useful in clinical practice for diagnostic and treatment purposes. A total of 65 serum cytokines, chemokines and related molecules like growth factors and soluble receptors were measured by Procartaplex multiplex immunoassays in 40 MOGAD, 40 AQP4+ NMOSD and 54 MS patients at baseline. Furthermore, follow-up samples of 25 AQP4+ NMOSD and 40 MOGAD patients were measured after 6-12 months. Selected analytes were validated in a subgroup of samples using other bead-based assays and ELISA. At baseline, 36 analytes in MOGAD and 30 in AQP4+ NMOSD were significantly increased compared to MS. K-means cluster analysis of all significantly altered molecules revealed three distinct groups: Cluster I, including 12 MOGAD, 2 AQP4+ NMOSD and 3 MS patients, had a specific association with 11 IL-6/IL-17A associated cytokines. In this cluster, 9/17 (53%) patients were children. Cluster II with 13 MOGAD, 24 AQP4+ NMOSD and 1 MS patient was associated with 31 upregulated analytes. Cluster III contained 15 MOGAD, 14 AQP4+ NMOSD and 50 MS patients. In cluster II and III the majority were adults (82% and 92%). Most measured analytes remained stable over time. Validation of selected cytokines and chemokines using other analytical methods revealed moderate to high correlation coefficients, but absolute values differed between assays. In conclusion, these results obtained by bead-based multiplex assays highlight a significant association of biomarkers of peripheral inflammation in patients with antibody-associated demyelinating diseases in comparison with MS