In this article, we discuss the development of molybdenum-gold bilayer transition-edge sensors on solid silicon substrate microcalorimeter designs suitable for real-time measurement of gamma-ray sources in the keV to MeV range. These novel detector designs incorporate tunable thermal conductance over a range from 1 & times;10(-9) to 4 & times;10(-7) W/K and are mechanically robust. We describe the microfabrication process and the gamma-ray absorber attachment in detail. Initial prototypes obtain detector response times twice as fast as our previous design while maintaining an energy resolution of less than 100 eV full-width-half-maximum at 100 keV.

Arrays of hundreds or thousands of low temperature detectors have been deployed for many experiments, both bolometers for long wavelength applications and calorimeters for shorter wavelength applications. One challenge that is common to many of these arrays is the efficient use of focal plane area to achieve a large fill fraction of absorbers coupled to detectors. We are developing an integrated fabrication of soft X-ray transition edge sensors (TES) and microwave SQUID multiplexers ($\mu$MUX) with the goal of maximizing the fill fraction of the focal plane area on a scale of many thousand pixel detectors. We will utilize lithographically defined high density interconnects to circumvent limitations in existing solutions that use wirebonds or flip-chip bonds. Here we report the first demonstration of combining TES and $\mu$MUX processes into a single TES-System-on-a-Chip (TES-SoC) fabrication on a silicon wafer. The $\mu$MUX SQUIDs and TES electrothermal feedback circuits are microfabricated first and protected with passivating SiO$_{2}$, then the TES devices and TES-to-SQUID interconnects are fabricated, and finally the protective layer is removed before the fabrication of the microwave resonators. We show that the microwave SQUIDs are functional and have reasonable yield, and that we are able to read out the transition temperature of the connected TESs using those SQUIDs.

We present the electro-thermal characterization of transition-edge sensor (TES) detectors suspended on Si membranes fabricated using a silicon-on-insulator (SOI) wafer. The use of an all-silicon fabrication platform, in contrast to the more commonly used silicon nitride membranes, is compatible with monolithic fabrication of integrated TES and SQUID circuits. The all-silicon architecture additionally allows efficient use of focal plane area; the readout circuitry may be positioned out of the focal plane by bending a thinned portion of the chip. Compatibility with integrated fabrication and efficient use of focal plane area provide a path to an efficient soft X-ray spectrometer. This work is motivated by our goal to develop a 10,000-pixel TES spectrometer to overcome critical measurement limitations in catalysis research. The characterization of fragile, carbon-based intermediates via techniques like Resonant Inelastic X-ray Scattering (RIXS) is often precluded by the slow, high-flux nature of existing technologies. The new instrument will allow for fast RIXS measurements to be made without causing sample damage. We verify the detector models and measure the energy resolution using a pulsed optical laser, demonstrating the viability of this approach for the final instrument to be deployed at the National Synchrotron Light Source II (NSLS-II).

Ultra-high energy resolution microcalorimeter gamma-ray spectroscopy—with energy resolution 5 to 10 times better than observed in spectra obtained by commercial-off-the-shelf high purity germanium detectors—is an enabling technology for ultra-precise isotope identification and quantification. Microcalorimeter gamma spectroscopy complements measurements requiring high-accuracy mass spectrometry, a costly, destructive analysis technique, and may offer benefits over mass spectrometry in the future. Microcalorimeter detectors are fabricated from superconducting materials and operate at ultra-low temperatures (<0.1 K), properties which permit measurement of spectra with peak full width half maximum (FWHM) of less than 100 eV at 100 keV. The microcalorimeter collaboration between Los Alamos National Laboratory, National Institute of Standards and Technology, and University of Colorado, Boulder has deployed three microcalorimeter gamma-ray spectrometers to nuclear facilities and analytical laboratories so far. These are the Spectrometer Optimized for Facility Integrated Applications (SOFIA), a portable system that can be moved to any facility, and two instruments called the High Efficiency and Resolution Microcalorimeter Spectrometers (HERMES) intended for permanent installation at Idaho National Laboratory and Pacific Northwest National Laboratory. Each spectrometer was customized to satisfy requirements for their specific applications. This work describes samples examined by microcalorimeter gamma-ray spectrometers, including recently irradiated materials, nuclear material from various stages of the fuel cycle, and medical isotope products. It also highlights useful signatures from actinide and fission product gamma-rays that are otherwise infeasible to observe or use for analysis without costly chemical separations and mass spectrometric assay. Microcalorimeter technology provides additional spectral signatures to existing techniques to better constrain the origin and intended use of nuclear and radioactive materials.

Time-resolved ultrafast extreme ultraviolet (EUV) magnetic scattering is used to study laser-driven ultrafast magnetization dynamics of labyrinthine domains in a [Co/Ni/Pt] multilayer. Our measurements at the Co and Ni M-edges reveal distinct ultrafast distortions of the scattering pattern position and width for Ni compared to Co. Ni shows a strong modification of the scattering pattern, 9 to 41 times stronger than Co. As distortions of the labyrinthine pattern in reciprocal space relate to the modification of domain textures in real space, significant differences in Co and Ni highlight a 3D distortion of the domain pattern in the far-from-equilibrium regime.

A Super-Conducting ENergetic x-ray Telescope (ASCENT) is a concept for a future balloon-borne high-energy X-ray telescope in the energy range 60–85 keV to study gamma-ray emissions of 67.87 keV and 78.32 keV from the radioactive isotope 44Ti. For the focal plane instrumentation, ASCENT will use Mo-Cu/Mo-Au bilayer transition edge sensor (TES) microcalorimeter gamma-ray detectors with tin (Sn) absorbers. ‘Spectrometer to Leverage Extensive Development of Gamma-ray TESs for Huge Arrays using Microwave Multiplexed Enabled Readout’ (SLEDGEHAMMER), a detector development project at the National Institute of Standards and Technology, acts as the basis for the detector arrays for ASCENT. SLEDGEHAMMER has tin (Sn) absorbers attached to the SU-8 epoxy posts, lithographically placed on the detectors, but we are also considering other geometries for the chips where the absorbers are attached to the chips separated from the TESs, which could help to avoid parallel path for a current flow around the detectors with these BiSn sphere attachments. In this work, we are reporting on developing a method to attach Tin (Sn) absorbers to the transition edge sensors (TESs) with 0.2 mm diameter BiSn solder spheres replacing epoxy. The goal is to improve the thermal conductivity between the absorbers and the TESs compared to what was achieved using epoxy, potentially reducing the presence of an athermal component in the tails of signal pulses. We describe our efforts toward finding optimal temperature and pressure conditions for making this contact and the progress toward contact resistance measurements of these joints.

Arrays of microcalorimeters based on transition-edge sensors (TESs) are being actively deployed to laboratories all over the world. A TES microcalorimeter array produces very large quantities of data and users of these devices have varying levels of experience, so it is important to provide robust software for data acquisition and analysis that can function with minimal user supervision. This software should be capable of addressing common phenomena that can adversely affect spectrum quality. Gain jumping is one such phenomenon that is characterized by abrupt changes in the gain of a device. Left unaddressed, gain jumps can degrade spectra by introducing false peaks. We are not aware of any previously published methods for resetting gain jumps during data acquisition or existing algorithms for correcting data that is degraded by gain jumps. We have developed automated methods for detecting and correcting gain jumps in gamma-ray TES microcalorimeters. We present a procedure for resetting gain jumps during a live data acquisition that involves briefly driving the TES into its normal state using the bias current. We also describe an algorithm for locating gain jumps and identifying unique gain states within existing microcalorimeter data. Finally, we provide a possible approach for correcting gain jumps after they have been identified.

Introduction: Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs) are signaling lipids with beneficial metabolic effects. Serum and adipose tissue (AT) PAHSA levels correlate highly with insulin sensitivity in people. PAHSAs enhance insulin sensitivity in diabetic mice. Thus, low PAHSA levels could contribute to the etiology of insulin resistance and T2D. PAHSAs are regulated by synthesis, degradation and incorporation into other lipids. We aimed to identify candidate enzymes that regulate PAHSAs using genetic mouse models in which large changes in PAHSAs are associated with major changes in glucose tolerance and/or insulin sensitivity. Methods: AT PAHSA levels are increased in mice with Adipose-specific Glucose Transporter 4 overexpression (AG4OX) which induces expression of the lipogenic transcription factor, Carbohydrate-response element-binding protein (ChREBP). Thus, we performed lipidomics and bulk RNA sequencing in perigonadal AT from wildtype, AG4OX, ChREBP knockout and AG4OX crossed to ChREBP KO which reverses the massive elevation of PAHSAs in AG4OX. We also measured PAHSAs in 8 genetically inbred mouse strains. We merged these datasets to identify genes strongly associated with PAHSAs in both models. A subsequent GWAS query for lipid-related SNPs delivered a discrete number of genes to validate as important PAHSA regulators. Results: All PAHSA regioisomers increase in AT with upregulation of glucose transport and decrease with ChREBP downregulation. PAHSA levels are higher in insulin-sensitive genetic strains. Many genes that strongly associate with 9-PAHSA belong to lipid metabolism pathways. Our single-gene queries in human GWAS support a role for 27 genes in the regulation of lipid metabolism in humans and, potentially, in PAHSA regulation. Conclusions: These studies provide novel insights into the metabolic pathways and enzymatic machinery responsible for PAHSA metabolism, which may be targeted to prevent or treat T2D in humans. Disclosure A. Santoro: None. M. Keller: None. Z. Chen: None. A.D. Attie: None. D. Siegel: None. G.A. Churchill: None. A. Saghatelian: None. B.B. Kahn: Advisory Panel; Janssen Pharmaceuticals, Inc. Consultant; Vida Ventures Advisors, Arrowhead Pharmaceuticals, Inc. Funding K01 DK128075 (Anna Santoro), NIH P30 DK135043 (Barbara B. Kahn), NIH R01 DK106210 (Barbara B. Kahn and Alan Saghatelian), and JPB foundation (Barbara B. Kahn)

Introduction & Objective: High-risk single-nucleotide polymorphisms (SNPs) account for only ~20% of type 2 diabetes heritability, implying islet genes greatly influence one another to alter diabetes risk. Correlative analysis does not reveal conditional dependencies between key players regulating islet function whereas machine learning (ML) may do so. Methods: Using data from 374 genetically diverse mice, we derived models predicting islet function from protein abundance with gradient-boosted decision tree algorithms. Some mice (70%) were used to train the models and the rest were used to validate them. We also applied our models to similar data from other mouse studies and to data from humans to see if the models’ accuracies replicated. We then determined if the models included any known islet regulators, proteins with human orthologues possessing glycemia-related SNPs, and enriched for islet-relevant functional pathways. Finally, using the proteins’ predictive influences as meta-traits, we ran quantitative trait locus (QTL) scans to identify genomic regions altering the influence of proteins on islet function. Results: Our analysis revealed < 150 of the ~ 5000 detected proteins sufficiently modeled any one functional trait, with > 90% of a model’s prediction influenced by < 50 proteins. Some models predicted as well or better in the other mouse sets (R > 0.6) and reasonably well in human data (R > 0.5). ML analysis correctly identified the direction of effect for candidates (e.g. DPP8) where prior studies using correlation alone failed. Models for islet traits enriched for pathways potentially relevant for islet function and several unstudied proteins (e.g. CRELD2) present in multiple models have SNPs for glycemia-related traits. Finally, QTL scans revealed genomic regions that may alter the influence of key proteins on islet function and are far from those proteins’ genomic positions. Conclusions: ML can be used to identify conditional dependencies regulating islet function. Disclosure C. Emfinger: None. E. Freiberger: Employee; AbbVie Inc. M. Rabaglia: None. J. Kolic: None. S. Simonett: Employee; Exact Sciences. M. Shortreed: None. L. Clark: None. D. Stapleton: None. K. Schueler: None. K. Mitok: None. T.R. Price: None. J.J. Coon: Research Support; Agilent, Eli Lilly and Company, Merck & Co., Inc. L. Smith: None. M.J. Merrins: None. J.D. Johnson: None. M. Keller: None. A.D. Attie: None. Funding American Diabetes Association (7-21-PDF-157); National Institutes of Health (R01-DK101573-06); National Institutes of Health (GM070683); National Institutes of Health (P41-GM108538); National Institutes of Health (R35GM126914); National Institutes of Health (R35-GM118110); National Institutes of Health (T32-HL007936); National Institutes of Health (R01-DK113103); National Institutes of Health (R01DK127637); Canadian Institutes for Health Research (CIHR) operating grant 168857 CIHR Team Grant (ASD-179092/5-SRA-2021-1149-S-B); CIHR-JDRF Team (ASD-173663/5-SRA-2020-1059-S-B); CIHR Banting fellowship United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (I01BX005113)

We present a method of creating high-density superconducting flexible wiring on flexible thin silicon substrates. The flexible wiring, called SOI flex , is created by depositing superconducting wiring on a silicon on insulator (SOI) wafer, selectively etching away the thicker silicon section handle layer, and bending the thinner silicon device layer. We show measurements of superconducting transition temperature and critical current for Mo, Nb, and Al on SOI flex. We discuss the expected advantages of SOI flex for low-temperature detector applications, as well as the role of stress and strain in bent silicon and niobium.

Superconducting transition-edge sensors (TESs) used in X-ray and γ -ray microcalorimeters suffer degraded performance if cooled in a magnetic field B sufficient to trap flux in the sensors. We report measurements of γ -ray TESs before and after implementing measures to reduce stray B fields from sources inside and outside the cryostat. These measurements showed a correlation between anomalous features in TES current–voltage (IV) curves and degraded energy resolution. After reducing internal sources of stray B field and improving shielding against external sources, both IV curves and energy resolution improved. Finally, we placed magnetized screws with remnant fields ∼ 10 T near similar γ -ray TESs in a different type of detector package and observed the same effects.

Mitochondria play an important role in both normal heart function and disease etiology. We report analysis of common genetic variations contributing to mitochondrial and heart functions using an integrative proteomics approach in a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). We performed a whole heart proteome study in the HMDP (72 strains, n=2-3 mice) and retrieved 848 mitochondrial proteins (quantified in ≥50 strains). High-resolution association mapping on their relative abundance levels revealed three trans-acting genetic loci on chromosomes (chr) 7, 13 and 17 that regulate distinct classes of mitochondrial proteins as well as cardiac hypertrophy. DAVID enrichment analyses of genes regulated by each of the loci revealed that the chr13 locus was highly enriched for complex-I proteins (24 proteins, P=2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, P=3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, P=6.9E-05). Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively, and both experimental and statistical analyses supported their causal roles. Furthermore, a large cohort of Diversity Outbred mice was used to corroborate Lrpprc gene as a driver of mitochondrial DNA (mtDNA)-encoded gene regulation, and to show that the chr17 locus is specific to heart. Variations in all three loci were associated with heart mass in at least one of two independent heart stress models, namely, isoproterenol-induced heart failure and diet-induced obesity. These findings suggest that common variations in certain mitochondrial proteins can act in trans to influence tissue-specific mitochondrial functions and contribute to heart hypertrophy, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations.

Time-resolved ultrafast EUV magnetic scattering was used to test a recent prediction of >10  km/s domain wall speeds by optically exciting a magnetic sample with a nanoscale labyrinthine domain pattern. Ultrafast distortion of the diffraction pattern was observed at markedly different timescales compared to the magnetization quenching. The diffraction pattern distortion shows a threshold dependence with laser fluence, not seen for magnetization quenching, consistent with a picture of domain wall motion with pinning sites. Supported by simulations, we show that a speed of ≈66  km/s for highly curved domain walls can explain the experimental data. While our data agree with the prediction of extreme, nonequilibrium wall speeds locally, it differs from the details of the theory, suggesting that additional mechanisms are required to fully understand these effects.

In this work, we are reporting on the development of a method to attach Sn absorbers to the Transition Edge Sensors (TESs) with BiSn spheres (metal-to-metal attachment), using a die bonder, with the aim of improving thermalization, potentially reducing the presence of an a-thermal component in the tails of signal pulses. We describe our efforts towards finding optimal temperature and pressure conditions for making this contact and the progress toward contact resistance measurements of these joints.

Hepatocyte nuclear factor 4α (HNF4α) is an established transcriptional master regulator of differentiation, maintenance, and metabolism. Polymorphisms in HNF4α are linked to several diseases in humans including diabetes and nonalcoholic fatty liver disease (NAFLD). Identifying novel regulation of lipid metabolism by HNF4α would inform on NAFLD development and progression. We directly assessed HNF4α activity through chromatin immunoprecipitation (ChIP)-sequencing and integration of untargeted lipidomics. Direct regulation by HNF4α can be difficult to assess due to the role of HNF4α in liver homeostasis; to rapidly disrupt activity, mice were exposed to cold stress which induces hepatic steatosis in several hours. Cold exposure shifted HNF4α activity with differential genome occupancy of more than 50% of HNF4α binding sites. Focusing on HNF4α binding to promoter with active transcription determined that HNF4α directly regulates fatty acid desaturation, ether lipid synthesis, and peroxisomal biogenesis in response to cold exposure. Integration of lipidomics found that cold exposure increases the very long chain polyunsaturated fatty acid composition of the hepatic lipid pool, including ether lipids, in an HNF4α dependent manner. Because portions of ether lipid synthesis are in the peroxisome and peroxisomal biogenesis is directly HNF4α regulated, we analyzed peroxisomal abundance and found increases with cold exposure that are ablated with loss of HNF4α. This peroxisomal regulation was independent of PPARα— a known regulator of peroxisomes and lipid metabolism—since loss of HNF4α was not rescued by PPARα overexpression. These data determined that regulation of hepatic steatosis by HNF4α is more complex than triglyceride accumulation and includes acyl chain modifications, ether lipid synthesis, and peroxisomal oxidation.

Introduction: Allotransplantation of pancreatic islets is currently a successful treatment option for type 1 diabetic patients. Donor phenotype affects islet transplantation outcomes. However, genetic factor predisposing for diabetes and metabolic disease are typically not assessed in donors. We sought to investigate the potential role of donor genetic factors influencing insulin secretion. Methods: We extracted the DNA of close to 200 pancreas donors and used the Cardio-MetaboChip to query the 196,725 single nucleotide polymorphisms (SNPs) associated with metabolic syndrome components. We used Glucose‐stimulated insulin secretion (GSIS) as main phenotypical variable to test our genotype dataset. We used islet graft survival as an additional phenotypical variable. We performed GSIS in INS-1 cells to test the potential insulin secretion molecules/genes identified. Results: We identified several loci associated with donor insulin secretion in vitro (Figure 1). We identified three specific SNPs in the same linkage disequilibrium (LD), mapping upstream of CCL2 gene, which were associated with GSIS. When we mapped the ATAC seq peaks to this region, we found that open chromatin status varied between diabetic versus non-diabetic individuals. Further, motif analysis suggested that these SNPs could participate to the disruption of a binding site of NF-κB transcription factor, a regulator of CCL2 gene. To investigate further, we induced NF-κB pathway using TNF-α in INS-1 cells and confirmed a reduction in insulin in response to glucose upon TNF-α stimulation (Figure 2).Conclusion: Our data suggest the potential involvement of an NF-κB binding site for CCL2 regulation and a potential role in glucose homeostasis. These observations could help identifying preclinical conditions with impaired insulin secretion and their potential impact on islet donor selection. Diabetes Research Connection Grant. References: 1. Niclauss, N., et al., Beta-Cell Replacement: Pancreas and Islet Cell Transplantation. Endocr Dev, 2016. 31: p. 146-62. 2. Meier, R.P.H., et al., Pancreas preservation fluid microbial contamination is associated with poor islet isolation outcomes - a multi-centre cohort study. Transpl Int, 2018. 31(8): p. 917-929. 3. Kim, H. E., et al., Tumour necrosis factor-alpha-induced glucose-stimulated insulin secretion inhibition in INS-1 cells is ascribed to a reduction of the glucose-stimulated Ca2+ influx.“ J Endocrinol, 2008.198(3): p.549-560.

Symmetry is a powerful concept in physics, but its applicability to far-from-equilibrium states is still being understood. Recent attention has focused on how far-from-equilibrium states lead to spontaneous symmetry breaking. Conversely, ultrafast optical pumping can be used to drastically change the energy landscape and quench the magnetic order parameter in magnetic systems. Here, we find a distinct symmetry-dependent ultrafast behaviour by use of ultrafast x-ray scattering from magnetic patterns with varying degrees of isotropic and anisotropic symmetry. After pumping with an optical laser, the scattered intensity reveals a radial shift exclusive to the isotropic component and exhibits a faster recovery time from quenching for the anisotropic component. These features arise even when both symmetry components are concurrently measured, suggesting a correspondence between the excitation and the magnetic order symmetry. Our results underline the importance of symmetry as a critical variable to manipulate the magnetic order in the ultrafast regime.

The advent of X-ray free-electron lasers (XFELs) has revolutionized fundamental science, from atomic to condensed matter physics, from chemistry to biology, giving researchers access to X-rays with unprecedented brightness, coherence and pulse duration. All XFEL facilities built until recently provided X-ray pulses at a relatively low repetition rate, with limited data statistics. Here, results from the first megahertz-repetition-rate X-ray scattering experiments at the Spectroscopy and Coherent Scattering (SCS) instrument of the European XFEL are presented. The experimental capabilities that the SCS instrument offers, resulting from the operation at megahertz repetition rates and the availability of the novel DSSC 2D imaging detector, are illustrated. Time-resolved magnetic X-ray scattering and holographic imaging experiments in solid state samples were chosen as representative, providing an ideal test-bed for operation at megahertz rates. Our results are relevant and applicable to any other non-destructive XFEL experiments in the soft X-ray range.