Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study.

BACKGROUND: The 523 poly-T length polymorphism (rs10524523) in TOMM40 has been reported to influence longitudinal cognitive test performance within APOE ε3/3 carriers. The results from prior studies are inconsistent. It is also unclear whether specific APOE and TOMM40 genotypes contribute to heterogeneity in longitudinal cognitive performance during the preclinical stages of AD. OBJECTIVES: To determine the effects of these genes on longitudinal cognitive change in early preclinical stages of AD, we used the clinical trial data from the recently concluded TOMMORROW study to examine the effects of APOE and TOMM40 genotypes on neuropsychological test performance. DESIGN: A phase 3, double-blind, placebo-controlled, randomized clinical trial. SETTING: Academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. PARTICIPANTS: Cognitively normal older adults aged 65 to 83. INTERVENTION: Pioglitazone tablet. MEASUREMENTS: Participants from the TOMMORROW trial were stratified based on APOE genotype (APOE ε3/3, APOE ε3/4, APOE ε4/4). APOE ε3/3 carriers were further stratified by TOMM40'523 genotype. The final analysis dataset consists of 1,330 APOE ε3/3 carriers and 7,001 visits. Linear mixed models were used to compare the rates of decline in cognition across APOE groups and the APOE ε3/3 carriers with different TOMM40'523 genotypes. RESULTS: APOE ε3/4 and APOE ε4/4 genotypes compared with the APOE ε3/3 genotype were associated with worse performance on measures of global cognition, episodic memory, and expressive language. Further, over the four years of observation, the APOE ε3/3 carriers with the TOMM40'523-S/S genotype showed better global cognition and accelerated rates of cognitive decline on tests of global cognition, executive function, and attentional processing compared to APOE ε3/3 carriers with TOMM40'523-S/VL and VL/VL genotypes and compared to the APOE ε3/4 and APOE ε4/4 carriers. CONCLUSIONS: We suggest that both APOE and TOMM40 genotypes may independently contribute to cognitive heterogeneity in the pre-MCI stages of AD. Controlling for this genetic variability will be important in clinical trials designed to slow the rate of cognitive decline and/or prevent symptom onset in preclinical AD.

Validation of the CogDrisk Instrument as Predictive of Dementia in Four General Community-Dwelling Populations.

BACKGROUND: Lack of external validation of dementia risk tools is a major limitation for generalizability and translatability of prediction scores in clinical practice and research. OBJECTIVES: We aimed to validate a new dementia prediction risk tool called CogDrisk and a version, CogDrisk-AD for predicting Alzheimer's disease (AD) using cohort studies. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Four cohort studies were identified that included majority of the dementia risk factors from the CogDrisk tool. Participants who were free of dementia at baseline were included. The predictors were component variables in the CogDrisk tool that include self-reported demographics, medical risk factors and lifestyle habits. Risk scores for Any Dementia and AD were computed and Area Under the Curve (AUC) was assessed. To examine modifiable risk factors for dementia, the CogDrisk tool was tested by excluding age and sex estimates from the model. RESULTS: The performance of the tool varied between studies. The overall AUC and 95% CI for predicting dementia was 0.77 (0.57, 0.97) for the Swedish National study on Aging and Care in Kungsholmen, 0.76 (0.70, 0.83) for the Health and Retirement Study - Aging, Demographics and Memory Study, 0.70 (0.67,0.72) for the Cardiovascular Health Study Cognition Study, and 0.66 (0.62,0.70) for the Rush Memory and Aging Project. CONCLUSIONS: The CogDrisk and CogDrisk-AD performed well in the four studies. Overall, this tool can be used to assess individualized risk factors of dementia and AD in various population settings.

Proof-of-Principle Experiment for Testing Strong-Field Quantum Electrodynamics with Exotic Atoms: High Precision X-Ray Spectroscopy of Muonic Neon.

To test bound-state quantum electrodynamics (BSQED) in the strong-field regime, we have performed high precision x-ray spectroscopy of the 5g-4f and 5f- 4d transitions (BSQED contribution of 2.4 and 5.2 eV, respectively) of muonic neon atoms in the low-pressure gas phase without bound electrons. Muonic atoms have been recently proposed as an alternative to few-electron high-Z ions for BSQED tests by focusing on circular Rydberg states where nuclear contributions are negligibly small. We determined the 5g_{9/2}- 4f_{7/2} transition energy to be 6297.08±0.04(stat)±0.13(syst) eV using superconducting transition-edge sensor microcalorimeters (5.2-5.5 eV FWHM resolution), which agrees well with the most advanced BSQED theoretical prediction of 6297.26 eV.

Adjudicating Mild Cognitive Impairment Due to Alzheimer's Disease as a Novel Endpoint Event in the TOMMORROW Prevention Clinical Trial.

BACKGROUND: The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer's disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. METHODS: The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant's clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages - independent review, collaborative review, and full committee review - requiring a unanimous decision and ratification by the chair. RESULTS: Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators' clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80-90% for the remainder of the study. CONCLUSIONS: The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.

Measurements of Strong-Interaction Effects in Kaonic-Helium Isotopes at Sub-eV Precision with X-Ray Microcalorimeters.

We have measured the 3d→2p transition x rays of kaonic ^{3}He and ^{4}He atoms using superconducting transition-edge-sensor microcalorimeters with an energy resolution better than 6 eV (FWHM). We determined the energies to be 6224.5±0.4(stat)±0.2(syst) eV and 6463.7±0.3(stat)±0.1(syst) eV, and widths to be 2.5±1.0(stat)±0.4(syst) eV and 1.0±0.6(stat)±0.3(stat) eV, for kaonic ^{3}He and ^{4}He, respectively. These values are nearly 10 times more precise than in previous measurements. Our results exclude the large strong-interaction shifts and widths that are suggested by a coupled-channel approach and agree with calculations based on optical-potential models.

Association of small vessel disease with tau pathology.

Emerging evidence suggests that small vessel disease (SVD) is a risk factor for clinical dementia and may contribute to AD neuropathological changes. Watershed brain regions are located at the most distal areas between arterial territories, making them vulnerable to SVD-related changes. We examined the association of pathologic markers of SVD, specifically arteriolosclerosis in watershed brain regions, with AD pathologic changes. Participants (N = 982; mean age-at-death = 90; 69% women) were enrolled as part of one of two cohort studies of aging and dementia. At autopsy, neuropathological evaluation included semi-quantitative grading of arteriolosclerosis pathology from 2 cortical watershed regions: the anterior watershed (AWS) and posterior watershed (PWS), densities for cortical ß-amyloid and tau-tangle pathology, and other common age-related pathologies. Linear regression models examined the association of watershed arteriolosclerosis pathology with ß-amyloid and tau-tangle burden. In follow-up analyses, available ex-vivo MRI and proteomics data in a subset of decedents were leveraged to examine the association of whole brain measure of WMH, as a presumed MRI marker of SVD, with ß-amyloid and tau-tangle burden, as well as to examine the association of watershed arteriolosclerosis with proteomic tau. Watershed arteriolosclerosis was common, with 45% of older persons having moderate-to-severe arteriolosclerosis pathology in the AWS region, and 35% in the PWS. In fully adjusted models that controlled for demographics and common age-related pathologies, an increase in severity of PWS arteriolosclerosis was associated with a higher burden of tau-tangle burden, specifically neocortical tau burden, but not with ß-amyloid. AWS arteriolosclerosis was not associated with ß-amyloid or tau pathology. Ex-vivo WMH was associated with greater tau-tangle pathology burden but not ß-amyloid. Furthermore, PWS arteriolosclerosis was associated with higher abundance of tau phosphopeptides, that promote formation of tau aggregates. These data provide compelling evidence that SVD, specifically posterior watershed arteriolosclerosis pathology, is linked with tau pathological changes in the aging brain.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

Absolute energies and emission line shapes of the L x-ray transitions of lanthanide metals.

We use an array of transition-edge sensors, cryogenic microcalorimeters with 4 eV energy resolution, to measure L x-ray emission-line profiles of four elements of the lanthanide series: praseodymium, neodymium, terbium, and holmium. The spectrometer also surveys numerous x-ray standards in order to establish an absolute-energy calibration traceable to the international system of units for the energy range 4 keV to 10 keV. The new results include emission line profiles for 97 lines, each expressed as a sum of one or more Voigt functions; improved absolute energy uncertainty on 71 of these lines relative to existing reference data; a median uncertainty on the peak energy of 0.24 eV, four to ten times better than the median of prior work; and six lines that lack any measured values in existing reference tables. The 97 lines comprise nearly all of the most intense L lines from these elements under broad-band x-ray excitation. The work improves on previous measurements made with a similar cryogenic spectrometer by the use of sensors with better linearity in the absorbed energy and a gold x-ray absorbing layer that has a Gaussian energy-response function. It also employs a novel sample holder that enables rapid switching between science targets and calibration targets with excellent gain balancing. Most of the results for peak energy values shown here should be considered as replacements for the currently tabulated standard reference values, while the line shapes given here represent a significant expansion of the scope of available reference data.

Deexcitation Dynamics of Muonic Atoms Revealed by High-Precision Spectroscopy of Electronic K X Rays.

We observed electronic K x rays emitted from muonic iron atoms using superconducting transition-edge sensor microcalorimeters. The energy resolution of 5.2 eV in FWHM allowed us to observe the asymmetric broad profile of the electronic characteristic Kα and Kß x rays together with the hypersatellite K^{h}α x rays around 6 keV. This signature reflects the time-dependent screening of the nuclear charge by the negative muon and the L-shell electrons, accompanied by electron side feeding. Assisted by a simulation, these data clearly reveal the electronic K- and L-shell hole production and their temporal evolution on the 10-20 fs scale during the muon cascade process.

Aß (Amyloid Beta) and Tau Tangle Pathology Modifies the Association Between Small Vessel Disease and Cortical Microinfarcts.

BACKGROUND AND PURPOSE: There is increasing recognition of the importance of cortical microinfarcts to overall brain health, cognition, and Alzheimer dementia. Cerebral small vessel pathologies are associated with microinfarcts and frequently coexist with Alzheimer disease; however, the extent to which Aß (amyloid beta) and tau pathology modulates microvascular pathogenesis is not fully understood. Study objective was to examine the relationship of small vessel pathologies, arteriolosclerosis, and cerebral amyloid angiopathy, with cortical microinfarcts in people with differing levels of Aß or tau tangle burden. METHODS: Participants were 1489 autopsied older people (mean age at death, 89 years; 67% women) from 1 of 3 ongoing clinical-pathological cohort studies of aging. Neuropathological evaluation identified cortical Aß and tau tangle burden using immunohistochemistry in 8 brain regions, provided semiquantitative grading of cerebral vessel pathologies, and identified the presence of cortical microinfarcts. Logistic regression models adjusted for demographics and atherosclerosis and examined whether Aß or tau tangle burden modified relations between small vessel pathologies and cortical microinfarcts. RESULTS: Cortical microinfarcts were present in 17% of older people, moderate-to-severe cerebral amyloid angiopathy pathology in 36%, and arteriolosclerosis in 34%. In logistic regression models, we found interactions with Aß and tau tangles, reflecting that the association between arteriolosclerosis and cortical microinfarcts was stronger in the context of greater Aß (estimate, 0.15; SE=0.07; P=0.02) and tau tangle burden (estimate, 0.13; SE=0.06; P=0.02). Interactions also emerged for cerebral amyloid angiopathy, suggesting that the association between cerebral amyloid angiopathy and cortical microinfarcts is more robust in the presence of higher Aß (estimate, 0.27; SE=0.07; P<0.001) and tangle burden (estimate, 0.16; SE=0.06; P=0.005). CONCLUSIONS: These findings suggest that in the presence of elevated Aß or tangle pathology, small vessel pathologies are associated with greater microvascular tissue injury, highlighting a potential link between neurodegenerative and vascular mechanisms.

Brain mural cell loss in the parietal cortex in Alzheimer's disease correlates with cognitive decline and TDP-43 pathology.

AIMS: Brain mural cells (BMC), smooth muscle cells and pericytes, interact closely with endothelial cells and modulate numerous cerebrovascular functions. A loss of BMC function is suspected to play a role in the pathophysiology of Alzheimer's Disease (AD). METHODS: BMC markers, namely smooth muscle alpha actin (α-SMA) for smooth muscle cells, as well as platelet-derived growth factor receptor ß (PDGFRß) and aminopeptidase N (ANPEP or CD13) for pericytes, were assessed by Western immunoblotting in microvessel extracts from the parietal cortex of 60 participants of the Religious Orders study, with ages at death ranging from 75 to 98 years old. RESULTS: Participants clinically diagnosed with AD had lower vascular levels of α-SMA, PDGFRß and CD13. These reductions were correlated with lower cognitive scores for global cognition, episodic and semantic memory, perceptual speed and visuospatial ability. In addition, α-SMA, PDGFRß and CD13 were negatively correlated with vascular Aß40 concentrations. Vascular levels of BMC markers were also inversely correlated with insoluble cleaved phosphorylated transactive response DNA binding protein 43 (TDP-43) (25 kDa) and positively correlated with soluble cleaved phosphorylated TDP-43 (35 kDa) in cortical homogenates, suggesting strong association between BMC loss and cleaved phosphorylated TDP-43 aggregation. CONCLUSIONS: The results of this study highlight a loss of BMC in AD. The associations between α-SMA, PDGFRß and CD13 vascular levels with cognitive scores, TDP-43 aggregation and cerebrovascular accumulation of Aß in the parietal cortex suggest that BMC loss contributes to both AD symptoms and pathology, further strengthening the link between cerebrovascular defects and dementia.

Expanding the Capability of Microwave Multiplexed Readout for Fast Signals in Microcalorimeters.

Microwave SQUID multiplexing has become a key technology for reading out large arrays of X-ray and gamma-ray microcalorimeters with mux factors of 100 or more. The desire for fast X-ray pulses that accommodate photon counting rates of hundreds or thousands of counts per second per sensor drives system design toward high sensor current slew rate. Typically, readout of high current slew rate events is accomplished by increasing the sampling rate, such that rates of order 1MHz may be necessary for some experiments. In our microwave multiplexed readout scheme, the effective sampling rate is set by the frequency of the flux-ramp modulation (f r) used to linearize the SQUID response. The maximum current slew rate between samples is then nominally Φ 0 f r/2M in (where M in is the input coupling) because it is generally not possible to distinguish phase shifts of > π from negative phase shifts of < -π. However, during a pulse, we know which direction the current ought to be slewing, and this makes it possible to reconstruct a pulse where the magnitude of the phase shift between samples is > π. We describe a practical algorithm to identify and reconstruct pulses that exceed this nominal slew rate limit on the rising edge. Using pulses produced by X-ray transition-edge sensors, we find that the pulse reconstruction has a negligible impact on energy resolution compared to arrival time effects induced by under-sampling the rising edge. This technique can increase the effective slew rate limit by more than a factor of two, thereby either reducing the resonator bandwidth required or extending the energy range of measurable photons. The extra margin could also be used to improve crosstalk or to decrease readout noise.

A transition-edge sensor-based x-ray spectrometer for the study of highly charged ions at the National Institute of Standards and Technology electron beam ion trap.

We report on the design, commissioning, and initial measurements of a Transition-Edge Sensor (TES) x-ray spectrometer for the Electron Beam Ion Trap (EBIT) at the National Institute of Standards and Technology (NIST). Over the past few decades, the NIST EBIT has produced numerous studies of highly charged ions in diverse fields such as atomic physics, plasma spectroscopy, and laboratory astrophysics. The newly commissioned NIST EBIT TES Spectrometer (NETS) improves the measurement capabilities of the EBIT through a combination of high x-ray collection efficiency and resolving power. NETS utilizes 192 individual TES x-ray microcalorimeters (166/192 yield) to improve upon the collection area by a factor of ∼30 over the 4-pixel neutron transmutation doped germanium-based microcalorimeter spectrometer previously used at the NIST EBIT. The NETS microcalorimeters are optimized for the x-ray energies from roughly 500 eV to 8000 eV and achieve an energy resolution of 3.7 eV-5.0 eV over this range, a more modest (<2×) improvement over the previous microcalorimeters. Beyond this energy range, NETS can operate with various trade-offs, the most significant of which are reduced efficiency at lower energies and being limited to a subset of the pixels at higher energies. As an initial demonstration of the capabilities of NETS, we measured transitions in He-like and H-like O, Ne, and Ar as well as Ni-like W. We detail the energy calibration and data analysis techniques used to transform detector counts into x-ray spectra, a process that will be the basis for analyzing future data.

MIND Diet Associated with Reduced Incidence and Delayed Progression of ParkinsonismA in Old Age.

BACKGROUND: In old age, motor impairments including parkinsonian signs are common, but treatment is lacking for many older adults. In this study, we examined the association of a diet specifically developed to promote brain health, called MIND (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), to the incidence and progression of parkinsonism in older adults. METHODS: A total of 706 Memory and Aging Project participants aged 59 -97 years and without parkinsonism at baseline were assessed annually for the presence of four parkinsonian signs using a 26-item modified version of the United Parkinson's Disease Rating Scale. Incident parkinsonism was defined as the first occurrence over 4.6 years of follow-up of two or more parkinsonian signs. The progression of parkinsonism was assessed by change in a global parkinsonian score (range: 0-100). MIND, Mediterranean, and DASH diet pattern scores were computed based on a validated food frequency questionnaire including 144 food items. We employed Cox-Proportional Hazard models and linear mixed models, to examine the associations of baseline diet scores with incident parkinsonism and the annual rate of change in global parkinsonian score, respectively. RESULTS: In models adjusted for age, sex, smoking, total energy intake, BMI and depressive symptoms, higher MIND diet scores were associated with a decreased risk of parkinsonism [(HR=0.89, 95% CI 0.83-0.96)]; and a slower rate of parkinsonism progression [(ß= -0.008; SE=0.0037; p=0.04)]. The Mediterranean diet was marginally associated with reduced parkinsonism progression (ß= -0.002; SE=0.0014; p=0.06). The DASH diet, by contrast, was not associated with either outcome. CONCLUSION: The MIND diet created for brain health may be a associated with decreased risk and slower progression of parkinsonism in older adults.

Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies.

Tauopathies, including Alzheimer's disease (AD) and other neurodegenerative conditions, are defined by a pathological hallmark: neurofibrillary tangles (NFTs). NFT accumulation is thought to be closely linked to cognitive decline in AD. Here, we perform a genome-wide association study for NFT pathologic burden and report the association of the PTPRD locus (rs560380, P=3.8 × 10-8) in 909 prospective autopsies. The association is replicated in an independent data set of 369 autopsies. The association of PTPRD with NFT is not dependent on the accumulation of amyloid pathology. In contrast, we found that the ZCWPW1 AD susceptibility variant influences NFT accumulation and that this effect is mediated by an accumulation of amyloid ß plaques. We also performed complementary analyses to identify common pathways that influence multiple neuropathologies that coexist with NFT and found suggestive evidence that certain loci may influence multiple different neuropathological traits, including tau, amyloid ß plaques, vascular injury and Lewy bodies. Overall, these analyses offer an evaluation of genetic susceptibility to NFT, a common end point for multiple different pathologic processes.

A 300-mK Test Bed for Rapid Characterization of Microwave SQUID Multiplexing Circuits.

Microwave SQUID multiplexing is a promising technique for multiplexing large arrays of transition edge sensors. A major bottleneck in the development and distribution of microwave SQUID multiplexer chips occurs in the time-intensive design testing and quality assurance stages. To obtain useful RF measurements, these devices must be cooled to temperatures below 500 mK. The need for a more efficient system to screen microwave multiplexer chips has grown as the number of chips requested by collaborators per year reaches into the hundreds. We have therefore assembled a test bed for microwave SQUID circuits, which decreases screening time for four 32-channel chips from 24 h in an adiabatic demagnetization refrigerator to approximately 5 h in a helium dip probe containing a closed cycle 3He sorption refrigerator. We discuss defining characteristics of these microwave circuits and the challenges of establishing an efficient testing setup for them.

A Dopamine Receptor genetic variant enhances perceptual speed in cognitive healthy subjects.

Cognition is under strong genetic control, yet the specific genes are unknown. To investigate genetic influences on specific cognitive domains, 153 cognitive healthy subjects of European ancestry from the Reference Abilities Study (RANN) were genotyped for 1,160 variants within 446 neuropsychiatric genes. Adjusted linear regression models evaluated the association between the genetic variants and four reference abilities, which capture variance in age-related cognitive function (Vocabulary, Episodic Memory, Perceptual Speed, and Reasoning). 159 variants nominally significant in the RANN cohort were then re-evaluated in an independent cohort of 868 cognitive healthy subjects from the Religious Orders Study and Rush Memory Aging Project. Meta-analysis yielded a Bonferroni adjusted statistically significant association between perceptual speed and a variant located in the promoter of the dopamine receptor D4 gene, rs3756450 (ß=0.23, SE=0.05, P meta =2.3 × 10-5). Our data suggest that genetic variation in a dopamine pathway gene influences perceptual speed performance in cognitively healthy individuals.

Neuronal-expressed microRNA-targeted pseudogenes compete with coding genes in the human brain.

MicroRNAs orchestrate brain functioning via interaction with microRNA recognition elements (MRE) on target transcripts. However, the global impact of potential competition on the microRNA pool between coding and non-coding brain transcripts that share MREs with them remains unexplored. Here we report that non-coding pseudogene transcripts carrying MREs (PSG+MRE) often show duplicated origin, evolutionary conservation and higher expression in human temporal lobe neurons than comparable duplicated MRE-deficient pseudogenes (PSG-MRE). PSG+MRE participate in neuronal RNA-induced silencing complexes (RISC), indicating functional involvement. Furthermore, downregulation cell culture experiments validated bidirectional co-regulation of PSG+MRE with MRE-sharing coding transcripts, frequently not their mother genes, and with targeted microRNAs; also, PSG+MRE single-nucleotide polymorphisms associated with schizophrenia, bipolar disorder and autism, suggesting interaction with mental diseases. Our findings indicate functional roles of duplicated PSG+MRE in brain development and cognition, supporting physiological impact of the reciprocal co-regulation of PSG+MRE with MRE-sharing coding transcripts in human brain neurons.

A practical superconducting-microcalorimeter X-ray spectrometer for beamline and laboratory science.

We describe a series of microcalorimeter X-ray spectrometers designed for a broad suite of measurement applications. The chief advantage of this type of spectrometer is that it can be orders of magnitude more efficient at collecting X-rays than more traditional high-resolution spectrometers that rely on wavelength-dispersive techniques. This advantage is most useful in applications that are traditionally photon-starved and/or involve radiation-sensitive samples. Each energy-dispersive spectrometer is built around an array of several hundred transition-edge sensors (TESs). TESs are superconducting thin films that are biased into their superconducting-to-normal-metal transitions. The spectrometers share a common readout architecture and many design elements, such as a compact, 65 mK detector package, 8-column time-division-multiplexed superconducting quantum-interference device readout, and a liquid-cryogen-free cryogenic system that is a two-stage adiabatic-demagnetization refrigerator backed by a pulse-tube cryocooler. We have adapted this flexible architecture to mate to a variety of sample chambers and measurement systems that encompass a range of observing geometries. There are two different types of TES pixels employed. The first, designed for X-ray energies below 10 keV, has a best demonstrated energy resolution of 2.1 eV (full-width-at-half-maximum or FWHM) at 5.9 keV. The second, designed for X-ray energies below 2 keV, has a best demonstrated resolution of 1.0 eV (FWHM) at 500 eV. Our team has now deployed seven of these X-ray spectrometers to a variety of light sources, accelerator facilities, and laboratory-scale experiments; these seven spectrometers have already performed measurements related to their applications. Another five of these spectrometers will come online in the near future. We have applied our TES spectrometers to the following measurement applications: synchrotron-based absorption and emission spectroscopy and energy-resolved scattering; accelerator-based spectroscopy of hadronic atoms and particle-induced-emission spectroscopy; laboratory-based time-resolved absorption and emission spectroscopy with a tabletop, broadband source; and laboratory-based metrology of X-ray-emission lines. Here, we discuss the design, construction, and operation of our TES spectrometers and show first-light measurements from the various systems. Finally, because X-ray-TES technology continues to mature, we discuss improvements to array size, energy resolution, and counting speed that we anticipate in our next generation of TES-X-ray spectrometers and beyond.