Search

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 β-amyloid and tau-tangle pathology, and other common age-related pathologies. Linear regression models examined the association of watershed arteriolosclerosis pathology with β-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 β-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 β-amyloid. AWS arteriolosclerosis was not associated with β-amyloid or tau pathology. Ex-vivo WMH was associated with greater tau-tangle pathology burden but not β-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.

We report on the use of a kinetic-inductance traveling-wave parametric amplifier (KITWPA) as the first amplifier in the readout chain of a microwave superconducting quantum interference device (SQUID) multiplexer (umux). This umux is designed to multiplex signals from arrays of low temperature detectors such as superconducting transition-edge sensor microcalorimeters. When modulated with a periodic flux-ramp to linearize the SQUID response, the flux noise improves, on average, from $1.6$ $\mu\Phi_0/\sqrt{\mathrm{Hz}}$ with the KITWPA off, to $0.77$ $\mu\Phi_0/\sqrt{\mathrm{Hz}}$ with the KITWPA on. When statically biasing the umux to the maximally flux-sensitive point, the flux noise drops from $0.45$ $\mu\Phi_0/\sqrt{\mathrm{Hz}}$ to $0.2$ $\mu\Phi_0/\sqrt{\mathrm{Hz}}$. We validate this new readout scheme by coupling a transition-edge sensor microcalorimeter to the umux and detecting background radiation. The combination of umux and KITWPA provides a variety of new capabilities including improved detector sensitivity and more efficient bandwidth utilization.

Proteomic investigations of Alzheimer’s and Parkinson’s disease have provided valuable insights into neurodegenerative disorders. Thus far, these investigations have largely been restricted to bottom-up approaches, hindering the degree to which one can characterize a protein’s “intact” state. Top-down proteomics (TDP) overcomes this limitation; however, it is typically limited to observing only the most abundant proteoforms and of a relatively small size. Therefore, fractionation techniques are commonly used to reduce sample complexity. Here, we investigate gas-phase fractionation through high-field asymmetric waveform ion mobility spectrometry (FAIMS) within TDP. Utilizing a high complexity sample derived from Alzheimer’s disease (AD) brain tissue, we describe how the addition of FAIMS to TDP can robustly improve the depth of proteome coverage. For example, implementation of FAIMS with external compensation voltage (CV) stepping at −50, −40, and −30 CV could more than double the mean number of non-redundant proteoforms, genes, and proteome sequence coverage compared to without FAIMS. We also found that FAIMS can influence the transmission of proteoforms and their charge envelopes based on their size. Importantly, FAIMS enabled the identification of intact amyloid beta (Aβ) proteoforms, including the aggregation-prone Aβ(1–42) variant which is strongly linked to AD. Raw data and associated files have been deposited to the ProteomeXchange Consortium via the MassIVE data repository with data set identifier PXD023607.

A useful function, called group trigger, is implemented in a data acquisition system of a 240-pixel X-ray transition-edge sensor array to store simultaneous waveforms from any desired set of pixels. It works as a diagnostic tool which can record both primary pulses and associated crosstalk events with enough freedom to optimize the data output. Under a high rate of charged particle background, such as in an accelerator, investigating signals from any combination of trigger patterns for a particular event is of high importance. We utilized this function throughout an entire experiment at J-PARC, measuring kaonic atom X-rays in 2018. This was the first time a group trigger was applied to exotic-atom spectroscopy. In this experiment, the primary trigger was distributed to the four physical nearest neighbor pixels for practical purposes. The function clarified the effect of thermal and electrical cross talk from X-rays and charged particles, resulting in a better understanding of the behavior of the TES array in such a high-background environment.

We integrated a TES X-ray spectrometer with a charged kaon beam line at J-PARC to perform X-ray spectroscopy of kaonic helium atoms. Limited beam intensity and a broad beam spot size made it crucial to increase the detector acceptance angle as much as possible, requiring significant development. To this end, our TES system shared the same vacuum with a cryogenic system of the liquid helium experimental target. We also specially developed a target cell for liquid helium and a thinned aperture array on top of the TES detector. Additionally, thermal and magnetic shields and infrared filters were optimized in terms of a larger acceptance angle and energy resolution of the detector. The scientific campaign was performed in June, 2018, where the whole system was stably operated for almost one month.

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.

One of the major challenges in nowadays particle physics and astrophysics is the determination of the absolute neutrino mass scale. A powerful tool to evaluate the effective neutrino mass is the calorimetric measurement of the energy released in a nuclear decay involving neutrino. In order to reach a sensitivity on the neutrino mass of the order of 1 eV, not only detectors characterized by high performances (i.e. energy and time resolution of eV at keV and 1 s, respectively) are needed but also many detectors working in parallel are required. Microwave frequency readout provide an effective technique to read out large arrays of low temperature detectors allowing to reach a multiplex factor of the order of thousands. This technique is the one used to read out the 1000 Transition Edge Sensors of HOLMES, an experiment that aims at measuring the electron neutrino mass by means of the electron capture (EC) decay of 163Ho with an expected sensitivity of the order of 1 eV. In this contribution we present the characterization of the microwave-multiplexed readout system, and the results obtained with the detectors specifically designed for HOLMES.

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.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.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.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.

Studies1,2 have shown that the remnants of destroyed planets and debris-disk planetesimals can survive the volatile evolution of their host stars into white dwarfs3,4, but few intact planetary bodies around white dwarfs have been detected5–8. Simulations predict9–11 that planets in Jupiter-like orbits around stars of ≲8 M☉ (solar mass) avoid being destroyed by the strong tidal forces of their stellar host, but as yet, there has been no observational confirmation of such a survivor. Here we report the non-detection of a main-sequence lens star in the microlensing event MOA-2010-BLG-477Lb12 using near-infrared observations from the Keck Observatory. We determine that this system contains a 0.53 ± 0.11 M☉ white-dwarf host orbited by a 1.4 ± 0.3 Jupiter-mass planet with a separation on the plane of the sky of 2.8 ± 0.5 astronomical units, which implies a semi-major axis larger than this. This system is evidence that planets around white dwarfs can survive the giant and asymptotic giant phases of their host’s evolution, and supports the prediction that more than half of white dwarfs have Jovian planetary companions13. Located at approximately 2.0 kiloparsecs towards the centre of our Galaxy, it is likely to represent an analogue to the end stages of the Sun and Jupiter in our own Solar System. © 2021, The Author(s), under exclusive licence to Springer Nature Limited., Data presented in this work were obtained at the W. M. Keck Observatory from telescope time allocated to the National Aeronautics and Space Administration through the agency’s scientific partnership with the California Institute of Technology and the University of California. This work was supported by the University of Tasmania through the UTAS Foundation, ARC grant DP200101909, and the endowed Warren Chair in Astronomy. We acknowledge the support of ANR COLD WORLDS (ANR-18-CE31-0002) at the Institut d’Astrophysique de Paris and the Laboratoire d’Astrophysique de Bordeaux. D.P.B., A.B., N.K., C.R. and S.K.T. were supported by NASA through grant NASA-80NSSC18K0274 and by NASA award no. 80GSFC17M0002. E.B. acknowledges support from NASA grant 80NSSC19K0291. Work by N.K. is supported by JSPS KAKENHI grant no. JP18J00897. C.D. acknowledges financial support from the State Agency for Research of the Spanish MCIU through the ‘Center of Excellence Severo Ochoa’ award to the Instituto de Astrofísica de Andalucía (SEV-2017-0709), and the Group project ref. PID2019-110689RB-I00/AEI/10.13039/501100011033. D.V. gratefully acknowledges the support of the STFC via an Ernest Rutherford Fellowship (grant ST/P003850/1).

The successful realization and broad deployment of transition edge sensor (TES)-based detector systems has led to significant demand for time-division and code-division superconducting quantum interference device (SQUID) multiplexers time division multiplexing (TDM) and code division multiplexing (CDM) as essential components of the cryogenic readout chain. TDM and CDM circuits are produced by the Boulder Microfabrication Facility in large quantities and in multiple varieties to meet the needs of various bolometric and calorimetric applications. In most cases, the basic functionality of these devices must be verified before they are passed along to internal or external collaborators for integration into scientific instruments. We have developed a test bed that utilizes the NIST TDM/CDM read-out electronics to make automated multiplexed measurements on sixteen devices simultaneously in a 4 K liquid-helium dip probe. The optimization of the measurement process has resulted in vastly improved throughput and enhanced data products. We present a thorough analysis of results from the application of the test process to flux-activated-switch-style multiplexers. The utility of this approach in identifying fabrication trends, yield indicators, and common failure modes will be demonstrated.

This article introduces NewGene, a complete redesign of the popular EUGene software. Like its predecessor, NewGene is designed to eliminate many of the difficulties commonly involved in constructin...

MOA-2006-BLG-074 was selected as one of the most promising planetary candidates in a retrospective analysis of the MOA collaboration: its asymmetric high-magnification peak can be perfectly explained by a source passing across a central caustic deformed by a small planet. However, after a detailed analysis of the residuals, we have realized that a single lens and a source orbiting with a faint companion provides a more satisfactory explanation for all the observed deviations from a Paczynski curve and the only physically acceptable interpretation. Indeed the orbital motion of the source is constrained enough to allow a very good characterization of the binary source from the microlensing light curve. The case of MOA-2006-BLG-074 suggests that the so-called xallarap effect must be taken seriously in any attempts to obtain accurate planetary demographics from microlensing surveys., 14 pages, 8 figures, accepted by AAS

Sensory and corticospinal (CST) pathways activate spinal GABAergic interneurons with axo-axonic connections onto proprioceptive (Ia) afferents that depolarize these afferents (termed primary afferent depolarization, PAD). In rodents sensory-evoked PAD is produced by GABAA receptors at nodes of Ranvier in Ia-afferents, rather than at presynaptic terminals, and facilitates action potential propagation to motoneurons by preventing branch point failures, rather than causing presynaptic inhibition. Here we examined if PAD likewise facilitates the Ia-afferent mediated H-reflex in humans by evoking PAD with both sensory and CST stimulation. H-reflexes in several lower limb muscles were facilitated by prior conditioning from low-threshold proprioceptive, cutaneous or CST pathways, with a similar time course (∼200 ms) to the PAD measured in rodent Ia-afferents. Long trains of repeated cutaneous or proprioceptive afferent stimulation produced long-lasting facilitation of the H-reflex for up to 2 minutes, consistent with the tonic depolarization of rodent Ia-afferents mediated by nodal 5-GABA receptors for similar stimulation trains. Facilitation of the conditioned H-reflexes was not mediated by direct facilitation of the motoneurons because isolated stimulation of sensory or CST pathways did not modulate the firing rate of tonically activated motor units in tested muscles. Furthermore, cutaneous conditioning increased the firing probability of a single motor unit during the H-reflex without increasing its firing rate at this time, indicating that the underlying excitatory postsynaptic potential (EPSP) was more probable, but not larger. These results are consistent with sensory and CST pathways activating nodal GABAA receptors that reduce intermittent failure of action potentials propagating into Ia-afferent branches.Key Points SummaryThe control of posture and movement requires peripheral sensory feedback, which was previously thought to be inhibited by specialized GABAergic neurons in the spinal cord.Based on new findings in rodents, we provide evidence in humans that sensory and corticospinal pathways that likely activate these GABAergic pathways facilitate, rather than inhibit, the flow of sensory feedback in afferents that carry information about body position, movement and effort.These new findings of how sensory and descending pathways facilitate this sensory feedback to spinal motor neurons can now be applied to people with injury to the brain or spinal cord where these GABA neurons are affected, allowing us to understand how altered sensory control may affect residual motor function and the production of involuntary muscle spasticity.

BACKGROUND: Meniscal tears, specifically lateral meniscal tears, have a larger than expected un-derdiagnosis rate in the presence of an ACL tear. The purpose of our study was to search for an MRI bone contusion pattern associated with MRI occult meniscal tears in patients with an ACL tear, specifically a contusion of the rim of the medial femoral condyle (RMFC). Our hypothesis was that there would be a significant association between RMFC contusions and MRI occult meniscal tears in patients with an ACL tear. We also searched for a difference between sexes with respect to the presence of the RMFC contusion in the setting of an occult meniscal tear. We also categorized the type, size, and location of these occult meniscal tears in the setting of an ACL tear. METHODS: This was a retrospective study that examined characteristics of occult meniscal tears and their association with a RMFC bone contusion. IRB approval was obtained. The date range of the study was June 2009 through December 2015. 6392 consecutive knee MRI reports in patients with an ACL deficient knee were reviewed. The study group included 22 patients with MRI occult meniscal tears, the control group included 110 patients. Relevant statistical values were calculated. RESULTS: The most common type of occult meniscal tears were small radial and small longitudinal tears of the lateral meniscus. Occult meniscal tears were associated with an RMFC contusion in the study group (p=0.0457), particularly in males (p = 0.0003). In males with a torn ACL, the sensitivity of an RMFC contusion for an occult meniscal tear was 80%. CONCLUSION: In males with an ACL tear, there was a significant association between a contusion of the RMFC and an occult meniscal tear (commonly small radial or small peripheral partial-thickness longitudinal tears). RMFC contusions were reliably identified by radiologists in this study. Level of Evidence: II

International audience; 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 Kβ x rays together with the hypersatellite Khα 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.

Background The complexity of oesophageal surgery and the significant risk of morbidity necessitates that oesophagectomy is predominantly performed by a consultant surgeon, or a senior trainee under their supervision. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on postoperative outcomes in an international multicentre setting. Methods Data from the multicentre Oesophago-Gastric Anastomosis Study Group (OGAA) cohort study were analysed, which comprised prospectively collected data from patients undergoing oesophagectomy for oesophageal cancer between April 2018 and December 2018. Procedures were grouped by the level of trainee involvement, and univariable and multivariable analyses were performed to compare patient outcomes across groups. Results Of 2232 oesophagectomies from 137 centres in 41 countries, trainees were involved in 29.1 per cent of them (n = 650), performing only the abdominal phase in 230, only the chest and/or neck phases in 130, and all phases in 315 procedures. For procedures with a chest anastomosis, those with trainee involvement had similar 90-day mortality, complication and reoperation rates to consultant-performed oesophagectomies (P = 0.451, P = 0.318, and P = 0.382, respectively), while anastomotic leak rates were significantly lower in the trainee groups (P = 0.030). Procedures with a neck anastomosis had equivalent complication, anastomotic leak, and reoperation rates (P = 0.150, P = 0.430, and P = 0.632, respectively) in trainee-involved versus consultant-performed oesophagectomies, with significantly lower 90-day mortality in the trainee groups (P = 0.005). Conclusion Trainee involvement was not found to be associated with significantly inferior postoperative outcomes for selected patients undergoing oesophagectomy. The results support continued supervised trainee involvement in oesophageal cancer surgery. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on perioperative outcomes in the international multicentre Oesophago-Gastric Anastomosis Audit (OGAA). Analysis of 2232 oesophagectomies has shown that trainee involvement did not negatively impact perioperative outcomes.

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.

Studies

HOLMES is an experiment aiming at performing a direct measurement of the neutrino mass from the electron capture (EC) spectrum of $$^{163}\hbox {Ho}$$. In order to reach a sensitivity of the order of $$\sim $$1 eV/c$$^2$$ on the neutrino mass, it is necessary to gather as many as $$10^{13}$$ events in the 3-year projected live time of HOLMES, keeping the pileup fraction as low as $$10^{-4}$$. This is not a trivial matter when it comes to low- temperature calorimeters, which usually have a rather slow time response. At the same time, a large number of detectors need to be operated simultaneously, and hence, in order to avoid an extremely large cryogenic facility, multiplexing is required. In this contribution, I will outline the current status and perspective of HOLMES, with special care devoted to the detectors and readout system, which have currently reached their target performance.

The HOLMES project aims to directly measure the electron neutrino mass using the electron capture decay (EC) of 163Ho down to the eV scale. It will perform a precise measurement of the end-point of the 163Ho calorimetric energy spectrum to search for the deformation caused by a finite electron neutrino mass. The choice of 163Ho as source is driven by the very low Q-value of the EC reaction (around 2.8 keV), which allows for a high sensitivity while keeping the overall activities to reasonable value (O(102)Hz/detector), thus reducing the pile-up probability. A large array made of thousands of Transition Edge Sensor based micro-calorimeters will be used for a calorimetric measurement of the EC 163Ho spectrum. The calorimetric approach, with the source embedded inside the detector, eliminates systematic uncertainties arising from the use of an external beta-source, and minimizes the effect of the atomic de-excitation process uncertainties. The commissioning of the first implanted sub-array is scheduled for the end of 2017. It will provide useful data about the EC decay of 163Ho together with a first limit on neutrino mass. In this paper the current status of the main tasks will be summarized: the TES array design and engineering, the isotope preparation and embedding, and the development of a high speed multiplexed SQUID read-out system for the data acquisition.

We are building a transition edge sensor (TES) X-ray spectrometer for the Linac Coherent Light Source (LCLS-II) at SLAC National Accelerator Laboratory (SLAC) to coincide with new upgrades for this free electron laser facility. This new X-ray spectrometer will have 1000 TES pixels with 0.5 eV energy resolution for soft X-rays below 1 keV. Multiplexing will be done with microwave SQUID resonators and new specialized electronic hardware developed at SLAC. This spectrometer will use a dilution refrigerator to achieve lower operating temperatures than previous TES spectrometers and will be coupled to the liquid jet endstation at LCLS-II. The spectrometer is designed to operate at much higher count rates than previous TES X-ray spectrometers to take advantage of the high repetition rate of the LCLS-II. Science applications will utilize the high photon collection efficiency and throughput, high energy resolution, as well as its ability to simultaneously measure its full calibrated energy range.