Conserved segmental expression of Krox-20 in the vertebrate hindbrain and its relationship to lineage restriction

6 páginas, 4 figuras.The zinc-finger gene Krox-20 is expressed in two alternating segments, rhombomeres (r) 3 and 5, in the developing mouse hindbrain. This expression pattern is established prior to rhombomere formation in the mouse, but it is not known how the timing of expression relates to cellular events of segmentation, such as lineage restriction. We have cloned Krox-20 sequences from Xenopus and the chick and shown that its alternating expression pattern is conserved in these systems, suggesting that its role in hindbrain development is conserved. Analysis of the early stages of Krox-20 expression in the chick show that both domains of expression precede the restriction of cell lineage to specific rhombomeres, consistent with a role of this gene in early events of hindbrain segmentation. The finding that expression is not coincident with lineage restriction indicates that early expression may not reflect an irreversible commitment of cells to r3 and r5 and/or may be mosaic.Peer reviewe

Quality improvement, implementation, and dissemination strategies to improve mental health care for children and adolescents: a systematic review

Abstract Background Some outcomes for children with mental health problems remain suboptimal because of poor access to care and the failure of systems and providers to adopt established quality improvement strategies and interventions with proven effectiveness. This review had three goals: (1) assess the effectiveness of quality improvement, implementation, and dissemination strategies intended to improve the mental health care of children and adolescents; (2) examine harms associated with these strategies; and (3) determine whether effectiveness or harms differ for subgroups based on system, organizational, practitioner, or patient characteristics. Methods Sources included MEDLINE®, the Cochrane Library, PsycINFO, and CINAHL, from database inception through February 17, 2017. Additional sources included gray literature, additional studies from reference lists, and technical experts. Two reviewers selected relevant randomized controlled trials (RCTs) and observational studies, extracted data, and assessed risk of bias. Dual analysis, synthesis, and grading of the strength of evidence for each outcome followed for studies meeting inclusion criteria. We also used qualitative comparative analysis to examine relationships between combinations of strategy components and improvements in outcomes. Results We identified 18 strategies described in 19 studies. Eleven strategies significantly improved at least one measure of intermediate outcomes, final health outcomes, or resource use. Moderate strength of evidence (from one RCT) supported using provider financial incentives such as pay for performance to improve the competence with which practitioners can implement evidence-based practices (EBPs). We found inconsistent evidence involving strategies with educational meetings, materials, and outreach; programs appeared to be successful in combination with reminders or providing practitioners with newly collected clinical information. We also found low strength of evidence for no benefit for initiatives that included only educational materials or meetings (or both), or only educational materials and outreach components. Evidence was insufficient to draw conclusions on harms and moderators of interventions. Conclusions Several strategies can improve both intermediate and final health outcomes and resource use. This complex and heterogeneous body of evidence does not permit us to have a high degree of confidence about the efficacy of any one strategy because we generally found only a single study testing each strategy. Trial registration PROSPERO, CRD42015024759

A Tabletop X-Ray Tomography Instrument for Nanometer-Scale Imaging: Integration of a Scanning Electron Microscope with a Transition-Edge Sensor Spectrometer

X-ray nanotomography is a powerful tool for the characterization of nanoscale materials and structures, but is difficult to implement due to competing requirements on X-ray flux and spot size. Due to this constraint, state-of-the-art nanotomography is predominantly performed at large synchrotron facilities. Compact X-ray nanotomography tools operated in standard analysis laboratories exist, but are limited by X-ray optics and destructive sample preparation techniques. We present a laboratory-scale nanotomography instrument that achieves nanoscale spatial resolution while changing the limitations of conventional tomography tools. The instrument combines the electron beam of a scanning electron microscope (SEM) with the precise, broadband X-ray detection of a superconducting transition-edge sensor (TES) microcalorimeter. The electron beam generates a highly focused X-ray spot in a metal target, while the TES spectrometer isolates target photons with high signal-to-noise. This combination of a focused X-ray spot, energy-resolved X-ray detection, and unique system geometry enable nanoscale, element-specific X-ray imaging in a compact footprint. The proof-of-concept for this approach to X-ray nanotomography is demonstrated by imaging 160 nm features in three dimensions in a Cu-SiO2 integrated circuit, and a path towards finer resolution and enhanced imaging capabilities is discussed.Comment: The following article has been submitted to Physical Review Applie

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

The Simons Observatory microwave SQUID multiplexing detector module design

Advances in cosmic microwave background (CMB) science depend on increasing the number of sensitive detectors observing the sky. New instruments deploy large arrays of superconducting transition-edge sensor (TES) bolometers tiled densely into ever larger focal planes. High multiplexing factors reduce the thermal loading on the cryogenic receivers and simplify their design. We present the design of focal-plane modules with an order of magnitude higher multiplexing factor than has previously been achieved with TES bolometers. We focus on the novel cold readout component, which employs microwave SQUID multiplexing ($\mu$mux). Simons Observatory will use 49 modules containing 60,000 bolometers to make exquisitely sensitive measurements of the CMB. We validate the focal-plane module design, presenting measurements of the readout component with and without a prototype detector array of 1728 polarization-sensitive bolometers coupled to feedhorns. The readout component achieves a $95\%$ yield and a 910 multiplexing factor. The median white noise of each readout channel is 65 $\mathrm{pA/\sqrt{Hz}}$. This impacts the projected SO mapping speed by $< 8\%$, which is less than is assumed in the sensitivity projections. The results validate the full functionality of the module. We discuss the measured performance in the context of SO science requirements, which are exceeded.Comment: Accepted to The Astrophysical Journa

Microwave multiplexing on the Keck Array

We describe an on-sky demonstration of a microwave-multiplexing readout system in one of the receivers of the Keck Array, a polarimetry experiment observing the cosmic microwave background at the South Pole. During the austral summer of 2018-2019, we replaced the time-division multiplexing readout system with microwave-multiplexing components including superconducting microwave resonators coupled to radio-frequency superconducting quantum interference devices at the sub-Kelvin focal plane, coaxial-cable plumbing and amplification between room temperature and the cold stages, and a SLAC Microresonator Radio Frequency system for the warm electronics. In the range 5-6 GHz, a single coaxial cable reads out 528 channels. The readout system is coupled to transition-edge sensors, which are in turn coupled to 150-GHz slot-dipole phased-array antennas. Observations began in April 2019, and we report here on an initial characterization of the system performance.Comment: 9 pages, 11 figures, Accepted by the Journal of Low Temperature Physics (Proceedings of the 18th International Workshop on Low Temperature Detectors

A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.</p

Structural constraints of vaccine-induced tier-2 autologous HIV neutralizing antibodies targeting the receptor-binding site.

CAPRISA, 2017.Abstract available in pdf

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202