Macrophage depletion blocks congenital SARM1-dependent neuropathy

Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified 2 rare NMNAT2 missense variants in 2 brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions V98M and R232Q, which reduced NMNAT2 NAD+-synthetase activity. We generated a mouse model to mirror the human syndrome and found that Nmnat2V98M/R232Q compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed neuropathic phenotypes in Nmnat2V98M/R232Q mice, identifying a SARM1-dependent neuroimmune mechanism as a key driver of disease pathogenesis. These findings demonstrate that SARM1 induced inflammatory neuropathy and highlight the potential of immune therapy as a treatment for this rare syndrome and other neurodegenerative conditions associated with NMNAT2 loss and SARM1 activation

A review of high impact weather for aviation meteorology

This review paper summarizes current knowledge available for aviation operations related to meteorology and provides suggestions for necessary improvements in the measurement and prediction of weather-related parameters, new physical methods for numerical weather predictions (NWP), and next-generation integrated systems. Severe weather can disrupt aviation operations on the ground or in-flight. The most important parameters related to aviation meteorology are wind and turbulence, fog visibility, aerosol/ash loading, ceiling, rain and snow amount and rates, icing, ice microphysical parameters, convection and precipitation intensity, microbursts, hail, and lightning. Measurements of these parameters are functions of sensor response times and measurement thresholds in extreme weather conditions. In addition to these, airport environments can also play an important role leading to intensification of extreme weather conditions or high impact weather events, e.g., anthropogenic ice fog. To observe meteorological parameters, new remote sensing platforms, namely wind LIDAR, sodars, radars, and geostationary satellites, and in situ instruments at the surface and in the atmosphere, as well as aircraft and Unmanned Aerial Vehicles mounted sensors, are becoming more common. At smaller time and space scales (e.g., < 1 km), meteorological forecasts from NWP models need to be continuously improved for accurate physical parameterizations. Aviation weather forecasts also need to be developed to provide detailed information that represents both deterministic and statistical approaches. In this review, we present available resources and issues for aviation meteorology and evaluate them for required improvements related to measurements, nowcasting, forecasting, and climate change, and emphasize future challenges

Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1).

OBJECTIVE: To extend the phenotypic description of Charcot-Marie-Tooth disease (CMTX1) and to draw new genotype-phenotype relationships. METHODS: Mutations in GJB1 cause the main X-linked form of CMTX (CMTX1). We report cross-sectional data from 160 patients (from 120 different families, with 89 different mutations) seen at the Inherited Neuropathies Consortium centers. RESULTS: We evaluated 87 males who had a mean age of 41 years (range 10-78 years) and 73 females who had a mean age of 46 years (range 15-84 years). Sensory-motor polyneuropathy affects both sexes, more severely in males than in females, and there was a strong correlation between age and disease burden in males but not in females. Compared with females, males had more severe reduction in motor and sensory neurophysiology parameters. In contrast to females, the radial nerve sensory response in older males tended to be more severely affected compared with younger males. Median and ulnar nerve motor amplitudes were also more severely affected in older males, whereas ulnar nerve motor potentials tended to be more affected in older females. Conversely, there were no statistical differences between the sexes in other features of the disease, such as problems with balance and hand dexterity. CONCLUSIONS: In the absence of a phenotypic correlation with specific GJB1 mutations, sex-specific distinctions and clinically relevant attributes need to be incorporated into the measurements for clinical trials in people with CMTX1. CLINICALTRIALSGOV IDENTIFIER: NCT01193075

Gravitational Waves From Known Pulsars: Results From The Initial Detector Era

We present the results of searches for gravitational waves from a large selection of pulsars using data from the most recent science runs (S6, VSR2 and VSR4) of the initial generation of interferometric gravitational wave detectors LIGO (Laser Interferometric Gravitational-wave Observatory) and Virgo. We do not see evidence for gravitational wave emission from any of the targeted sources but produce upper limits on the emission amplitude. We highlight the results from seven young pulsars with large spin-down luminosities. We reach within a factor of five of the canonical spin-down limit for all seven of these, whilst for the Crab and Vela pulsars we further surpass their spin-down limits. We present new or updated limits for 172 other pulsars (including both young and millisecond pulsars). Now that the detectors are undergoing major upgrades, and, for completeness, we bring together all of the most up-to-date results from all pulsars searched for during the operations of the first-generation LIGO, Virgo and GEO600 detectors. This gives a total of 195 pulsars including the most recent results described in this paper.United States National Science FoundationScience and Technology Facilities Council of the United KingdomMax-Planck-SocietyState of Niedersachsen/GermanyAustralian Research CouncilInternational Science Linkages program of the Commonwealth of AustraliaCouncil of Scientific and Industrial Research of IndiaIstituto Nazionale di Fisica Nucleare of ItalySpanish Ministerio de Economia y CompetitividadConselleria d'Economia Hisenda i Innovacio of the Govern de les Illes BalearsNetherlands Organisation for Scientific ResearchPolish Ministry of Science and Higher EducationFOCUS Programme of Foundation for Polish ScienceRoyal SocietyScottish Funding CouncilScottish Universities Physics AllianceNational Aeronautics and Space AdministrationOTKA of HungaryLyon Institute of Origins (LIO)National Research Foundation of KoreaIndustry CanadaProvince of Ontario through the Ministry of Economic Development and InnovationNational Science and Engineering Research Council CanadaCarnegie TrustLeverhulme TrustDavid and Lucile Packard FoundationResearch CorporationAlfred P. Sloan FoundationAstronom

Compartmental Genomics in Living Cells Revealed by Single-Cell Nanobiopsy

The ability to study the molecular biology of living single cells in heterogeneous cell populations is essential for next generation analysis of cellular circuitry and function. Here, we developed a single-cell nanobiopsy platform based on scanning ion conductance microscopy (SICM) for continuous sampling of intracellular content from individual cells. The nanobiopsy platform uses electrowetting within a nanopipette to extract cellular material from living cells with minimal disruption of the cellular milieu. We demonstrate the subcellular resolution of the nanobiopsy platform by isolating small subpopulations of mitochondria from single living cells, and quantify mutant mitochondrial genomes in those single cells with high throughput sequencing technology. These findings may provide the foundation for dynamic subcellular genomic analysis

Microphysical characteristics of frozen droplet aggregates from deep convective clouds

During the 2012 Deep Convective Clouds and Chemistry (DC3) experiment the National Science Foundation/National Center for Atmospheric Research Gulfstream V (GV) aircraft sampled the upper anvils of two storms that developed in eastern Colorado on 6 June 2012. A cloud particle imager (CPI) mounted on the GV aircraft recorded images of ice crystals at altitudes of 12.0 to 12.4&thinsp;km and temperatures (T) from −61 to −55&thinsp;∘C. A total of 22&thinsp;393 CPI crystal images were analyzed, all with maximum dimension (Dmax⁡)&lt;433&thinsp;µm and with an average Dmax⁡ of 80.7±45.4&thinsp;µm. The occurrence of well-defined pristine crystals (e.g., columns and plates) was less than 0.04&thinsp;% by number. Single frozen droplets and frozen droplet aggregates (FDAs) were the dominant habits with fractions of 73.0&thinsp;% (by number) and 46.3&thinsp;% (by projected area), respectively. The relative frequency of occurrence of single frozen droplets and FDAs depended on temperature and position within the anvil cloud. A new algorithm that uses the circle Hough transform technique was developed to automatically identify the number, size, and relative position of element frozen droplets within FDAs. Of the FDAs, 42.0&thinsp;% had two element frozen droplets with an average of 4.7±5.0 element frozen droplets. The frequency of occurrence gradually decreased with the number of element frozen droplets. Based on the number, size, and relative position of the element frozen droplets within the FDAs, possible three-dimensional (3-D) realizations of FDAs were generated and characterized by two different shape parameters, the aggregation index (AI) and the fractal dimension (Df), that describe 3-D shapes and link to scattering properties with an assumption of spherical shape of element frozen droplets. The AI of FDAs decreased with an increase in the number of element frozen droplets, with larger FDAs with more element frozen droplets having more compact shapes. The Df of FDAs was about 1.20–1.43 smaller than that of black carbon (BC) aggregates (1.53–1.85) determined in previous studies. Such a smaller Df of FDAs indicates that FDAs have more linear chain-like branched shapes than the compact shapes of BC aggregates. Determined morphological characteristics of FDAs along with the proposed reconstructed 3-D representations of FDAs in this study have important implications for improving the calculations of the microphysical (e.g., fall velocity) and radiative (e.g., asymmetry parameter) properties of ice crystals in upper anvil clouds.</p

Electrochemical Nanoprobes for Single-Cell Analysis

The measurement of key molecules in individual cells with minimal disruption to the biological milieu is the next frontier in single-cell analyses. Nanoscale devices are ideal analytical tools because of their small size and their potential for high spatial and temporal resolution recordings. Here, we report the fabrication of disk-shaped carbon nanoelectrodes whose radius can be precisely tuned within the range 5–200 nm. The functionalization of the nanoelectrode with platinum allowed the monitoring of oxygen consumption outside and inside a brain slice. Furthermore, we show that nanoelectrodes of this type can be used to impale individual cells to perform electrochemical measurements within the cell with minimal disruption to cell function. These nanoelectrodes can be fabricated combined with scanning ion conductance microscopy probes, which should allow high resolution electrochemical mapping of species on or in living cells

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

BACKGROUND: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data was donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups