Global patterns of diapycnal mixing from measurements of the turbulent dissipation rate

The authors present inferences of diapycnal diffusivity from a compilation of over 5200 microstructure profiles. As microstructure observations are sparse, these are supplemented with indirect measurements of mixing obtained from (i) Thorpe-scale overturns from moored profilers, a finescale parameterization applied to (ii) shipboard observations of upper-ocean shear, (iii) strain as measured by profiling floats, and (iv) shear and strain from full-depth lowered acoustic Doppler current profilers (LADCP) and CTD profiles. Vertical profiles of the turbulent dissipation rate are bottom enhanced over rough topography and abrupt, isolated ridges. The geography of depth-integrated dissipation rate shows spatial variability related to internal wave generation, suggesting one direct energy pathway to turbulence. The global-averaged diapycnal diffusivity below 1000-m depth is O(10?4) m2 s?1 and above 1000-m depth is O(10?5) m2 s?1. The compiled microstructure observations sample a wide range of internal wave power inputs and topographic roughness, providing a dataset with which to estimate a representative global-averaged dissipation rate and diffusivity. However, there is strong regional variability in the ratio between local internal wave generation and local dissipation. In some regions, the depth-integrated dissipation rate is comparable to the estimated power input into the local internal wave field. In a few cases, more internal wave power is dissipated than locally generated, suggesting remote internal wave sources. However, at most locations the total power lost through turbulent dissipation is less than the input into the local internal wave field. This suggests dissipation elsewhere, such as continental margins

Calcium-Dependent Protein Kinases from Arabidopsis Show Substrate Specificity Differences in an Analysis of 103 Substrates

The identification of substrates represents a critical challenge for understanding any protein kinase-based signal transduction pathway. In Arabidopsis, there are more than 1000 different protein kinases, 34 of which belong to a family of Ca2+-dependent protein kinases (CPKs). While CPKs are implicated in regulating diverse aspects of plant biology, from ion transport to transcription, relatively little is known about isoform-specific differences in substrate specificity, or the number of phosphorylation targets. Here, in vitro kinase assays were used to compare phosphorylation targets of four CPKs from Arabidopsis (CPK1, 10, 16, and 34). Significant differences in substrate specificity for each kinase were revealed by assays using 103 different substrates. For example CPK16 phosphorylated Serine 109 in a peptide from the stress-regulated protein, Di19-2 with KM ∼70 μM, but this site was not phosphorylated significantly by CPKs 1, 10, or 34. In contrast, CPKs 1, 10, and 34 phosphorylated 93 other peptide substrates not recognized by CPK16. Examples of substrate specificity differences among all four CPKs were verified by kinetic analyses. To test the correlation between in vivo phosphorylation events and in vitro kinase activities, assays were performed with 274 synthetic peptides that contained phosphorylation sites previously mapped in proteins isolated from plants (in vivo-mapped sites). Of these, 74 (27%) were found to be phosphorylated by at least one of the four CPKs tested. This 27% success rate validates a robust strategy for linking the activities of specific kinases, such as CPKs, to the thousands of in planta phosphorylation sites that are being uncovered by emerging technologies

Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study

Background: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of \u3e 4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS]). Objective: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD. Methods: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to \u3c 10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed. Results: For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study. Conclusions: Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping

On Critchfield's proposal: student concerns and recommendations

This is the published version, reproduced here with the publisher's permission. This article is also available electronically from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359848/.No abstract available for this item

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks

Abstract Acute hepatic porphyria comprises a group of rare, genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months prior to the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a healthcare facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased healthcare utilization. Conclusions: Patients experienced attacks often requiring treatment in a healthcare facility and/or with hemin, as well as chronic symptoms that adversely influence day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. This article is protected by copyright. All rights reserved.Peer reviewe

A13K-0336: Airborne Multi-Wavelength High Spectral Resolution Lidar for Process Studies and Assessment of Future Satellite Remote Sensing Concepts

NASA Langley recently developed the world's first airborne multi-wavelength high spectral resolution lidar (HSRL). This lidar employs the HSRL technique at 355 and 532 nm to make independent, unambiguous retrievals of aerosol extinction and backscatter. It also employs the standard backscatter technique at 1064 nm and is polarization-sensitive at all three wavelengths. This instrument, dubbed HSRL-2 (the secondgeneration HSRL developed by NASA Langley), is a prototype for the lidar on NASA's planned Aerosols- Clouds-Ecosystems (ACE) mission. HSRL-2 completed its first science mission in July 2012, the Two-Column Aerosol Project (TCAP) conducted by the Department of Energy (DOE) in Hyannis, MA. TCAP presents an excellent opportunity to assess some of the remote sensing concepts planned for ACE: HSRL-2 was deployed on the Langley King Air aircraft with another ACE-relevant instrument, the NASA GISS Research Scanning Polarimeter (RSP), and flights were closely coordinated with the DOE's Gulfstream-1 aircraft, which deployed a variety of in situ aerosol and trace gas instruments and the new Spectrometer for Sky-Scanning, Sun-Tracking Atmospheric Research (4STAR). The DOE also deployed their Atmospheric Radiation Measurement Mobile Facility and their Mobile Aerosol Observing System at a ground site located on the northeastern coast of Cape Cod for this mission. In this presentation we focus on the capabilities, data products, and applications of the new HSRL-2 instrument. Data products include aerosol extinction, backscatter, depolarization, and optical depth; aerosol type identification; mixed layer depth; and rangeresolved aerosol microphysical parameters (e.g., effective radius, index of refraction, single scatter albedo, and concentration). Applications include radiative closure studies, studies of aerosol direct and indirect effects, investigations of aerosol-cloud interactions, assessment of chemical transport models, air quality studies, present (e.g., CALIPSO) and future (e.g., EarthCARE) satellite calibration/validation, and development/assessment of advanced retrieval techniques for future satellite applications (e.g., lidar+polarimeter retrievals of aerosol and cloud properties). We will also discuss the relevance of HSRL-2 measurement capabilities to the ACE remote sensing concept

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. (Hepatology 2020;71:1546-1558)

EXPLORE: A prospective, multinational natural history study of patients with acute hepatic porphyria with recurrent attacks

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. (Hepatology 2020;71:1546-1558)

Mixed Layer Heights Derived from the NASA Langley Research Center Airborne High Spectral Resolution Lidar

The NASA airborne High Spectral Resolution Lidar (HSRL) has been deployed on board the NASA Langley Research Center's B200 aircraft to several locations in North America from 2006 to 2012 to aid in characterizing aerosol properties for over fourteen field missions. Measurements of aerosol extinction (532 nm), backscatter (532 and 1064 nm), and depolarization (532 and 1064 nm) during 349 science flights, many in coordination with other participating research aircraft, satellites, and ground sites, constitute a diverse data set for use in characterizing the spatial and temporal distribution of aerosols, as well as properties and variability of the Mixing Layer (ML) height. We describe the use of the HSRL data collected during these missions for computing ML heights and show how the HSRL data can be used to determine the fraction of aerosol optical thickness within and above the ML, which is important for air quality assessments. We describe the spatial and temporal variations in ML heights found in the diverse locations associated with these experiments. We also describe how the ML heights derived from HSRL have been used to help assess simulations of Planetary Boundary Layer (PBL) derived using various models, including the Weather Research and Forecasting Chemistry (WRF-Chem), NASA GEOS-5 model, and the ECMWF/MACC models