Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation–Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials

Purpose: To report the durability of voretigene neparvovec-rzyl (VN) adeno-associated viral vector–based gene therapy for RPE65 mutation–associated inherited retinal dystrophy (IRD), including results of a phase 1 follow-on study at year 4 and phase 3 study at year 2. Design: Open-label phase 1 follow-on clinical trial and open-label, randomized, controlled phase 3 clinical trial. Participants: Forty subjects who received 1.5×1011 vector genomes (vg) of VN per eye in at least 1 eye during the trials, including 11 phase 1 follow-on subjects and 29 phase 3 subjects (20 original intervention [OI] and 9 control/intervention [CI]). Methods: Subretinal injection of VN in the second eye of phase 1 follow-on subjects and in both eyes of phase 3 subjects. Main Outcome Measures: End points common to the phase 1 and phase 3 studies included change in performance on the Multi-Luminance Mobility Test (MLMT) within the illuminance range evaluated, full-field light sensitivity threshold (FST) testing, and best-corrected visual acuity (BCVA). Safety end points included adverse event reporting, ophthalmic examination, physical examination, and laboratory testing. Results: Mean (standard deviation) MLMT lux score change was 2.4 (1.3) at 4 years compared with 2.6 (1.6) at 1 year after administration in phase 1 follow-on subjects (n = 8), 1.9 (1.1) at 2 years, and 1.9 (1.0) at 1 year post-administration in OI subjects (n = 20), and 2.1 (1.6) at 1 year post-administration in CI subjects (n = 9). All 3 groups maintained an average improvement in FST, reflecting more than a 2 log10(cd.s/m2) improvement in light sensitivity at 1 year and subsequent available follow-up visits. The safety profile was consistent with vitrectomy and the subretinal injection procedure, and no deleterious immune responses occurred. Conclusions: After VN gene augmentation therapy, there was a favorable benefit-to-risk profile with similar improvement demonstrated in navigational ability and light sensitivity among 3 groups of subjects with RPE65 mutation–associated IRD, a degenerative disease that progresses to complete blindness. The safety profile is consistent with the administration procedure. These data suggest that this effect, which is nearly maximal by 30 days after VN administration, is durable for 4 years, with observation ongoing

A Novel Behavioral Assay for Measuring Cold Sensation in Mice

Behavioral models of cold responses are important tools for exploring the molecular mechanisms of cold sensation. To complement the currently cold behavioral assays and allow further studies of these mechanisms, we have developed a new technique to measure the cold response threshold, the cold plantar assay. In this assay, animals are acclimated on a glass plate and a cold stimulus is applied to the hindpaw through the glass using a pellet of compressed dry ice. The latency to withdrawal from the cooled glass is used as a measure of the cold response threshold of the rodents, and the dry ice pellet provides a ramping cold stimulus on the glass that allows the correlation of withdrawal latency values to rough estimates of the cold response threshold temperature. The assay is highly sensitive to manipulations including morphine-induced analgesia, Complete Freund's Adjuvant-induced inflammatory allodynia, and Spinal Nerve Ligation-induced neuropathic allodynia

The CAMELS Project: Public Data Release

The Cosmology and Astrophysics with Machine Learning Simulations (CAMELS) project was developed to combine cosmology with astrophysics through thousands of cosmological hydrodynamic simulations and machine learning. CAMELS contains 4233 cosmological simulations, 2049 N-body simulations, and 2184 state-of-the-art hydrodynamic simulations that sample a vast volume in parameter space. In this paper, we present the CAMELS public data release, describing the characteristics of the CAMELS simulations and a variety of data products generated from them, including halo, subhalo, galaxy, and void catalogs, power spectra, bispectra, Lyα spectra, probability distribution functions, halo radial profiles, and X-rays photon lists. We also release over 1000 catalogs that contain billions of galaxies from CAMELS-SAM: a large collection of N-body simulations that have been combined with the Santa Cruz semianalytic model. We release all the data, comprising more than 350 terabytes and containing 143,922 snapshots, millions of halos, galaxies, and summary statistics. We provide further technical details on how to access, download, read, and process the data at https://camels.readthedocs.io

The digital music lab: A big data infrastructure for digital musicology

In musicology and music research generally, the increasing availability of digital music, storage capacities, and computing power enable and require new and intelligent systems. In the transition from traditional to digital musicology, many techniques and tools have been developed for the analysis of individual pieces of music, but large-scale music data that are increasingly becoming available require research methods and systems that work on the collection-level and at scale. Although many relevant algorithms have been developed during the past 15 years of research in Music Information Retrieval, an integrated system that supports large-scale digital musicology research has so far been lacking. In the Digital Music Lab (DML) project, a collaboration among music librarians, musicologists, computer scientists, and human-computer interface specialists, the DML software system has been developed that fills this gap by providing intelligent large-scale music analysis with a user-friendly interactive interface supporting musicologists in their exploration and enquiry. The DML system empowers musicologists by addressing several challenges: distributed processing of audio and other music data, management of the data analysis process and results, remote analysis of data under copyright, logical inference on the extracted information and metadata, and visual web-based interfaces for exploring and querying the music collections. The DML system is scalable and based on SemanticWeb technology and integrates into Linked Data with the vision of a distributed system that enables music research across archives, libraries, and other providers of music data. A first DML system prototype has been set up in collaboration with the British Library and I Like Music Ltd. This system has been used to analyse a diverse corpus of currently 250,000 music tracks. In this article, we describe the DML system requirements, design, architecture, components, and available data sources, explaining their interaction. We report use cases and applications with initial evaluations of the proposed system

Can the understory affect the Hymenoptera parasitoids in a Eucalyptus plantation?

The understory in forest plantations can increase richness and diversity of natural enemies due to greater plant species richness. The objective of this study was to test the hypothesis that the presence of the understory and climatic season in the region (wet or dry) can increase the richness and abundance of Hymenoptera parasitoids in Eucalyptus plantations, in the municipality of Belo Oriente, Minas Gerais State, Brazil. In each eucalyptus cultivation (five areas of cultivation) ten Malaise traps were installed, five with the understory and five without it. A total of 9,639 individuals from 30 families of the Hymenoptera parasitoids were collected, with Mymaridae, Scelionidae, Encyrtidae and Braconidae being the most collected ones with 4,934, 1,212, 619 and 612 individuals, respectively. The eucalyptus stands with and without the understory showed percentage of individuals 45.65% and 54.35% collected, respectively. The understory did not represent a positive effect on the overall abundance of the individuals Hymenoptera in the E. grandis stands, but rather exerted a positive effect on the specific families of the parasitoids of this order

Structural brain correlates of childhood inhibited temperament: an ENIGMA-Anxiety Mega-analysis

NWORubicon 019.201SG.022Pathways through Adolescenc

Unjamming and cell shape in the asthmatic airway epithelium

From coffee beans flowing in a chute to cells remodelling in a living tissue, a wide variety of close-packed collective systems— both inert and living—have the potential to jam. The collective can sometimes flow like a fluid or jam and rigidify like a solid. The unjammed-to-jammed transition remains poorly understood, however, and structural properties characterizing these phases remain unknown. Using primary human bronchial epithelial cells, we show that the jamming transition in asthma is linked to cell shape, thus establishing in that system a structural criterion for cell jamming. Surprisingly, the collapse of critical scaling predicts a counter-intuitive relationship between jamming, cell shape and cell–cell adhesive stresses that is borne out by direct experimental observations. Cell shape thus provides a rigorous structural signature for classification and investigation of bronchial epithelial layer jamming in asthma, and potentially in any process in disease or development in which epithelial dynamics play a prominent role

Assessing Theoretical Conclusions With Blinded Inference to Investigate a Potential Inference Crisis

Scientific advances across a range of disciplines hinge on the ability to make inferences about unobservable theoretical entities on the basis of empirical data patterns. Accurate inferences rely on both discovering valid, replicable data patterns and accurately interpreting those patterns in terms of their implications for theoretical constructs. The replication crisis in science has led to widespread efforts to improve the reliability of research findings, but comparatively little attention has been devoted to the validity of inferences based on those findings. Using an example from cognitive psychology, we demonstrate a blinded-inference paradigm for assessing the quality of theoretical inferences from data. Our results reveal substantial variability in experts’ judgments on the very same data, hinting at a possible inference crisis