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Abstract Honey bee, Apis mellifera, drones are typically haploid, developing from an unfertilized egg, inheriting only their queen’s alleles and none from the many drones she mated with. Thus the ordered combination or ‘phase’ of alleles is known, making drones a valuable haplotype resource. We collated whole-genome sequence data for 1,407 drones, including 45 newly sequenced Scottish drones, collectively representing 19 countries, 8 subspecies and various hybrids. Following alignment to Amel_HAv3.1, variant calling and quality filtering, we retained 17.4 M high quality variants across 1,328 samples with a genotyping rate of 98.7%. We demonstrate the utility of this haplotype resource, AmelHap, for genotype imputation, returning >95% concordance when up to 61% of data is missing in haploids and up to 12% of data is missing in diploids. AmelHap will serve as a useful resource for the community for imputation from low-depth sequencing or SNP chip data, accurate phasing of diploids for association studies, and as a comprehensive reference panel for population genetic and evolutionary analyses.

Concepts and practices surrounding measurement uncertainty are vital knowledge for physicists and are often emphasized in undergraduate physics laboratory courses. We have previously developed a research-based assessment instrument--the Survey of Physics Reasoning on Uncertainty Concepts in Experiments (SPRUCE)--to examine student proficiency with measurement uncertainty along a variety of axes, including sources of uncertainty, handling of uncertainty, and distributions and repeated measurements. We present here initial results from the assessment representing over 1500 students from 20 institutions. We analyze students' performance pre- and postinstruction in lab courses and examine how instruction impacts students with different majors and gender. We find that students typically excel in certain areas, such as reporting the mean of a distribution as their result, while they struggle in other areas, such as comparing measurements with uncertainty and correctly propagating errors using formulas. Additionally, we find that the importance that an instructor places in certain areas of measurement uncertainty is uncorrelated with student performance in those areas.

Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.

PURPOSE: To evaluate the effectiveness of plasma exchange (PLEX) for optic neuritis (ON). METHODS: We conducted an international multicenter retrospective study evaluating the outcomes of ON following PLEX. Outcomes were compared to raw data from the Optic Neuritis Treatment Trial (ONTT) using a matched subset. RESULTS: A total of 395 ON attack treated with PLEX from 317 patients were evaluated. The median age was 37 years (range 9-75), and 71% were female. Causes of ON included multiple sclerosis (108), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (92), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) (75), seronegative-NMOSD (34), idiopathic (83), and other (3). Median time from onset of vision loss to PLEX was 2.6 weeks (interquartile range [IQR], 1.4-4.0). Median visual acuity (VA) at the time of PLEX was count fingers (IQR, 20/200-hand motion), and median final VA was 20/25 (IQR, 20/20-20/60) with no differences among etiologies except MOGAD-ON, which had better outcomes. In 81 (20.5%) ON attacks, the final VA was 20/200 or worse. Patients with poor outcomes were older (P = .002), had worse VA at the time of PLEX (P < .001), and longer delay to PLEX (P < .001). In comparison with the ONTT subset with severe corticosteroid-unresponsive ON, a final VA of worse than 20/40 occurred in 6 of 50 (12%) PLEX-treated ON vs 7 of 19 (37%) from the ONTT treated with intravenous methylprednisolone without PLEX (P = .04). CONCLUSION: Most ON attacks improved with PLEX, and outcomes were better than attacks with similar severity in the ONTT. The presence of severe vision loss at nadir, older age, and longer delay to PLEX predicted a worse outcome whereas MOGAD-ON had a more favorable prognosis. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

INTRODUCTION: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. METHODS: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. RESULTS: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P

La démocratisation des outils de la génomique et plus particulièrement du séquençage à haut débit a permis le séquençage du génome du canard commun. Des projets complémentaires sont déjà initiés pour prolonger et exploiter au mieux ces premiers acquis. En tout premier lieu, il s’agit de poursuivre la description de la structure du génome et d’en exploiter les connaissances : cartes d’hybrides irradiés pour ordonner la séquence le long des chromosomes ; génomique comparée avec le génome de la poule pour bénéficier des connaissances sur ce génome modèle ; recherche de SNP (Single Nucleotide Polymorphism) pour les études et la gestion de populations ; carte génétique pour la détection des QTL (Quantitative Trait Locus). La première détection de QTL influençant les performances du mulard, réalisée à l’aide de marqueurs microsatellites chez la cane commune, sera complétée par une seconde étude utilisant des marqueurs SNP développés spécifiquement et permettant une bien meilleure couverture du génome. Par ailleurs, il est important de réaliser une annotation fonctionnelle du génome, ce qui peut être abordé par le séquençage de transcrits. A terme, le génome annoté sera utilisé pour analyser son expression dans différents tissus et/ou conditions d’élevage, la connaissance des modèles de transcrits et de protéines facilitant les études en transcriptomique et protéomique. Le canard mulard, produit du croisement de la cane commune avec le canard de Barbarie, devra également être étudié en raison de son intérêt agronomique, lié à ses performances exceptionnelles dans la filière des palmipèdes gras.

[This paper is part of the Focused Collection on Instructional labs: Improving traditions and new directions.] Measurement uncertainty is a critical feature of experimental research in the physical sciences, and the concepts and practices surrounding measurement uncertainty are important components of physics lab courses. However, there has not been a broadly applicable, research-based assessment tool that allows physics instructors to easily measure students' knowledge of measurement uncertainty concepts and practices. To address this need, we employed evidence-centered design to create the Survey of Physics Reasoning on Uncertainty Concepts in Experiments (SPRUCE). SPRUCE is a pre-post assessment instrument intended for use in introductory (first and second year) physics lab courses to help instructors and researchers identify student strengths and challenges with measurement uncertainty. In this paper, we discuss the development of SPRUCE's assessment items guided by evidence-centered design, focusing on how instructors' and researchers' assessment priorities were incorporated into the assessment items and how students' reasoning from pilot testing informed decisions around item answer options. We also present an example of some of the feedback an instructor would receive after implementing SPRUCE in a pre-post fashion, along with a brief discussion of how that feedback could be interpreted and acted upon.

Depuis la première publication du génome humain en 2001, les génomes de nombreuses espèces animales d’intérêt agronomique ontété séquencés ou sont en cours de séquençage. Après la réalisation de l’assemblage des génomes pour les espèces majeures par laméthode de Sanger* et des séquenceurs capillaires, la nouvelle génération de séquenceurs parallèles (NGS : Next GenerationSequencing) permet maintenant le séquençage rapide et à bas coût d’un nombre bien plus grand d’espèces. Un rappel sur les diversprincipes du séquençage et de l’assemblage des génomes, permettant de mieux comprendre leurs avantages et leurs limites, est suivid’une description de l’état d’avancement de la connaissance des génomes des animaux d’intérêt agronomique. Finalement, quelquesexemples de domaines d’utilisation des génomes assemblés sont rapidement décrits.

La majorité des cas de salmonellose humaine dans les pays industrialisés est liée à la consommation d’oeufs et de viande de volaille mais aussi de charcuteries contaminées. Pour réduire ce risque alimentaire, la stratégie développée à l’INRA, en collaboration avec l’AFSSA, vise principalement à réduire la contamination des matières premières alimentaires d’origine animale, en particulier celles issues des volailles et du porc. Cela implique d’améliorer l’état sanitaire des animaux et de lutter contre le portage asymptomatique de cette bactérie par des animaux qui abritent, voire excrètent de grande quantité de pathogènes sans signe de maladie. Une telle démarche implique une meilleure compréhension des mécanismes qui permettent à la bactérie de coloniser l’animal, mais aussi des réponses immunitaires mises en place par l’hôte pour résister à ce pathogène. Ces études débouchent sur le développement de vaccins ou de moyens thérapeutiques et sur la sélection d’animaux plus résistants à ce portage asymptomatique. Enfin, une approche intégrative complémentaire des études expérimentales et observationnelles de terrain permet de modéliser la contamination des animaux ou des industries agroalimentaires pour analyser les risques de transmission et l’impact des mesures prophylactiques.

En décembre 2004, soit trois ans seulement après celle de l’homme, la première version de la séquence du génome de la poule a été publiée. Ce travail est le résultat de plus de dix années de recherches en génomique. Celles-ci ont débuté par la réalisation des premières cartes génétiques, puis de banques de clones BAC*, de cartes cytogénétiques incluant les microchromosomes, de cartes d’hybrides irradiés et la production de séquences d’EST. En effet, c’est la mise en commun de l’ensemble de ces données disponibles qui a contribué à l’assemblage final de la séquence. Bien entendu, comme la première version de celle du génome humain, la séquence de la poule n’est pas parfaite et des travaux de vérification et de corrections, notamment des microchromosomes, seront nécessaires. De plus, un effort d’annotation* est maintenant à réaliser. Cependant, le fait de disposer de la séquence du génome d’un nombre croissant de vertébrés va permettre d’affiner nos connaissances grâce aux études comparatives. La disponibilité de la séquence de la poule va permettre de remplacer une bonne partie des longs et fastidieux travaux de biologie moléculaire nécessaires à la détermination de la structure, de la fonction et du polymorphisme des gènes par des analyses in silico. Ceci devrait accélérer la mise au point de marqueurs moléculaires utilisables pour la sélection de phénotypes intéressants pour les productions animales

Les bases de données en biologie doivent permettre le stockage d’une quantité croissante d’informations dont la nature est hétérogène. Des entités parfois très différentes sont à représenter, ainsi que leurs relations. De plus, les techniques variées utilisées pour générer les données doivent être prises en compte. De ce fait, il existe un foisonnement de bases de données spécialisées, dont nous décrivons ici les principales, ainsi que leurs interrelations.

La carte génétique de la poule est développée depuis plusieurs années à l’aide de deux familles de référence de type rétro-croisement. Plus récemment, une troisième famille a été utilisée pour affiner la carte. La structure actuelle est d’environ 1800 locus répartis en 50 groupes de liaison couvrant 3800 cM, dont 785 repérés par des marqueurs de type microsatellite. La carte contient 350 marqueurs dans des séquences exprimées, dont 235 représentent des gènes identifiés, permettant de mettre en évidence des synténies conservées avec les génomes de mammifères. La particularité du génome de la poule, composé de macrochromosomes et de microchromosomes, complique la nécessaire intégration avec la carte cytogénétique.

OBJECTIVE: This report presents a cross-sectional analysis of the baseline characteristics of subjects with Leber hereditary optic neuropathy enrolled in the gene therapy trials RESCUE and REVERSE, to illustrate the evolution of visual parameters over the first year after vision loss. METHODS: RESCUE and REVERSE were 2 phase III clinical trials designed to assess the efficacy of rAAV2/2-ND4 gene therapy in ND4-LHON subjects. At enrollment, subjects had vision loss for ≤6 months in RESCUE, and between 6 and 12 months in REVERSE. Functional visual parameters (best-corrected visual acuity [BCVA], contrast sensitivity [CS], and Humphrey Visual Field [HVF]) and structural parameters assessed by spectral-domain optical coherence tomography were analyzed in both cohorts before treatment. The cross-sectional analysis of functional and anatomic parameters included the baseline values collected in all eyes at 2 different visits (Screening and Inclusion). RESULTS: Seventy-six subjects were included in total, 39 in RESCUE and 37 in REVERSE. Mean BCVA was significantly worse in RESCUE subjects compared with REVERSE subjects (1.29 and 1.61 LogMAR respectively, P = 0.0029). Similarly, mean CS and HVF were significantly more impaired in REVERSE vs RESCUE subjects (P < 0.005). The cross-sectional analysis showed that the monthly decrease in BCVA, ganglion cell layer macular volume, and retinal nerve fiber layer thickness was much more pronounced in the first 6 months after onset (+0.24 LogMAR, -0.06 mm3, and -6.00 μm respectively) than between 6 and 12 months after onset (+0.02 LogMAR, -0.01 mm3, and -0.43 μm respectively). CONCLUSION: LHON progresses rapidly in the first months following onset during the subacute phase, followed by relative stabilization during the dynamic phase.

BACKGROUND: RESCUE and REVERSE were 2 Phase 3 clinical trials that assessed the efficacy and safety of intravitreal gene therapy with lenadogene nolparvovec (rAAV2/2-ND4) for the treatment of Leber hereditary optic neuropathy (LHON). RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials. METHODS: In RESCUE and REVERSE, 76 subjects with LHON because of the m.11778 G>A mutation in the mitochondrial gene ND4 received a single unilateral intravitreal injection of lenadogene nolparvovec. After 96 weeks, 61 subjects were enrolled in the long-term follow-up study RESTORE. The best-corrected visual acuity (BCVA) was assessed over a period of up to 52 months after onset of vision loss. A locally estimated scatterplot smoothing regression model was used to analyze changes in BCVA over time. Vision-related quality of life was reported using the visual function questionnaire-25 (VFQ-25). RESULTS: The population of MT-ND4 subjects enrolled in RESTORE was representative of the combined cohorts of RESCUE and REVERSE for mean age (35.1 years) and gender distribution (79% males). There was a progressive and sustained improvement of BCVA up to 52 months after the onset of vision loss. The final mean BCVA was 1.26 logarithm of the minimal angle of resolution 48 months after the onset of vision loss. The mean VFQ-25 composite score increased by 7 points compared with baseline. CONCLUSION: The treatment effect of lenadogene nolparvovec on BCVA and vision-related quality of life observed 96 weeks (2 years) after treatment in RESCUE and REVERSE was sustained at 3 years in RESTORE, with a maximum follow-up of 52 months (4.3 years) after the onset of vision loss.

In Supplementary Table 1 of this Article, 23 samples (B10K-DU-029-32, B10K-DU-029-33, B10K-DU-029-36 to B10K-DU-029-44, B10K-DU- 029-46, B10K-DU-029-47, B10K-DU-029-49 to B10K-DU-029-53, B10K-DU- 029-75 to B10K-DU-029-77, B10K-DU-029-80, and B10K-DU-030-03; styled in boldface in the revised table) were assigned to the incorrect institution. Supplementary Table 1 has been amended to reflect the correct source institution for these samples, and associated data (tissue, museum ID/source specimen ID, site, state/province, latitude, longitude, date collected and sex) have been updated accordingly. The original table is provided as Supplementary Information to this Amendment, and the original Article has been corrected online.

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control. Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss. Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4. Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of -0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (-0.32 LogMAR, p < 0.0001). Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.

Currently there are no assessment instruments available for upper-division thermal physics, though several introductory assessments are currently available. Notably missing from these introductory assessment are items targeting statistical mechanics. This leaves a gap in the content that can be assessed by upper-division thermal physics faculty. In this paper, we present a new, upper-division thermal physics assessment that explicitly addresses both classical thermodynamics and statistical mechanics: The Upper-level Statistical and Thermodynamics Evaluation for Physics (U-STEP). We piloted the U-STEP in multiple classes across various institutions during three semesters, and collected over 600 student responses in total. Here, we present multiple measures of validity and reliability for the U-STEP. We utilized classical test theory to determine item difficulties and discriminations, and differential item functioning to identify potential bias in assessment items that can manifest as performance gaps between different genders and races. The completed U-STEP will be the first upper-division thermal physics assessment available, and one of the first standardized physics assessments to explicitly address identification of possible item bias during the development process.

Diagrams are ubiquitous in physics, especially in physics education and physics problem solving. Physics problem solvers may generate diagrams to orient to a scenario, to organize information, to directly obtain an answer, or as a tool of communication. In this study, we asked 19 undergraduate and graduate physics majors to answer 18 multiple-choice (MC) physics questions and then complete six diagramming tasks of situations similar to six of the MC problems: the MC problems contained no prompting regarding diagrams, while the diagramming tasks explicitly asked participants to carefully generate diagrams. This prompting placed participants in one of two epistemic frames, problem solving or communicating, which allowed us to explore which elements and features the students include (or not) in diagrams generated when students are working within these two frames. By comparing students' spontaneously generated diagrams to their prompted diagrams, we found differences in size, accuracy, and amount of detail in unprompted problem-solving diagrams and prompted communicating diagrams. We also looked at correlations between the presence and features of unprompted diagrams with participants' answer choice. Looking at the different cohorts (e.g., lower-division undergraduate and graduate students), we found that the differences in diagramming between cohorts were generally smaller than the differences within a cohort. We also explore implications for teaching and research.