Near-Surface Oceanic Kinetic Energy Distributions From Drifter Observations and Numerical Models

The geographical variability, frequency content, and vertical structure of near-surface oceanic kinetic energy (KE) are important for air-sea interaction, marine ecosystems, operational oceanography, pollutant tracking, and interpreting remotely sensed velocity measurements. Here, KE in high-resolution global simulations (HYbrid Coordinate Ocean Model; HYCOM, and Massachusetts Institute of Technology general circulation model; MITgcm), at the sea surface (0 m) and at 15 m, are compared with KE from undrogued and drogued surface drifters, respectively. Global maps and zonal averages are computed for low-frequency

Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.</p

CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.CAG was supported by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number P50 HD103525. This work was funded by PID2020-112831GB-I00 AEI /10.13039/501100011033 (MN). SS was supported by a grant from the NIH/NINDS (K23NS119666). SWS is supported by the Hospital for Sick Children Foundation, Autism Speaks, and the University of Toronto McLaughlin Center. EM-G was supported by a grant from MICIU FPU18/06240. EVS. was supported by a grant from the NIH (EY025718). CRF was supported by the fund to support clinical research careers in the Region of Southern Denmark (Region Syddanmarks pulje for kliniske forskerkarriereforløb).Peer reviewe

Near‐Surface Oceanic Kinetic Energy Distributions From Drifter Observations and Numerical Models

The geographical variability, frequency content, and vertical structure of near-surface oceanic kinetic energy (KE) are important for air-sea interaction, marine ecosystems, operational oceanography, pollutant tracking, and interpreting remotely sensed velocity measurements. Here, KE in high-resolution global simulations (HYbrid Coordinate Ocean Model; HYCOM, and Massachusetts Institute of Technology general circulation model; MITgcm), at the sea surface (0 m) and at 15 m, are compared with KE from undrogued and drogued surface drifters, respectively. Global maps and zonal averages are computed for low-frequency (<0.5 cpd), near-inertial, diurnal, and semidiurnal bands. Both models exhibit low-frequency equatorial KE that is low relative to drifter values. HYCOM near-inertial KE is higher than in MITgcm, and closer to drifter values, probably due to more frequently updated atmospheric forcing. HYCOM semidiurnal KE is lower than in MITgcm, and closer to drifter values, likely due to inclusion of a parameterized topographic internal wave drag. A concurrent tidal harmonic analysis in the diurnal band demonstrates that much of the diurnal flow is nontidal. We compute simple proxies of near-surface vertical structure—the ratio 0 m KE/(0 m KE + 15 m KE) in model outputs, and the ratio undrogued KE/(undrogued KE + drogued KE) in drifter observations. Over most latitudes and frequency bands, model ratios track the drifter ratios to within error bars. Values of this ratio demonstrate significant vertical structure in all frequency bands except the semidiurnal band. Latitudinal dependence in the ratio is greatest in diurnal and low-frequency bands. Key Points We examine frequency content of ocean kinetic energy (KE) at the sea surface (0 m) and 15 m depth with global drifter data and two models Near-surface near-inertial and tidal KE in numerical models are sensitive to atmospheric forcing frequency and damping The ratio 0 m KE/(0 m KE + 15 m KE) in models lies within error bars of the observational ratios over some latitudes and frequency bands Plain Language Summary It is important to map and understand ocean surface currents because they affect climate and marine ecosystems. Recent advances in global ocean models include the addition of astronomical tidal forcing alongside atmospheric forcing and the usage of more powerful computers that can resolve finer features. Here, we evaluate ocean surface currents in high-resolution simulations of two different ocean models through comparison with observations from surface drifting buoys. We examine near-inertial motions, forced by fast-changing winds; semidiurnal tides, forced by the astronomical tidal potential; diurnal motions, arising from tidal and other sources; and low-frequency currents and eddies, forced by atmospheric fields. Global patterns in the models and drifters are broadly consistent. The two models differ in their degree of proximity to drifter measurements in the near-inertial band, most likely due to different update intervals for atmospheric forcing and in the semidiurnal band, most likely due to different damping schemes. A simple proxy for vertical structure of the currents, measured by differences in drifter flows at the surface versus 15 m depth, is tracked reasonably well by the models. Discrepancies between models and observations motivate future improvements in the models

Frequency dependence of near-surface oceanic kinetic energy from drifter observations and global high-resolution models

The geographical variability, frequency content, and vertical structure of near-surface oceanic kinetic energy (KE) are important for air-sea interaction, marine ecosystems, operational oceanography, pollutant tracking, and interpreting remotely sensed velocity measurements. Here, KE in high-resolution global simulations (HYbrid Coordinate Ocean Model; HYCOM, and Massachusetts Institute of Technology general circulation model; MITgcm), at the sea surface (0 m) and 15 m, are respectively compared with KE from undrogued and drogued surface drifters. Global maps and zonal averages are computed for low-frequency ($<$ 0.5 cpd), near-inertial, diurnal, and semi-diurnal bands. Both models exhibit low-frequency equatorial KE that is low relative to drifter values. HYCOM near-inertial KE is higher than in MITgcm, and closer to drifter values, probably due to more frequently updated atmospheric forcing. HYCOM semi-diurnal KE is lower than in MITgcm, and closer to drifter values, likely due to inclusion of a parameterized topographic internal wave drag. A concurrent tidal harmonic analysis in the diurnal band demonstrates that much of the diurnal flow is non-tidal. We compute a simple proxy of near-surface vertical structure, the ratio of 0 m KE to 0 m KE plus 15 m KE in model outputs, and undrogued KE to undrogued KE plus drogued KE in drifter observations. Over most latitudes and frequency bands, model ratios track the drifter ratios to within error bars. Values of this ratio demonstrate significant vertical structure in all frequency bands except the semidiurnal band. Latitudinal dependence in the ratio is greatest in diurnal and low-frequency bands.Comment: revised for AGU JGR: Ocean

Expansion of the neurodevelopmental phenotype of individuals with <i>EEF1A2 </i>variants and genotype-phenotype study

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.</p

Expansion of the neurodevelopmental phenotype of individuals with <i>EEF1A2 </i>variants and genotype-phenotype study

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.</p

Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.</p

Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.</p