The 16p11.2 homologs fam57ba and doc2a generate certain brain and body phenotypes

Deletion of the 16p11.2 CNV affects 25 core genes and is associated with multiple symptoms affecting brain and body, including seizures, hyperactivity,macrocephaly, and obesity. Available data suggest thatmost symptoms are controlled by haploinsufficiency of two or more 16p11.2 genes. To identify interacting 16p11.2 genes, we used a pairwise partial loss of function antisense screen for embryonic brainmorphology, using the accessible zebrafish model. fam57ba, encoding a ceramide synthase, was identified as interacting with the doc2a gene, encoding a calcium-sensitive exocytosis regulator, a genetic interaction not previously described. Using genetic mutants, we demonstrated that doc2a+/-fam57ba+/-double heterozygotes show hyperactivity and increased seizure susceptibility relative to wild-type or single doc2a-/-or fam57ba-/-mutants. Additionally, doc2a+/-fam57ba+/-double heterozygotes demonstrate the increased body length and head size. Single doc2a+/-and fam57ba+/-heterozygotes do not show a body size increase; however, fam57ba-/-homozygous mutants show a strongly increased head size and body length, suggesting a greater contribution from fam57ba to the haploinsufficient interaction between doc2a and fam57ba. The doc2a+/-fam57ba+/-interaction has not been reported before, nor has any 16p11.2 gene previously been linked to increased body size. These findings demonstrate that one pair of 16p11.2 homologs can regulate both brain and body phenotypes that are reflective of those in people with 16p11.2 deletion. Together, these findings suggest that dysregulation of ceramide pathways and calcium sensitive exocytosis underlies seizures and large body size associated with 16p11.2 homologs in zebrafish. The data inform consideration of mechanisms underlying human 16p11.2 deletion symptoms

Efficacy of Cognitive and Metacognitive Interventions on Executive Functioning Post Traumatic Brain Injury to Enhance Occupational Performance

Cognitive rehabilitation (CR) is proposed as an effective intervention for individuals post Traumatic Brain Injury (TBI), by addressing cognitive function through remediating skills and practicing new compensatory skills. While there is considerable research, including systematic reviews that explore cognitive interventions post TBI, more research is needed in which occupational performance is the primary outcome of cognitive intervention. This current systematic review aims to synthesize the current body of evidence available on how using CR techniques to address executive functioning impact occupational performance in individuals who sustained a mild or moderate TBI

The North Atlantic subpolar circulation in an eddy-resolving global ocean model

The subpolar North Atlantic represents a key region for global climate, but most numerical models still have well-described limitations in correctly simulating the local circulation patterns. Here, we present the analysis of a 30-year run with a global eddy-resolving (1/12°) version of the NEMO ocean model. Compared to the 1° and 1/4° equivalent versions, this simulation more realistically represents the shape of the Subpolar Gyre, the position of the North Atlantic Current, and the Gulf Stream separation. Other key improvements are found in the representation of boundary currents, multi-year variability of temperature and depth of winter mixing in the Labrador Sea, and the transport of overflows at the Greenland–Scotland Ridge. However, the salinity, stratification and mean depth of winter mixing in the Labrador Sea, and the density and depth of overflow water south of the sill, still present challenges to the model. This simulation also provides further insight into the spatio-temporal development of the warming event observed in the Subpolar Gyre in the mid 1990s, which appears to coincide with a phase of increased eddy activity in the southernmost part of the gyre. This may have provided a gateway through which heat would have propagated into the gyre's interior

Challenging the Perceptions of Human Tendon Allografts: Influence of Donor Age, Sex, Height, and Tendon on Biomechanical Properties

Background: The use of allograft tendons has increased for primary and revision anterior cruciate ligament reconstruction, but allograft supply is currently limited to a narrow range of tendons and donors up to the age of 65 years. Expanding the range of donors and tendons could help offset an increasing clinical demand. Purpose: To investigate the effects of donor age, sex, height, and specific tendon on the mechanical properties of a range of human lower leg tendons. Study Design: Descriptive laboratory study. Methods: Nine tendons were retrieved from 39 fresh-frozen human cadaveric lower legs (35 donors [13 female, 22 male]; age, 49-99 years; height, 57-85 inches [145-216 cm]) including: Achilles tendon, tibialis posterior and anterior, fibularis longus and brevis, flexor and extensor hallucis longus, plantaris, and flexor digitorum longus. Tendons underwent tensile loading to failure measuring cross-sectional area (CSA), maximum load, strain at failure, ultimate tensile strength, and elastic modulus. Results from 332 tendons were analyzed using mixed-effects linear regression, accounting for donor age, sex, height, and weight. Results: Mechanical properties were significantly different among tendons and were substantially greater than the effects of donor characteristics. Significant effects of donor sex, age, and height were limited to specific tendons: Achilles tendon, tibialis posterior, and tibialis anterior. All other tendons were unaffected. The Achilles tendon was most influenced by donor variables: greater CSA in men (β = 15.45 mm2; Šidák adjusted P < .0001), decreased maximum load with each year of increased age (β = −17.20 N per year; adjusted P = .0253), and increased CSA (β = 1.92 mm2 per inch; adjusted P < .0001) and maximum load (β = 86.40 N per inch; adjusted P < .0001) with each inch of increased height. Conclusion: Mechanical properties vary significantly across different human tendons. The effects of donor age, sex, and height are relatively small, are limited to specific tendons, and affect different tendons uniquely. The findings indicate that age negatively affected only the Achilles tendon (maximum load) and challenge the exclusion of donors aged >65 years across all tendon grafts. Clinical Relevance: The findings support including a broader range of tendons for use as allografts for anterior cruciate ligament reconstruction and reviewing the current exclusion criterion of donors aged >65 years

Wind-driven oscillations in meridional overturning circulations near the equator. Part II: idealized simulations

Large-amplitude [±100 Sv (1 Sv ≡ 106 m3 s−1)], high-frequency oscillations in the Pacific Ocean’s meridional overturning circulation within 10° of the equator have been found in integrations of the NEMO ocean general circulation model. Part I of this paper showed that these oscillations are dominated by two bands of frequencies with periods close to 4 and 10 days and that they are driven by the winds within about 10° of the equator. This part shows that the oscillations can be well simulated by small-amplitude, wind-driven motions on a horizontally uniform, stably stratified state of rest. Its main novelty is that, by focusing on the zonally integrated linearized equations, it presents solutions for the motions in a basin with sloping side boundaries. The solutions are found using vertical normal modes and equatorial meridional modes representing Yanai and inertia–gravity waves. Simulations of 16-day-long segments of the time series for the Pacific of each of the first three meridional and vertical modes (nine modes in all) capture between 85% and 95% of the variance of matching time series segments diagnosed from the NEMO integrations. The best agreement is obtained by driving the solutions with the full wind forcing and the full pressure forces on the bathymetry. Similar results are obtained for the corresponding modes in the Atlantic and Indian Oceans. Slower variations in the same meridional and vertical modes of the MOC are also shown to be well simulated by a quasi-stationary solution driven by zonal wind and pressure forces

PKA-Dependent Phosphorylation of Serum Response Factor Inhibits Smooth Muscle-Specific Gene Expression

Our goal was to identify phosphorylation sites that regulate serum response factor (SRF) activity to gain a better understanding of the signaling mechanisms that regulate SRF’s involvement in smooth muscle cell (SMC)-specific and early response gene expression

Chaotic variability of the Atlantic meridional overturning circulation at subannual time scales

This study describes the intra- to interannual variability of the Atlantic meridional overturning circulation (AMOC) and the relative dynamical contributions to the total variability in an eddy-resolving 1/128 resolution ocean model. Based on a 53-yr-long hindcast and two 4-yr-long ensembles, we assess the total AMOC variability as well as the variability arising from small differences in the ocean initial state that rapidly imprints on the mesoscale eddy fields and subsequently on large-scale features. This initial-condition-dependent variability will henceforth be referred to as “chaotic” variability. We find that intra-annual AMOC fluctuations are mainly driven by the atmospheric forcing, with the chaotic variability fraction never exceeding 26% of the total variance in the whole meridional Atlantic domain. To understand the nature of the chaotic variability we decompose the AMOC (into its Ekman, geostrophic, barotropic, and residual components). The barotropic and geostrophic AMOC contributions exhibit strong, partly compensating fluctuations, which are linked to chaotic spatial variations of currents over topography. In the North Atlantic, the largest chaotic divergence of ensemble members is found around 248, 388, and 648N. At 26.58N, where the AMOC is monitored by the RAPID– MOCHA array, the chaotic fraction of the AMOC variability is 10%. This fraction is slightly overestimated with the reconstruction methodology as used in the observations (∼15%). This higher fraction of chaotic variability is due to the barotropic contribution not being completely captured by the monitoring system. We look at the strong AMOC decline observed in 2009/10 and find that the ensemble spread (our measure for chaotic variability) was not particularly large during this event