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Internal solitary waves (ISWs) propagate in stratified waters, enhancing diapycnal mixing, sediment and mass transport on shelves. They have typical wavelengths of hundreds of meters and tens of minutes periods, requiring high resolution and high frequency measurements for their sampling. But such in-situ measurements are scarce and ISWs remain largely unpredictable. We evidence that large amplitude ISWs propagating in the Strait of Gibraltar have a signature in the sea level at the Tarifa tide gauge and we propose an algorithm to automatically detect them. We validate the algorithm with in-situ measurements and satellite Sentinel-1 images. Thanks to the accuracy of this method, we analyse the ISW emission in the SoG from 2015 to 2023 from tidal to seasonal scales. This promising new method of in-situ ISW measurements offers potential benefits by supplying data on ISWs at various locations. These data will enhance our understanding of ISW dynamics, their parameterization and prediction.

This paper considers the diapycnal transport of passive tracers during a Kelvin–Helmholtz mixing event. Numerical simulations of a traditional Kelvin–Helmholtz (KH) configuration of a stratified shear flow are extended to include layers of passive tracer at different locations relative to the shear layer. The evolution of the tracers during the simulation is followed and is analysed using different theoretical approaches. One is to consider the evolution via the distribution in density–tracer space which clearly reveals how the tracers are redistributed across isopycnals by the mixing driven by the growing and saturating KH billow. The shape of the distribution places constraints on the redistribution of the tracer and, for this problem of symmetrically stratified shear, it is shown that the distribution typically tends to a compact form, with significant regions that are nearly linear. The redistribution across isopycnals is also considered via a diffusion equation for the tracer relative to coordinates based on the geometry of density surfaces. The equation is a generalisation of an equation previously derived for transport of density in these coordinates and includes an extra eddy term that arises because there is variation of the tracer along density surfaces. Under certain circumstances and at later stages of the flow, the eddy term can be neglected, and the evolution of the mean tracer profile can be adequately represented using a simple diffusion equation where diffusivity is defined as the effective diffusivity of density, scaled by the molecular diffusion of the tracer.

Numerical modeling was used to provide a new estimate of the amount of 137Cs released directly into the ocean from the Fukushima Daiichi nuclear power plant (NPP) after the accident in March 2011 and to gain insights into the physical processes that led to its dispersion in the marine environment during the months following the accident. An inverse method was used to determine the time‐dependent137Cs input responsible for the concentrations observed at the NPP's two liquid discharge outlets. The method was then validated through comparisons of the simulated concentrations with concentrations measured in seawater at different points in the neighborhood of the plant. An underestimation was noticed for stations located 30 km offshore. The resulting bias in the release inventory was estimated. Finally, the maximum 137Cs activity released directly to the ocean was estimated to lie between 5.1 and 5.5 PBq (Peta Becquerel = 1015 Bq) but uncertainties remain on the amount of radionuclides released during the first few days after the accident. This estimate was compared to previous ones and differences were analyzed further. The temporal and spatial variations of the 137Cs concentration present in the coastal waters were shown to be strongly related to the wind intensity and direction. During the first month after the accident, winds blowing toward the south confined the radionuclides directly released into the ocean to a narrow coastal band. Afterwards, frequent northward wind events increased the dispersion over the whole continental shelf, leading to strongly reduced concentrations. Key Points Assessment of cesium‐137 released from Fukushima power plant Dispersion of radionuclides induced by winds

Free surface coastal models currently suffer from the difficulty of having to specify the global circulation during the initialization process and along the open boundaries. As an alternative to the long spinup periods, an original explicit approach based on inverse techniques has been developed.

F15599 is a novel agonist with high selectivity and efficacy at serotonin 5-HT1A receptors (5-HT1ARs). In signal transduction, electrophysiological and neurochemical tests, F15599 preferentially activates post-synaptic 5-HT1ARs in rat frontal cortex. Such a profile may translate to an improved profile of therapeutic activity for mood disorders. The in-vivo effects of F15599 were therefore compared with those of a related compound, F13714, in rat models of antidepressant activity and 5-HT1AR activation: forced swimming test (FST), conditioned stress-induced ultrasonic vocalization, 5-HT syndrome, plasma corticosterone and body temperature. Acute administration of F15599 or F13714 reduced immobility in the FST at low doses; these effects were long lasting and the effects of F15599 were maintained after repeated (5 d, p.o.) administration. Both compounds decreased ultrasonic vocalization duration at low doses. In contrast, higher doses of F15599 were required to induce lower lip retraction, elements of the 5-HT behavioural syndrome, hypothermia and to increase plasma corticosterone levels. Notably, there was a greater separation of ED50 between FST and other effects for F15599 than for F13714. Thus, the in-vivo potency of F15599 in models of antidepressant/anti-stress activity is similar to that of F13714, despite the fact that the latter has an in-vitro potency two orders of magnitude greater. In contrast F15599 has a lower propensity than F13714 to induce other serotonergic signs. The distinctive pharmacological profile of F15599 suggests that preferential targeting of post-synaptic 5-HT1ARs constitutes a promising strategy for improved antidepressant therapy.

Whole-exome sequencing of circulating tumor cells enables accurate and powered calling of somatic point mutations. Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two patients with prostate cancer, including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were present in matched tissue. Moreover, we identified 10 early trunk and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these mutations, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.

This paper reports one of the largest breast cancer whole-exome and whole-genome sequencing efforts so far, identifying previously unknown recurrent mutations in CBFB , deletions of RUNX1 and recurrent MAGI1 – AKT3 fusion; the fusion suggests that the use of ATP-competitive AKT inhibitors should be evaluated in clinical trials. Mutations and translocations in breast cancer This paper reports one of the largest whole-exome sequencing efforts in human breast cancers so far, complemented by whole-genome sequences of 22 breast cancer/normal pairs. The authors analysed diverse subtypes from patients in Mexico and Vietnam and identified recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1 , as well as a recurrent MAGI3–AKT3 fusion enriched in triple-negative breast cancers (those lacking oestrogen and progesterone receptors and ERBB2 expression). The fusion leads to constitutive activation of AKT kinase, which can be counteracted by treatment with a small-molecule inhibitor. Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone 1 . This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy 2 , 3 , 4 . Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration 5 . Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements 6 , 7 , 8 , 9 , 10 . Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA 11 , TP53 6 , AKT1 12 , GATA3 13 and MAP3K1 10 , we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1 . Furthermore, we have identified a recurrent MAGI3–AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3–AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.

Matthew Meyerson and colleagues report whole-exome and whole-genome sequencing of 55 small intestine neuroendocrine tumors. They identify recurrent somatic mutations in CDKN1B , implicating cell cycle dysregulation in the pathogenesis of these tumors. The diagnosed incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, and the underlying genomic mechanisms have not yet been defined. Using exome- and genome-sequence analysis of SI-NETs, we identified recurrent somatic mutations and deletions in CDKN1B , the cyclin-dependent kinase inhibitor gene, which encodes p27. We observed frameshift mutations of CDKN1B in 14 of 180 SI-NETs, and we detected hemizygous deletions encompassing CDKN1B in 7 out of 50 SI-NETs, nominating p27 as a tumor suppressor and implicating cell cycle dysregulation in the etiology of SI-NETs.

Phospholipase A/acyltransferase 3 (PLAAT3) is a phospholipid-modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome, as Plaat3 deficiency in mice protects against diet-induced obesity. We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3 , who presented with a lipodystrophy syndrome with loss of fat varying from partial to generalized and associated with metabolic complications, as well as variable neurological features including demyelinating neuropathy and intellectual disability. Multi-omics analysis of mouse Plaat3 −/− and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipocyte differentiation. Accordingly, CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPARγ-dependent defect in WAT differentiation and function. Homozygous loss-of-function variants in phospholipase A/acyltransferase 3 (PLAAT3) underlie a new lipodystrophy syndrome. Functional studies link PLAAT3 loss with peroxisome proliferator-activated receptor gamma (PPARγ)-mediated defects in white adipose tissue differentiation and function.

Retinoid-related orphan receptor α (RORα ) is a member of the nuclear receptor superfamily. To study its physiological role we generated null-mutant mice by targeted insertion of a lacZ reporter gene encoding the enzyme β -galactosidase. In heterozygous RORα+/-mice we found β -galactosidase activity, indicative of RORα protein expression, confined to the central nervous system, skin and testis. In the central nervous system, the RORα gene is expressed in cerebellar Purkinje cells, the thalamus, the suprachiasmatic nuclei, and retinal ganglion cells. In skin, RORα is strongly expressed in the hair follicle, the epidermis, and the sebaceous gland. Finally, the peritubular cells of the testis and the epithelial cells of the epididymis also strongly express RORα . Recently, it was reported that the ataxic mouse mutant staggerer (sg/sg) is caused by a deletion in the RORα gene. The analysis of the cerebellar and the behavioral phenotype of homozygous RORα-/-mice proves identity to sg/sg mice. Although the absence of RORα causes dramatic developmental effects in the cerebellum, it has no apparent morphological effect on thalamus, hypothalamus, and retina. Similarly, testis and skin of RORα-/-mice display a normal phenotype. However, the pelage hair of both sg/sg and RORα-/-is significantly less dense and when shaved shows reluctance to regrow.