Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex integrity and activity

Mammalian target of rapamycin (mTOR) plays essential roles in cell proliferation, survival and metabolism by forming at least two functional distinct multi-protein complexes, mTORC1 and mTORC2. External growth signals can be received and interpreted by mTORC2 and further transduced to mTORC1. On the other hand, mTORC1 can sense inner-cellular physiological cues such as amino acids and energy states and can indirectly suppress mTORC2 activity in part through phosphorylation of its upstream adaptors, IRS-1 or Grb10, under insulin or IGF-1 stimulation conditions. To date, upstream signaling pathways governing mTORC1 activation have been studied extensively, while the mechanisms modulating mTORC2 activity remain largely elusive. We recently reported that Sin1, an essential mTORC2 subunit, was phosphorylated by either Akt or S6K in a cellular context-dependent manner. More importantly, phosphorylation of Sin1 at T86 and T398 led to a dissociation of Sin1 from the functional mTORC2 holo-enzyme, resulting in reduced Akt activity and sensitizing cells to various apoptotic challenges. Notably, an ovarian cancer patient-derived Sin1-R81T mutation abolished Sin1-T86 phosphorylation by disrupting the canonical S6K-phoshorylation motif, thereby bypassing Sin1-phosphorylation-mediated suppression of mTORC2 and leading to sustained Akt signaling to promote tumorigenesis. Our work therefore provided physiological and pathological evidence to reveal the biological significance of Sin1 phosphorylation-mediated suppression of the mTOR/Akt oncogenic signaling, and further suggested that misregulation of this process might contribute to Akt hyper-activation that is frequently observed in human cancers

Sex Ratio of Twin at Birth and its Significance in Population Management

AbstractIn clue of twins, this paper studies the sex ratio of twin at birth and its functions in population science, explores to exploit deeply the information of twin birth in China which was hidden in data structure of Censuses and bearing investigations, and raises the possibilities of analyzing the natural sex ratio at birth and evaluating the reliability of sex ratio at birth in China. The goal of this paper is to give a suggestion for exploiting and studying the data of the sixth Census deeply.Key words: Twin; Sex ratio at birth; Census; Population ManagementRésumé Dans les idées de jumeaux, ce document étudie le sex-ratio à la naissance de jumeaux et de ses fonctions dans les sciences de la population, il explore profondément à exploiter les informations de naissance de jumeaux en Chine, qui était caché dans la structure des données des recensements et des enquêtes portant, et soulève la possibilité d’analysant le sex-ratio à la naissance naturelle et d'évaluer la fiabilité des sex-ratio à la naissance en Chine. L'objectif de ce texte est de donner une suggestion pour l'exploitation et l'étude des données du Recensement de sixième profondément. Mots clés: Jumeaux; Naissance du Sexe-ratio; Recensement; Gestion de la populatio

A modeling study of shelf circulation off northern California in the region of the Coastal Ocean Dynamics Experiment : response to relaxation of upwelling winds

A two-part modeling study of the wind-forced flow on the continental shelf off northern California in the region (37°–40°N) of the Coastal Ocean Dynamics Experiment (CODE) is pursued. This paper involves a process-oriented study with idealized wind stress forcing. Gan and Allen [2002] involves forcing with observed winds and heat flux for April–May 1982 and comparison of model results with CODE observations. A characteristic, but previously unexplained, response observed during CODE following the weakening, or relaxation, of southward upwelling favorable winds is the time-dependent development of northward currents over the inner shelf next to the coast. The presence of northward winds is not necessary for this occurrence. The objective in this paper is to investigate the dynamics of the shelf flow response to upwelling wind relaxation events under idealized conditions. In the basic case experiment a spatially uniform upwelling favorable southward wind stress of 0.1 Pa is applied to the ocean initially at rest. The stress is held constant for 10 days and then decreased linearly to zero over 3 days. In response to the southward wind stress, southward alongshore currents develop on the shelf accompanied by upwelling of cold, dense water near the coast. Considerable spatial variability in the shelf flow, clearly related to the alongshore variations in coastline and bottom topography, is found. The alongshore currents tend to separate from the coast south of capes, and the coldest surface water is found at those locations. As the winds decrease, northward currents, similar to those observed, develop on the inner shelf next to the coast at many alongshore locations. Examination of the alongshore momentum balances shows that the northward currents are forced by a northward pressure gradient force associated with negative alongshore pressure gradients. These pressure gradients are set up by the interaction of the wind-forced flow with the alongshore variations in shelf topography. In general, negative alongshore pressure gradients, intensified off Pt. Reyes and Pt. Arena by the gradient wind balance, are found south of capes. The negative pressure gradients geostrophically balance onshore flow at depth, and upwelling is strengthened in these locations. North of capes, positive pressure gradients that are primarily in balance with nonlinear advective effects are found. After the winds cease the forced across-shelf circulation weakens, and the resulting unbalanced negative pressure gradients south of the capes accelerate the alongshore currents northward. Processes with similar dynamics are found embedded in the more complex coastal ocean response to observed time varying winds by Gan and Allen [2002].Keywords: shelf circulation, relaxation, upwelling, numerical modelin

Modeling upwelling circulation off the Oregon coast

Time‐dependent, three‐dimensional, upwelling circulation on the continental shelf off the Oregon coast is studied using a primitive equation numerical model. A limited area domain with a high‐resolution curvilinear grid is utilized. The response of the coastal ocean to forcing by observed wind stress and heat flux during the summer 2001 time period of the Coastal Ocean Advances in Shelf Transport (COAST) field experiment is investigated. Model results are compared to COAST current and hydrographic measurements. The shelf velocity and density fields are generally characterized by the presence of a southward alongshore coastal jet with an upwelling density front on the shoreward side of the jet. The large variability in shelf topography associated with Heceta Bank exerts a major influence on the shelf velocity and density fields. Over the bank the alongshore coastal jet is displaced offshore, and colder upwelled water extends farther from the coast. Northward mean flow and upward motion are found inshore of the jet. Three‐dimensional flow structures in response to variable shelf bottom topography are presented, and an analysis of time‐ and space‐dependent alongshore momentum balances is applied to clarify the associated dynamics. In general, northward pressure gradients, set up over the bank during southward upwelling winds, accelerate currents on the inshore side of the jet northward when the winds relax. Analysis of term balances in the depth‐averaged equation for potential temperature shows that during upwelling, across‐shore advection makes the major contribution to cooling over most of the region, except inshore over Heceta Bank, where alongshore advection also plays a significant role

A modeling study of shelf circulation off northern California in the region of the Coastal Ocean Dynamics Experiment 2. Simulations and comparisons with observations

This is the second part of a modeling study of wind-forced flow on the continental shelf off northern California in the region (37°-40°N) of the Coastal Ocean Dynamics Experiment (CODE). Gan and Allen [2002] analyzed the shelf flow response to idealized wind stress forcing in a process-oriented study. The study here applies forcing from observed winds and heat flux for April-May 1982 and compares the model results with moored current and temperature measurements. The Princeton Ocean Model (POM) is used in a three-dimensional limited area domain with a high-resolution curvilinear grid (approximately 1 km horizontal spacing, 60 vertical levels) and realistic coastline and bottom topography. The objectives of the study are to simulate the response of the shelf circulation field to time-varying observed wind stress and heat flux, to compare model results with oceanographic observations to establish confidence in the model, and to subsequently analyze the model fields and the model dynamical balances to help understand the behavior of the observed flow. The model variables show overall good agreement with corresponding observations. Similar to the conclusions by Gan and Allen [2002], it is found that the alongshore variability of upwelling is mainly controlled by the interaction of the wind-forced shelf flow with the coastline and bottom topography. Different dynamical regimes in the regions north and south of the coastal capes formed by Pt. Reyes and Pt. Arena and in the more uniform region between these capes are identified and investigated. The results demonstrate that the coastal capes play a dominant role in causing alongshore variability of the upwelling flow, including the setup of an alongshore pressure gradient that forces northward currents during relaxation of southward upwelling favorable winds. An analysis of the balance of terms in the equation for potential temperature indicates that across-shore temperature advection is the major contributor to the cooling of coastal water during upwelling, with a larger magnitude to the south of the capes. To the north of the capes, however, alongshore temperature advection is the dominant contributor to the colder water near the coast

Editorial-The 6th International Workshop on Modeling the Ocean (IWMO 2014)

The 6th International Workshop on Modeling the Ocean (IWMO 2014) was held on June 23–27, 2014, at Dalhousie University in Halifax, Nova Scotia, Canada. After three meetings in Asia (Oey et al. 2010, 2013a, b) and one in Europe (Berntsen et al. 2014), the IWMO returned to North America for the second time (since IWMO 2010 in the USA; Ezer et al. 2011). Readers are referred to https://www.dal.ca/sites/iwmo. html for more information on IWMO 2014 and http://www. ccpo.odu.edu/POMWEB /meetings.htm for information on the past meetings and future planned meetings

Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction

Amyloid beta (Aβ) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (Aβ)-mediated mitochondrial and neuronal dysfunction, and cognitive decline in transgenic Alzheimer's disease (AD) mouse models. Targeting mitochondrial ABAD may represent a novel therapeutic strategy against AD. Here, we report the biological activity of small molecule ABAD inhibitors. Using in vitro surface plasmon resonance (SPR) studies, we synthesized compounds with strong binding affinities for ABAD. Further, these ABAD inhibitors (ABAD-4a and 4b) reduced ABAD enzyme activity and administration of phosphonate derivatives of ABAD inhibitors antagonized calcium-mediated mitochondrial swelling. Importantly, these compounds also abolished Aβ-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase and adenosine-5′-triphosphate levels, suggesting protective mitochondrial function effects of these synthesized compounds. Thus, these compounds are potential candidates for further pharmacologic development to target ABAD to improve mitochondrial function

pVHL suppresses kinase activity of Akt in a proline-hydroxylation-dependent manner

Activation of the serine-threonine kinase Akt promotes the survival and proliferation of various cancers. Hypoxia promotes the resistance of tumor cells to specific therapies. We therefore explored a possible link between hypoxia and Akt activity. We found that Akt was prolyl-hydroxylated by the oxygen-dependent hydroxylase EglN1. The von Hippel–Lindau protein (pVHL) bound directly to hydroxylated Akt and inhibited Akt activity. In cells lacking oxygen or functional pVHL, Akt was activated to promote cell survival and tumorigenesis. We also identified cancer-associated Akt mutations that impair Akt hydroxylation and subsequent recognition by pVHL, thus leading to Akt hyperactivation. Our results show that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering Akt activation, which has a critical role in tumor growth and therapeutic resistance