Targeting SOCS proteins to control JAK-STAT signalling in disease

No abstract available

Interaction of suppressor of cytokine signalling 3 with cavin-1 links SOCS3 function and cavin-1 stability

YesEffective suppression of JAK–STAT signalling by the inducible inhibitor “suppressor of cytokine signalling 3” (SOCS3) is essential for limiting signalling from cytokine receptors. Here we show that cavin-1, a component of caveolae, is a functionally significant SOCS3- interacting protein. Biochemical and confocal imaging demonstrate that SOCS3 localisation to the plasma membrane requires cavin-1. SOCS3 is also critical for cavin-1 stabilisation, such that deletion of SOCS3 reduces the expression of cavin-1 and caveolin-1 proteins, thereby reducing caveola abundance in endothelial cells. Moreover, the interaction of cavin-1 and SOCS3 is essential for SOCS3 function, as loss of cavin-1 enhances cytokine-stimulated STAT3 phosphorylation and abolishes SOCS3-dependent inhibition of IL-6 signalling by cyclic AMP. Together, these findings reveal a new functionally important mechanism linking SOCS3-mediated inhibition of cytokine signalling to localisation at the plasma membrane via interaction with and stabilisation of cavin-1.This work was supported by project grants to T.M.P. from the Chief Scientist Office (ETM/226), British Heart Foundation (PG12/1/ 29276, PG 14/32/30812), and a National Health Service Greater Glasgow and Clyde Research Endowment Fund (2011REFCH08). P.F.P. was supported by the National Institutes of Health grant DK097708. J.J.L.W. was supported by a doctoral training studentship from the Biotechnology and Biological Sciences Research Council Doctoral Training Programme in Biochemistry and Molecular Biology at the University of Glasgow (BB/F016735/1). N.A. was supported by a Saudi Government PhD Scholarship. This work was also supported in part by equipment grants to T.M.P. from Diabetes UK (BDA 11/0004309) and Alzheimer’s Research UK (ARUK-EG2016A-3)

Fermions from Half-BPS Supergravity

We discuss collective coordinate quantization of the half-BPS geometries of Lin, Lunin and Maldacena (hep-th/0409174). The LLM geometries are parameterized by a single function $u$ on a plane. We treat this function as a collective coordinate. We arrive at the collective coordinate action as well as path integral measure by considering D3 branes in an arbitrary LLM geometry. The resulting functional integral is shown, using known methods (hep-th/9309028), to be the classical limit of a functional integral for free fermions in a harmonic oscillator. The function $u$ gets identified with the classical limit of the Wigner phase space distribution of the fermion theory which satisfies u * u = u. The calculation shows how configuration space of supergravity becomes a phase space (hence noncommutative) in the half-BPS sector. Our method sheds new light on counting supersymmetric configurations in supergravity.Comment: 28 pages, 2 figures, epsf;(v3) eq. (3.3) clarified and notationally simplified; version to appear in JHE

Linking energy sensing to suppression of JAK-STAT signalling: a potential route for repurposing AMPK activators?

YesExaggerated Janus kinase-signal transducer and activator of transcription (JAKSTAT) signalling is key to the pathogenesis of pro-inflammatory disorders, such as rheumatoid arthritis and cardiovascular diseases. Mutational activation of JAKs is also responsible for several haematological malignancies, including myeloproliferative neoplasms and acute lymphoblastic leukaemia. Accumulating evidence links adenosine 5′-monophosphate (AMP)–activated protein kinase (AMPK), an energy sensor and regulator of organismal and cellular metabolism, with the suppression of immune and inflammatory processes. Recent studies have shown that activation of AMPK can limit JAK-STAT-dependent signalling pathways via several mechanisms. These novel findings support AMPK activation as a strategy for management of an array of disorders characterised by hyper-activation of the JAKSTAT pathway. This review discusses the pivotal role of JAK-STAT signalling in a range of disorders and how both established clinically used and novel AMPK activators might be used to treat these conditions.British Heart Foundation; Diabetes UK; Chief Scientist Office; NHS Greater Glasgow and Clyde Research Endowment Fund; Chest, Heart and Stroke Scotlan

Stochastic processes with finite correlation time: modeling and application to the generalized Langevin equation

The kangaroo process (KP) is characterized by various forms of the covariance and can serve as a useful model of random noises. We discuss properties of that process for the exponential, stretched exponential and algebraic (power-law) covariances. Then we apply the KP as a model of noise in the generalized Langevin equation and simulate solutions by a Monte Carlo method. Some results appear to be incompatible with requirements of the fluctuation-dissipation theorem because probability distributions change when the process is inserted into the equation. We demonstrate how one can construct a model of noise free of that difficulty. This form of the KP is especially suitable for physical applications.Comment: 22 pages (RevTeX) and 4 figure

Patellar cartilage volume of the back leg versus the higher loaded front leg in current elite male english cricket fast bowlers

Patellar cartilage volume of the back leg versus the higher loaded front leg in current elite male english cricket fast bowler

Relaxation Effects in the Transition Temperature of Superconducting HgBa2CuO4+delta

In previous studies on a number of under- and overdoped high temperature superconductors, including YBa_{2}Cu_{3}O_{7-y} and Tl_{2}Ba_{2}CuO_{6+\delta}, the transition temperature T_c has been found to change with time in a manner which depends on the sample's detailed temperature and pressure history. This relaxation behavior in T_c is believed to originate from rearrangements within the oxygen sublattice. In the present high-pressure studies on HgBa_{2}CuO_{4+\delta} to 0.8 GPa we find clear evidence for weak relaxation effects in strongly under- and overdoped samples ($T_c\simeq 40 - 50 K$) with an activation energy $E_{A}(1 bar) \simeq 0.8 - 0.9 eV$. For overdoped HgBa_{2}CuO_{4+\delta} E_{A} increases under pressure more rapidly than previously observed for YBa_{2}Cu_{3}O_{6.41}, yielding an activation volume of +11 \pm 5 cm^{3}; the dependence of T_c on pressure is markedly nonlinear, an anomalous result for high-T_c superconductors in the present pressure range, giving evidence for a change in the electronic and/or structural properties near 0.4 GPa

Race, ethnicity and risk of second primary contralateral breast cancer in the United States

Breast cancer survivors have a high risk of a second primary contralateral breast cancer (CBC), but there are few studies of CBC risk in racial/ethnic minority populations. We examined whether the incidence and risk factors for CBC differed by race/ethnicity in the United States. Women with a first invasive Stage I-IIB breast cancer diagnosis at ages 20-74 years between 2000 and 2015 in the Surveillance, Epidemiology, and End Results Program (SEER) 18 registries were followed through 2016 for a diagnosis of invasive CBC ≥1 year after the first breast cancer diagnosis. We used cause-specific Cox proportional hazards models to test the association between race/ethnicity and CBC, adjusting for age, hormone receptor status, radiation therapy, chemotherapy and stage at first diagnosis, and evaluated the impact of contralateral prophylactic mastectomy, socioeconomic status, and insurance status on the association. After a median follow-up of 5.9 years, 9247 women (2.0%) were diagnosed with CBC. Relative to non-Hispanic (NH) White women, CBC risk was increased in NH Black women (hazard ratio = 1.44, 95% CI 1.35-1.54) and Hispanic women (1.11, 95% CI 1.02-1.20), with the largest differences among women diagnosed at younger ages. Adjustment for contralateral prophylactic mastectomy, socioeconomic status and health insurance did not explain the associations. Therefore, non-Hispanic Black and Hispanic women have an increased risk of CBC that is not explained by clinical or socioeconomic factors collected in SEER. Large studies of diverse breast cancer survivors with detailed data on treatment delivery and adherence are needed to inform interventions to reduce this disparity