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)

Effect of recipient age on prioritisation for liver transplantation in the UK:a population-based modelling study

BACKGROUND: Following the introduction of an algorithm aiming to maximise life-years gained from liver transplantation in the UK (the transplant benefit score [TBS]), donor livers were redirected from younger to older patients, mortality rate equalised across the age range and short-term waiting list mortality reduced. Understanding age-related prioritisation has been challenging, especially for younger patients and clinicians allocating non-TBS-directed livers. We aimed to assess age-related prioritisation within the TBS algorithm by modelling liver transplantation prioritisation based on data from a UK transplant unit and comparing these data with other regions.METHODS: In this population-based modelling study, serum parameters and age at liver transplantation assessment of patients attending the Scottish Liver Transplant Unit, Edinburgh, UK, between December, 2002, and November, 2023, were combined with representative synthetic data to model TBS survival predictions, which were compared according to age group (25-49 years vs ≥60 years), chronic liver disease severity, and disease cause. Models for end-stage liver disease (UKELD [UK], MELD [Eurotransplant region], and MELD 3.0 [USA]) were used as validated comparators of liver disease severity.FINDINGS: Of 2093 patients with chronic liver disease, 1808 (86%) had complete datasets and liver disease parameters consistent with eligibility for the liver transplant waiting list in the UK (UKELD ≥49). Disease severity as assessed by UKELD, MELD, and MELD 3.0 did not differ by age (median UKELD scores of 56 for patients aged ≥60 years vs 56 for patients aged 25-49 years; MELD scores of 16 vs 16; and MELD 3.0 scores of 18 vs 18). TBS increased with advancing age (R=0·45, p&lt;0·0001). TBS predicted that transplantation in patients aged 60 years or older would provide a two-fold greater net benefit at 5 years than in patients aged 25-49 years (median TBS 1317 [IQR 1116-1436] in older patients vs 706 [411-1095] in younger patients; p&lt;0·0001). Older patients were predicted to have shorter survival without transplantation than younger patients (263 days [IQR 144-473] in older patients vs 861 days [448-1164] in younger patients; p&lt;0·0001) but similar survival after transplantation (1599 days [1563-1628] vs 1573 days [1525-1614]; p&lt;0·0001). Older patients could reach a TBS for which a liver offer was likely below minimum criteria for transplantation (UKELD &lt;49), whereas many younger patients were required to have high-urgent disease (UKELD &gt;60). US and Eurotransplant programmes did not prioritise according to age.INTERPRETATION: The UK liver allocation algorithm prioritises older patients for transplantation by predicting that advancing age increases the benefit from liver transplantation. Restricted follow-up and biases in waiting list data might limit the accuracy of these benefit predictions. Measures beyond overall waiting list mortality are required to fully capture the benefits of liver transplantation.FUNDING: None.</p

Perceptions of competence: Age moderates views of healthy aging and Alzheimer’s disease

Background/Study Context: Older adults have more complex and differentiated views of aging than do younger adults, but less is known about age-related perceptions of Alzheimer’s disease. This study investigated age-related perceptions of competence of an older adult labeled as “in good health” (healthy) or “has Alzheimer’s disease” (AD), using a person-perception paradigm. It was predicted that older adults would provide more differentiated assessments of the two targets than would younger adults.Methods: Younger (n = 86; 18–36 years) and older (n = 66; 61–95 years) adults rated activities of daily living (ADL), instrumental activities of daily living (IADL), and memory abilities of a female target aged 75 years, described as healthy or with AD. Data on anxiety about aging, knowledge of and experience with aging and AD, knowledge of memory aging, and positive and negative biases toward aging and AD were also collected.Results: Older adults perceived the healthy target as more capable of cognitively effortful activities (e.g., managing finances) and as possessing better memory abilities than the AD target. As predicted, these differences were greater than differences between targets perceived by younger adults. The interaction effect remained significant after statistically controlling for relevant variables, including education and gender. Additionally, exploratory analyses revealed that older adults held less positively biased views of AD than younger adults, but negatively biased views were equivalent between age groups.Conclusion: The results demonstrate that mere labels of “healthy” and “Alzheimer’s disease” produce significant and subtle age differences in perceived competencies of older adults, and that biases towards AD vary by age group and valence. Our findings extend the person-perception paradigm to an integrative analysis of aging and AD, are consistent with models of adult development, and complement current research and theory on stereotypes of aging. Future directions for research on perceptions of aging are suggested

The 2022 super-Eddington outburst of the source SMC X-2

SMC X-2 exhibits X-ray outburst behaviour that makes it one of the most luminous X-ray sources in the Small Magellanic Cloud. In the last decade it has undergone two such massive outbursts - in 2015 and 2022. The first outburst is well reported in the literature, but the 2022 event has yet to be fully described and discussed. That is the goal of this paper. In particular, the post-peak characteristics of the two events are compared. This reveals clear similarities in decay profiles, believed to be related to different accretion mechanisms occurring at different times as the outbursts evolve. The H{\alpha} emission line indicates that the Be disc undergoes complex structural variability, with evidence of warping as a result of its interaction with the neutron star. The detailed observations reported here will be important for modelling such interactions in this kind of binary systems.Comment: Accepted for publication in MNRA

Experimental and theoretical electron density analysis of copper pyrazine nitrate quasi-low-dimensional quantum magnets

The accurate electron density distribution and magnetic properties of two metal-organic polymeric magnets, the quasi-one-dimensional (1D) Cu(pyz)(NO3)2 and the quasi-two-dimensional (2D) [Cu(pyz)2(NO3)]NO3·H2O, have been investigated by high-resolution single-crystal X-ray diffraction and Density Functional Theory calculations on the whole periodic systems and on selected fragments. Topological analyses, based on Quantum Theory of Atoms in Molecules, enabled the characterization of possible magnetic exchange pathways and the establishment of relationships between the electron (charge and spin) densities and the exchange-coupling constants. In both compounds, the experimentally observed anti-ferromagnetic coupling can be quantitatively explained by the Cu-Cu super-exchange pathway mediated by the pyrazine bridging ligands, via a σ-type interaction. From topological analyses of experimental charge-density data, we show for the first time that the pyrazine tilt angle does not play a role in determining the strength of the magnetic interaction. Taken in combination with molecular orbital analysis and spin density calculations, we find a synergistic relationship between spin delocalization and spin polarization mechanisms and that both determine the bulk magnetic behavior of these Cu(II)-pyz coordination polymers

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

Two weeks of watermelon juice supplementation improves nitric oxide bioavailability but not endurance exercise performance in humans

This study tested the hypothesis that watermelon juice supplementation would improve nitric oxide bioavailability and exercise performance. Eight healthy recreationally-active adult males reported to the laboratory on two occasions for initial testing without dietary supplementation (control condition). Thereafter, participants were randomly assigned, in a cross-over experimental design, to receive 16 days of supplementation with 300 mL·day-1 of a watermelon juice concentrate, which provided ~3.4g L-citrulline·day-1 and an apple juice concentrate as a placebo. Participants reported to the laboratory on days 14 and 16 of supplementation to assess the effects of the interventions on blood pressure, plasma [Lcitrulline], plasma [L-arginine], plasma [nitrite], muscle oxygenation and time-to-exhaustion during severe-intensity exercise. Compared to control and placebo, plasma [L-citrulline] (29 ± 4, 22 ± 6 and 101 ± 23 μM), [L-arginine] (74 ± 9, 67 ± 13 and 116 ± 9 μM) and [nitrite] (102 ± 29, 106 ± 21 and 201 ± 106 nM) were higher after watermelon juice supplementation (P<0.01). However, systolic blood pressure was higher in the watermelon juice (130 ± 11) and placebo (131 ± 9) conditions compared to the control condition (124 ± 8 mmHg; P<0.05). The skeletal muscle oxygenation index during moderate-intensity exercise was greater in the watermelon juice condition than the placebo and control conditions (P<0.05), but time-to-exhaustion during the severe-intensity exercise test (control: 478 ± 80, placebo: 539 ± 108, watermelon juice: 550 ± 143 s) was not significantly different between conditions (P<0.05). In conclusion, while watermelon juice supplementation increased baseline plasma [nitrite] and improved muscle oxygenation during moderate-intensity exercise, it increased resting blood pressure and did not improve time-to-exhaustion during severe-intensity exercise. These findings do not support the use of watermelon juice supplementation as a nutritional intervention to lower blood pressure or improve endurance exercise performance in healthy adults

Hawaiʻi Coral Disease database (HICORDIS):species-specific coral health data from across the Hawaiian archipelago

AbstractThe Hawaiʻi Coral Disease database (HICORDIS) houses data on colony-level coral health condition observed across the Hawaiian archipelago, providing information to conduct future analyses on coral reef health in an era of changing environmental conditions. Colonies were identified to the lowest taxonomic classification possible (species or genera), measured and assessed for visual signs of health condition. Data were recorded for 286,071 coral colonies surveyed on 1819 transects at 660 sites between 2005 and 2015. The database contains observations for 60 species from 22 genera with 21 different health conditions. The goals of the HICORDIS database are to: i) provide open access, quality controlled and validated coral health data assembled from disparate surveys conducted across Hawaiʻi; ii) facilitate appropriate crediting of data; and iii) encourage future analyses of coral reef health. In this article, we describe and provide data from the HICORDIS database. The data presented in this paper were used in the research article “Satellite SST-based Coral Disease Outbreak Predictions for the Hawaiian Archipelago” (Caldwell et al., 2016) [1]