Climate-carbon cycle uncertainties and the Paris Agreement

The Paris Agreement aims to address the gap between existing climate policies and policies consistent with ‘holding the increase in global average temperature to well below 2C’. The feasibility of meeting the target has been questioned both in terms of the possible requirement for negative emissions, and ongoing debate on the sensitivity of the climate-carbon cycle system. Using a sequence of ensembles of a fully dynamic three-dimensional climate-carbon cycle model, forced by emissions from an integrated assessment model of regional-level climate policy, economy, and technological transformation, we show that a reasonable interpretation of the Paris Agreement is still technically achievable. Specifically, limiting peak (decadal) warming to less than 1.7°C, or end-century warming to less than 1.54°C, occurs in 50% of our simulations in a policy scenario without net negative emissions or excessive stringency in any policy domain. We evaluate two mitigation scenarios, with 200 GTC and 307 GTC post-2017 emissions, quantifying spatio-temporal variability of warming, precipitation, ocean acidification and marine productivity. Under rapid decarbonisation decadal variability dominates the mean response in critical regions, with significant implications for decision making, demanding impact methodologies that address non-linear spatio-temporal responses. Ignoring carbon-cycle feedback uncertainties (explaining 47% of peak warming uncertainty) becomes unreasonable under strong mitigation conditions.We acknowledge C-EERNG and Cambridge Econometrics for support, and funding from EPSRC (to J.-F.M., fellowship number EP/ K007254/1); the Newton Fund (to J.-F.M., P.S. and J.E.V., EPSRC grant number EP/N002504/1 and ESRC grant number ES/N013174/1), NERC (to N.R.E., P.H. and H.P., grant number NE/P015093/1), CONICYT (to P.S.), the Philomathia Foundation (to J.E.V.) and Horizon 2020 (to H.E.P. and J.-F.M., the Sim4Nexus project)

Study protocol to investigate the effect of a lifestyle intervention on body weight, psychological health status and risk factors associated with disease recurrence in women recovering from breast cancer treatment

Background Breast cancer survivors often encounter physiological and psychological problems related to their diagnosis and treatment that can influence long-term prognosis. The aim of this research is to investigate the effects of a lifestyle intervention on body weight and psychological well-being in women recovering from breast cancer treatment, and to determine the relationship between changes in these variables and biomarkers associated with disease recurrence and survival. Methods/design Following ethical approval, a total of 100 patients will be randomly assigned to a lifestyle intervention (incorporating dietary energy restriction in conjunction with aerobic exercise training) or normal care control group. Patients randomised to the dietary and exercise intervention will be given individualised healthy eating dietary advice and written information and attend moderate intensity aerobic exercise sessions on three to five days per week for a period of 24 weeks. The aim of this strategy is to induce a steady weight loss of up to 0.5 Kg each week. In addition, the overall quality of the diet will be examined with a view to (i) reducing the dietary intake of fat to ~25% of the total calories, (ii) eating at least 5 portions of fruit and vegetables a day, (iii) increasing the intake of fibre and reducing refined carbohydrates, and (iv) taking moderate amounts of alcohol. Outcome measures will include body weight and body composition, psychological health status (stress and depression), cardiorespiratory fitness and quality of life. In addition, biomarkers associated with disease recurrence, including stress hormones, estrogen status, inflammatory markers and indices of innate and adaptive immune function will be monitored. Discussion This research will provide valuable information on the effectiveness of a practical, easily implemented lifestyle intervention for evoking positive effects on body weight and psychological well-being, two important factors that can influence long-term prognosis in breast cancer survivors. However, the added value of the study is that it will also evaluate the effects of the lifestyle intervention on a range of biomarkers associated with disease recurrence and survival. Considered together, the results should improve our understanding of the potential role that lifestyle-modifiable factors could play in saving or prolonging lives

Hunting for the high-affinity state of G-protein coupled receptors with agonist tracers:Theoretical and practical considerations for positron emission tomography (PET) imaging

The concept of the high-affinity state postulates that a certain subset of G-protein-coupled receptors is primarily responsible for receptor signaling in the living brain. Assessing the abundance of this subset is thus potentially highly relevant for studies concerning the responses of neurotransmission to pharmacological or physiological stimuli, and the dysregulation of neurotransmission in neurological or psychiatric disorders. The high-affinity state is preferentially recognized by agonists in vitro. For this reason, agonist tracers have been developed as tools for the non-invasive imaging of the high-affinity state with positron emission tomography (PET). This review provides an overview of agonist tracers that have been developed for PET imaging of the brain, and the experimental paradigms that have been developed for the estimation of the relative abundance of receptors configured in the high-affinity state. Agonist tracers appear to be more sensitive to endogenous neurotransmitter challenge than antagonists, as was originally expected. However, other expectations regarding agonist tracers have not been fulfilled. Potential reasons for difficulties in detecting the high-affinity state in vivo are discussed

Surface TRAIL decoy receptor-4 expression is correlated with TRAIL resistance in MCF7 breast cancer cells

BACKGROUND: Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) selectively induces apoptosis in cancer cells but not in normal cells. Despite this promising feature, TRAIL resistance observed in cancer cells seriously challenged the use of TRAIL as a death ligand in gene therapy. The current dispute concerns whether or not TRAIL receptor expression pattern is the primary determinant of TRAIL sensitivity in cancer cells. This study investigates TRAIL receptor expression pattern and its connection to TRAIL resistance in breast cancer cells. In addition, a DcR2 siRNA approach and a complementary gene therapy modality involving IKK inhibition (AdIKKβKA) were also tested to verify if these approaches could sensitize MCF7 breast cancer cells to adenovirus delivery of TRAIL (Ad5hTRAIL). METHODS: TRAIL sensitivity assays were conducted using Molecular Probe's Live/Dead Cellular Viability/Cytotoxicity Kit following the infection of breast cancer cells with Ad5hTRAIL. The molecular mechanism of TRAIL induced cell death under the setting of IKK inhibition was revealed by Annexin V binding. Novel quantitative Real Time RT-PCR and flow cytometry analysis were performed to disclose TRAIL receptor composition in breast cancer cells. RESULTS: MCF7 but not MDA-MB-231 breast cancer cells displayed strong resistance to adenovirus delivery of TRAIL. Only the combinatorial use of Ad5hTRAIL and AdIKKβKA infection sensitized MCF7 breast cancer cells to TRAIL induced cell death. Moreover, novel quantitative Real Time RT-PCR assays suggested that while the level of TRAIL Decoy Receptor-4 (TRAIL-R4) expression was the highest in MCF7 cells, it was the lowest TRAIL receptor expressed in MDA-MB-231 cells. In addition, conventional flow cytometry analysis demonstrated that TRAIL resistant MCF7 cells exhibited substantial levels of TRAIL-R4 expression but not TRAIL decoy receptor-3 (TRAIL-R3) on surface. On the contrary, TRAIL sensitive MDA-MB-231 cells displayed very low levels of surface TRAIL-R4 expression. Furthermore, a DcR2 siRNA approach lowered TRAIL-R4 expression on surface and this sensitized MCF7 cells to TRAIL. CONCLUSION: The expression of TRAIL-R4 decoy receptor appeared to be well correlated with TRAIL resistance encountered in breast cancer cells. Both adenovirus mediated IKKβKA expression and a DcR2 siRNA approach sensitized MCF7 breast cancer cells to TRAIL

Airway smooth muscle relaxation results from a reduction in the frequency of Ca(2+ )oscillations induced by a cAMP-mediated inhibition of the IP(3 )receptor

BACKGROUND: It has been shown that the contractile state of airway smooth muscle cells (SMCs) in response to agonists is determined by the frequency of Ca(2+ )oscillations occurring within the SMCs. Therefore, we hypothesized that the relaxation of airway SMCs induced by agents that increase cAMP results from the down-regulation or slowing of the frequency of the Ca(2+ )oscillations. METHODS: The effects of isoproterenol (ISO), forskolin (FSK) and 8-bromo-cAMP on the relaxation and Ca(2+ )signaling of airway SMCs contracted with methacholine (MCh) was investigated in murine lung slices with phase-contrast and laser scanning microscopy. RESULTS: All three cAMP-elevating agents simultaneously induced a reduction in the frequency of Ca(2+ )oscillations within the SMCs and the relaxation of contracted airways. The decrease in the Ca(2+ )oscillation frequency correlated with the extent of airway relaxation and was concentration-dependent. The mechanism by which cAMP reduced the frequency of the Ca(2+ )oscillations was investigated. Elevated cAMP did not affect the re-filling rate of the internal Ca(2+ )stores after emptying by repetitive exposure to 20 mM caffeine. Neither did elevated cAMP limit the Ca(2+ )available to stimulate contraction because an elevation of intracellular Ca(2+ )concentration induced by exposure to a Ca(2+ )ionophore (ionomycin) or by photolysis of caged-Ca(2+ )did not reverse the effect of cAMP. Similar results were obtained with iberiotoxin, a blocker of Ca(2+)-activated K(+ )channels, which would be expected to increase Ca(2+ )influx and contraction. By contrast, the photolysis of caged-IP(3 )in the presence of agonist, to further elevate the intracellular IP(3 )concentration, reversed the slowing of the frequency of the Ca(2+ )oscillations and relaxation of the airway induced by FSK. This result implied that the sensitivity of the IP(3)R to IP(3 )was reduced by FSK and this was supported by the reduced ability of IP(3 )to release Ca(2+ )in SMCs in the presence of FSK. CONCLUSION: These results indicate that the relaxant effect of cAMP-elevating agents on airway SMCs is achieved by decreasing the Ca(2+ )oscillation frequency by reducing internal Ca(2+ )release through IP(3 )receptors

In Search of HPA Axis Dysregulation in Child and Adolescent Depression

Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative perspective on research investigating the various components of HPA axis functioning among depressed young people. The present narrative review synthesizes evidence from the following five categories of studies conducted with children and adolescents: (1) those examining the HPA system’s response to the dexamethasone suppression test (DST); (2) those assessing basal HPA axis functioning; (3) those administering corticotropin-releasing hormone (CRH) challenge; (4) those incorporating psychological probes of the HPA axis; and (5) those examining HPA axis functioning in children of depressed mothers. Evidence is generally consistent with models of developmental psychopathology that hypothesize that atypical HPA axis functioning precedes the emergence of clinical levels of depression and that the HPA axis becomes increasingly dysregulated from child to adult manifestations of depression. Multidisciplinary approaches and longitudinal research designs that extend across development are needed to more clearly and usefully elucidate the role of the HPA axis in depression

Discovery of X-Ray Polarization from the Black Hole Transient Swift J1727.8−1613

We report the first detection of the X-ray polarization of the bright transient Swift J1727.8−1613 with the Imaging X-ray Polarimetry Explorer. The observation was performed at the beginning of the 2023 discovery outburst, when the source resided in the bright hard state. We find a time- and energy-averaged polarization degree of 4.1% ± 0.2% and a polarization angle of 2.°2 ± 1.°3 (errors at 68% confidence level; this translates to ∼20σ significance of the polarization detection). This finding suggests that the hot corona emitting the bulk of the detected X-rays is elongated, rather than spherical. The X-ray polarization angle is consistent with that found in submillimeter wavelengths. Since the submillimeter polarization was found to be aligned with the jet direction in other X-ray binaries, this indicates that the corona is elongated orthogonal to the jet

X-Ray Polarization of the Black Hole X-Ray Binary 4U 1630-47 Challenges the Standard Thin Accretion Disk Scenario

A large energy-dependent X-ray polarization degree is detected by the Imaging X-ray Polarimetry Explorer (IXPE) in the high-soft emission state of the black hole X-ray binary 4U 1630-47. The highly significant detection (at ≈50σ confidence level) of an unexpectedly high polarization, rising from ∼6% at 2 keV to ∼10% at 8 keV, cannot be easily reconciled with standard models of thin accretion disks. In this work, we compare the predictions of different theoretical models with the IXPE data and conclude that the observed polarization properties are compatible with a scenario in which matter accretes onto the black hole through a thin disk covered by a partially ionized atmosphere flowing away at mildly relativistic velocities

Discovery of X-Ray Polarization from the Black Hole Transient Swift J1727.8−1613

\ua9 2023. The Author(s). Published by the American Astronomical Society.We report the first detection of the X-ray polarization of the bright transient Swift J1727.8−1613 with the Imaging X-ray Polarimetry Explorer. The observation was performed at the beginning of the 2023 discovery outburst, when the source resided in the bright hard state. We find a time- and energy-averaged polarization degree of 4.1% \ub1 0.2% and a polarization angle of 2.\ub02 \ub1 1.\ub03 (errors at 68% confidence level; this translates to ∼20σ significance of the polarization detection). This finding suggests that the hot corona emitting the bulk of the detected X-rays is elongated, rather than spherical. The X-ray polarization angle is consistent with that found in submillimeter wavelengths. Since the submillimeter polarization was found to be aligned with the jet direction in other X-ray binaries, this indicates that the corona is elongated orthogonal to the jet

Tracking the X-Ray Polarization of the Black Hole Transient Swift J1727.8-1613 during a State Transition

\ua9 2024. The Author(s). Published by the American Astronomical Society.We report on an observational campaign on the bright black hole (BH) X-ray binary Swift J1727.8-1613 centered around five observations by the Imaging X-ray Polarimetry Explorer. These observations track for the first time the evolution of the X-ray polarization of a BH X-ray binary across a hard to soft state transition. The 2-8 keV polarization degree decreased from ∼4% to ∼3% across the five observations, but the polarization angle remained oriented in the north-south direction throughout. Based on observations with the Australia Telescope Compact Array, we find that the intrinsic 7.25 GHz radio polarization aligns with the X-ray polarization. Assuming the radio polarization aligns with the jet direction (which can be tested in the future with higher-spatial-resolution images of the jet), our results imply that the X-ray corona is extended in the disk plane, rather than along the jet axis, for the entire hard intermediate state. This in turn implies that the long (≳10 ms) soft lags that we measure with the Neutron star Interior Composition ExploreR are dominated by processes other than pure light-crossing delays. Moreover, we find that the evolution of the soft lag amplitude with spectral state does not follow the trend seen for other sources, implying that Swift J1727.8-1613 is a member of a hitherto undersampled subpopulation