A model of inflammatory arthritis highlights a role for oncostatin M in pro-inflammatory cytokine-induced bone destruction via RANK/RANKL

Oncostatin M is a pro-inflammatory cytokine previously shown to promote marked cartilage destruction both in vitro and in vivo when in combination with IL-1 or tumour necrosis factor alpha. However, the in vivo effects of these potent cytokine combinations on bone catabolism are unknown. Using adenoviral gene transfer, we have overexpressed oncostatin M in combination with either IL-1 or tumour necrosis factor alpha intra-articularly in the knees of C57BL/6 mice. Both of these combinations induced marked bone damage and markedly increased tartrate-resistant acid phosphatase-positive multinucleate cell staining in the synovium and at the front of bone erosions. Furthermore, there was increased expression of RANK and its ligand RANKL in the inflammatory cells, in inflamed synovium and in articular cartilage of knee joints treated with the cytokine combinations compared with expression in joints treated with the cytokines alone or the control. This model of inflammatory arthritis demonstrates that, in vivo, oncostatin M in combination with either IL-1 or tumour necrosis factor alpha represents cytokine combinations that promote bone destruction. The model also provides further evidence that increased osteoclast-like, tartrate-resistant acid phosphatase-positive staining multinucleate cells and upregulation of RANK/RANKL in joint tissues are key factors in pathological bone destruction

Metalloproteinase and inhibitor expression profiling of resorbing cartilage reveals pro-collagenase activation as a critical step for collagenolysis

Excess proteolysis of the extracellular matrix (ECM) of articular cartilage is a key characteristic of arthritis. The main enzymes involved belong to the metalloproteinase family, specifically the matrix metalloproteinases (MMPs) and a group of proteinases with a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS). Chondrocytes are the only cell type embedded in the cartilage ECM, and cell-matrix interactions can influence gene expression and cell behaviour. Thus, although the use of monolayer cultures can be informative, it is essential to study chondrocytes encapsulated within their native environment, cartilage, to fully assess cellular responses. The aim of this study was to profile the temporal gene expression of metalloproteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), reversion-inducing cysteine-rich protein with Kazal motifs (RECK), and α(2)-macroglobulin (α(2)M), in actively resorbing cartilage. The addition of the pro-inflammatory cytokine combination of interleukin-1 (IL-1) + oncostatin M (OSM) to bovine nasal cartilage induces the synthesis and subsequent activation of pro-metalloproteinases, leading to cartilage resorption. We show that IL-1+OSM upregulated the expression of MMP-1, -2, -3, -9, 12, -13, -14, TIMP-1, and ADAMTS-4, -5, and -9. Differences in basal expression and the magnitude of induction were observed, whilst there was no significant modulation of TIMP-2, -3, RECK, or ADAMTS-15 gene expression. IL-1+OSM downregulated MMP-16,TIMP-4, and α(2)M expression. All IL-1+OSM-induced metalloproteinases showed marked upregulation early in the culture period, whilst inhibitor expression was reduced throughout the stimulation period such that metalloproteinase production would be in excess of inhibitors. Moreover, although pro-collagenases were upregulated and synthesized early (by day 5), collagenolysis became apparent later with the presence of active collagenases (day 10) when inhibitor levels were low. These findings indicate that the activation cascades for pro-collagenases are delayed relative to collagenase expression, further confirm the coordinated regulation of metalloproteinases in actively resorbing cartilage, and support the use of bovine nasal cartilage as a model system to study the mechanisms that promote cartilage degradation

Outcome-Driven Reinforcement Learning via Variational Inference

While reinforcement learning algorithms provide automated acquisition of optimal policies, practical application of such methods requires a number of design decisions, such as manually designing reward functions that not only define the task, but also provide sufficient shaping to accomplish it. In this paper, we view reinforcement learning as inferring policies that achieve desired outcomes, rather than as a problem of maximizing rewards. To solve this inference problem, we establish a novel variational inference formulation that allows us to derive a well-shaped reward function which can be learned directly from environment interactions. From the corresponding variational objective, we also derive a new probabilistic Bellman backup operator and use it to develop an off-policy algorithm to solve goal-directed tasks. We empirically demonstrate that this method eliminates the need to hand-craft reward functions for a suite of diverse manipulation and locomotion tasks and leads to effective goal-directed behaviors.Comment: Published in Advances in Neural Information Processing Systems 34 (NeurIPS 2021

Variability of the North Atlantic summer storm track: mechanisms and impacts on European climate

The summertime variability of the extratropical storm track over the Atlantic sector and its links to European climate have been analysed for the period 1948–2011 using observations and reanalyses. The main results are as follows. (1) The dominant mode of the summer storm track density variability is characterized by a meridional shift of the storm track between two distinct paths and is related to a bimodal distribution in the climatology for this region. It is also closely related to the Summer North Atlantic Oscillation (SNAO). (2) A southward shift is associated with a downstream extension of the storm track and a decrease in blocking frequency over the UK and northwestern Europe. (3) The southward shift is associated with enhanced precipitation over the UK and northwestern Europe and decreased precipitation over southern Europe (contrary to the behaviour in winter). (4) There are strong ocean–atmosphere interactions related to the dominant mode of storm track variability. The atmosphere forces the ocean through anomalous surface fluxes and Ekman currents, but there is also some evidence consistent with an ocean influence on the atmosphere, and that coupled ocean–atmosphere feedbacks might play a role. The ocean influence on the atmosphere may be particularly important on decadal timescales, related to the Atlantic Multidecadal Oscillation (AMO)

Unveiling Dust-enshrouded Star Formation in the Early Universe: a Sub-mm Survey of the Hubble Deep Field

The advent of sensitive sub-mm array cameras now allows a proper census of dust-enshrouded massive star-formation in very distant galaxies, previously hidden activity to which even the faintest optical images are insensitive. We present the deepest sub-mm survey of the sky to date, taken with the SCUBA camera on the James Clerk Maxwell Telescope and centred on the Hubble Deep Field. The high source density found in this image implies that the survey is confusion-limited below a flux density of 2 mJy. However, within the central 80 arcsec radius independent analyses yield 5 reproducible sources with S(850um) > 2 mJy which simulations indicate can be ascribed to individual galaxies. We give positions and flux densities for these, and furthermore show using multi-frequency photometric data that the brightest sources in our map lie at redshifts z~3. These results lead to integral source counts which are completely inconsistent with a no-evolution model, and imply that massive star-formation activity continues at redshifts > 2. The combined brightness of the 5 most secure sources in our map is sufficient to account for 30 - 50% of the previously unresolved sub-mm background, and we estimate statistically that the entire background is resolved at about the 0.3 mJy level. Finally we discuss possible optical identifications and redshift estimates for the brightest sources. One source appears to be associated with an extreme starburst galaxy at z~1, whilst the remaining four appear to lie in the redshift range 2 < z < 4. This implies a star-formation density over this redshift range that is at least five times higher than that inferred from the ultraviolet output of HDF galaxies.Comment: 19 pages, 6 figures (to appear as a Nature Article

a trimolecular composition

Photochemical upconversion based on triplet–triplet annihilation (TTA-UC) is employed to enhance the short-circuit currents generated by two varieties of thin-film solar cells, a hydrogenated amorphous silicon (a-Si:H) solar cell and a dye-sensitized solar cell (DSC). TTA-UC is exploited to harvest transmitted sub-bandgap photons, combine their energies and re-radiate upconverted photons back towards the solar cells. In the present study we employ a dual-emitter TTA-UC system which allows for significantly improved UC quantum yields as compared to the previously used single-emitter TTA systems. In doing so we achieve record photo-current enhancement values for both the a-Si:H device and the DSC, surpassing 10−3 mA cm−2 sun−2 for the first time for a TTA-UC system and marking a record for upconversion-enhanced solar cells in general. We discuss pertinent challenges of the TTA-UC technology which need to be addressed in order to achieve its viable device application

Increased upconversion performance for thin film solar cells: A trimolecular composition

Photochemical upconversion based on triplet-triplet annihilation (TTA-UC) is employed to enhance the short-circuit currents generated by two varieties of thin-film solar cells, a hydrogenated amorphous silicon (a-Si:H) solar cell and a dye-sensitized solar cell (DSC). TTA-UC is exploited to harvest transmitted sub-bandgap photons, combine their energies and re-radiate upconverted photons back towards the solar cells. In the present study we employ a dual-emitter TTA-UC system which allows for significantly improved UC quantum yields as compared to the previously used single-emitter TTA systems. In doing so we achieve record photo-current enhancement values for both the a-Si:H device and the DSC, surpassing 10-3 mA cm-2 sun-2 for the first time for a TTA-UC system and marking a record for upconversion-enhanced solar cells in general. We discuss pertinent challenges of the TTA-UC technology which need to be addressed in order to achieve its viable device application

Improving the light-harvesting of amorphous silicon solar cells with photochemical upconversion

Single-threshold solar cells are fundamentally limited by their ability to harvest only those photons above a certain energy. Harvesting below-threshold photons and re-radiating this energy at a shorter wavelength would thus boost the efficiency of such devices. We report an increase in light harvesting efficiency of a hydrogenated amorphous silicon (a-Si:H) thin-film solar cell due to a rear upconvertor based on sensitized triplet–triplet-annihilation in organic molecules. Low energy light in the range 600–750 nm is converted to 550–600 nm light due to the incoherent photochemical process. A peak efficiency enhancement of (1.0 ± 0.2)% at 720 nm is measured under irradiation equivalent to (48 ± 3) suns (AM1.5). We discuss the pathways to be explored in adapting photochemical UC for application in various single threshold devices