Search

Plastic pollution negatively affects ecosystems and human health globally, with single-use plastic representing the majority of marine litter in some areas. Life science laboratories prefer pristine conditions for experimental reliability and therefore make use of factory standardized single-use plastic products. This contributes to overall plastic waste in the United States and globally. Here, we investigate the potential of reusing plastic culture dishes and subsequently propose methods to mitigate single-use plastic waste in developmental biology research laboratories. We tested the efficacy of bleach and ethyl alcohol in sterilizing used dishes. We then tested the feasibility of washing and reusing plastic to culture Xenopus laevis embryos subjected to various manipulations. Cleaning and reusing laboratory plastic did not affect the development or survival of X. laevis, indicating that these cleaning methods do not adversely affect experimental outcome and can be used to sterilize plastic before reuse or recycling. Lastly, we performed a survey of various life science laboratories to estimate both waste reduction and savings associated with recycling single-use plastics. Standardization of these procedures would allow research laboratories to benefit economically while practicing environmentally conscious consumption.

Muricate planktonic foraminifera comprise an extinct clade that was diverse and abundant in the Paleogene oceans and are widely used in palaeoclimate research as geochemical proxy carriers for the upper oceans. Their characteristic wall texture has surface projections called "muricae" formed by upward deflection and mounding of successive layers of the test wall. The group is generally considered to have lacked "true spines": that is, acicular calcite crystals embedded in and projecting from the test surface such as occur in many modern and some Paleogene groups. Here we present evidence from polished sections, surface wall scanning electron microscope images and test dissections, showing that radially orientated crystalline spine-like structures occur in the centre of muricae in various species of Acarinina and Morozovella and projected from the test wall in life. Their morphology and placement in the wall suggest that they evolved independently of true spines. Nevertheless, they may have served a similar range of functions as spines in modern species, including aiding buoyancy and predation and especially harbouring algal photosymbionts, the function for which we suggest they probably first evolved. Our observations strengthen the analogy between Paleogene mixed-layer-dwelling planktonic foraminifera and their modern spinose counterparts. This research has been supported by the Natural Environment Research Council (grant nos. NE/P019102/1, GR3/12618, NE/X509345/1, and NE/B503225/1) Funding was provided by NERC grant NE/P019102/1 to Caroline H. Lear and Paul N. Pearson as part of the SWEET (Super-Warm Early Eocene Temperatures and climate) consortium (https://www.deepmip.org/sweet/, last access: 22 July 2022). We are grateful to Chris Poole for Fig. 3b and c. We thank Dan Lunt (University of Bristol) for coordinating that project and funding the artwork in Fig. 12. The Belgian American Educational Foundation and the Fulbright Commission of Belgium and Luxemburg provided support to Simon D’haenens. Tanzanian foraminifera were previously obtained with NERC grants GR3/12618, NE/X509345/1 and NE/B503225/1 to Paul N. Pearson. We thank the Tanzania Commission of Science and Technology (Costech) and Tanzania Petroleum Development Corporation (TPDC) for assistance in that research and the various members of the Tanzania Drilling Project field teams, especially Joyce Singano of TPDC. We thank Brian Huber, Michal Kucera and an anonymous reviewer for their constructive comments in review.

HIV continues to be a critical health issue for sexual minority men (SMM) in the USA. Chronic pain is common in individuals with HIV, including older SMM, and is associated with substance use behaviors. This cross-sectional study sought to address a gap in the literature by characterizing interrelationships among chronic pain, substance use disorders (SUDs), medication adherence, and engagement in HIV care among older (≥50) SMM living with HIV and chronic pain (N = 63). The unadjusted relationship between an opioid use disorder and pain indicated that participants with an opioid use disorder reported higher pain ratings than those without. Presence of alcohol use disorder was significantly associated with missed HIV-care appointments due to chronic pain or substance use, showing that individuals with an alcohol use disorder reported more missed appointments in the past year. Higher pain was significantly associated with the same missed appointments variable, such that those reporting higher pain ratings also reported more missed appointments in the past year. These findings provide preliminary evidence of the interrelationships among chronic pain, SUDs, and engagement in HIV care among older SMM living with HIV and suggest that pain management in this population might support fuller engagement in HIV care.

Paleontological reconstructions of plankton community structure during warm periods of the Cenozoic (last 66 million years) reveal that deep-dwelling ‘twilight zone’ (200–1000 m) plankton were less abundant and diverse, and lived much closer to the surface, than in colder, more recent climates. We suggest that this is a consequence of temperature’s role in controlling the rate that sinking organic matter is broken down and metabolized by bacteria, a process that occurs faster at warmer temperatures. In a warmer ocean, a smaller fraction of organic matter reaches the ocean interior, affecting food supply and dissolved oxygen availability at depth. Using an Earth system model that has been evaluated against paleo observations, we illustrate how anthropogenic warming may impact future carbon cycling and twilight zone ecology. Our findings suggest that significant changes are already underway, and without strong emissions mitigation, widespread ecological disruption in the twilight zone is likely by 2100, with effects spanning millennia thereafter.

BACKGROUND Lack of validated and responsive outcome measures in the management of Frontal Fibrosing Alopecia (FFA) significantly limits our ability to assess disease progression and treatment response over time. OBJECTIVES The aim of this study was to understand how FFA extent and progression is currently assessed in UK specialist centres, validate components of the International FFA Cooperative Group (IFFACG) statement on FFA assessment, and identify pragmatic advice to improve FFA management in clinic. METHODS Consultant Dermatologists with a specialist interest in hair loss (n=17) were invited to take part. Preferred FFA assessment methods were explored using questionnaires and clinical scenarios. Participants were asked to identify and mark the current hairline in 10 frontal and 10 temporal hairline images, with assessment repeated 3 months later (to assess intra-individual variability) and 12 months later (to test whether inter-individual accuracy could be improved with simple instruction). RESULTS All 17 clinicians (100%) completed the questionnaire at each time interval. We identified a wide variation in assessment techniques between our experts. Measurements were perceived as the most accurate method of assessing frontal recession whereas photography was preferred for temporal recession. Inter-rater reliability between clinicians measuring the frontal hairline scenarios indicated a moderate strength of agreement (ICC 0.613; 95% CI: 0.398 to 0.848), yet intra-rater reliability was found to be poor with wide limits of agreement (-8.71mm to 9.92mm) on follow-up. Importantly, when clear guidance was provided on how the hairline should be identified (questionnaire 3), inter-rater reliability improved significantly, with an ICC 0.702 suggesting moderate agreement (95% CI: 0.508 to 0.890; p

Supplementary Figure 5 from Wnt5A Regulates Expression of Tumor-Associated Antigens in Melanoma via Changes in Signal Transducers and Activators of Transcription 3 Phosphorylation

Supplementary Figure 3 from Wnt5A Regulates Expression of Tumor-Associated Antigens in Melanoma via Changes in Signal Transducers and Activators of Transcription 3 Phosphorylation

Supplementary Figure 1 from Wnt5A Regulates Expression of Tumor-Associated Antigens in Melanoma via Changes in Signal Transducers and Activators of Transcription 3 Phosphorylation

Supplementary Table 1 from Wnt5A Regulates Expression of Tumor-Associated Antigens in Melanoma via Changes in Signal Transducers and Activators of Transcription 3 Phosphorylation

Supplementary Figure 2 from Wnt5A Regulates Expression of Tumor-Associated Antigens in Melanoma via Changes in Signal Transducers and Activators of Transcription 3 Phosphorylation

Supplementary Figure 4 from Wnt5A Regulates Expression of Tumor-Associated Antigens in Melanoma via Changes in Signal Transducers and Activators of Transcription 3 Phosphorylation

Bayesian cluster analysis offers substantial benefits over algorithmic approaches by providing not only point estimates but also uncertainty in the clustering structure and patterns within each cluster. An overview of Bayesian cluster analysis is provided, including both model-based and loss-based approaches, along with a discussion on the importance of the kernel or loss selected and prior specification. Advantages are demonstrated in an application to cluster cells and discover latent cell types in single-cell RNA sequencing data to study embryonic cellular development. Lastly, we focus on the ongoing debate between finite and infinite mixtures in a model-based approach and robustness to model misspecification. While much of the debate and asymptotic theory focuses on the marginal posterior of the number of clusters, we empirically show that quite a different behaviour is obtained when estimating the full clustering structure. This article is part of the theme issue ‘Bayesian inference: challenges, perspectives, and prospects’.

The Paleogene history of biogenic opal accumulation in the North Atlantic provides insight into both the evolution of deepwater circulation in the Atlantic basin and weathering responses to major climate shifts. However, existing records are compromised by low temporal resolution and/or stratigraphic discontinuities. In order to address this problem, we present a multi-site, high-resolution record of biogenic silica (bioSiO2) accumulation from Blake Nose (ODP Leg 171B, western North Atlantic) spanning the early Paleocene to late Eocene time interval (∼65–34 Ma). This record represents the longest single-locality history of marine bioSiO2 burial compiled to date and offers a unique perspective into changes in bioSiO2 fluxes through the early to middle Paleogene extreme greenhouse interval and the subsequent period of long-term cooling. Blake Nose bioSiO2 fluxes display prominent fluctuations that we attribute to variations in sub-thermocline nutrient supply via cyclonic eddies associated with the Gulf Stream. Following elevated and pulsed bioSiO2 accumulation through the Paleocene to early Eocene greenhouse interval, a prolonged interval of markedly elevated bioSiO2 flux in the middle Eocene between ∼46 and 42 Ma is proposed to reflect nutrient enrichment at Blake Nose due to invigorated overturning circulation following an early onset of Northern Component Water export from the Norwegian–Greenland Sea at ∼49 Ma. Reduced bioSiO2 flux in the North Atlantic, in combination with increased bioSiO2 flux documented in existing records from the equatorial Pacific between ∼42 and 38 Ma, is interpreted to indicate diminished nutrient supply and reduced biosiliceous productivity at Blake Nose in response to weakening of the overturning circulation. Subsequently, in the late Eocene, a deepwater circulation regime favoring limited bioSiO2 burial in the Atlantic and enhanced bioSiO2 burial in the Pacific was established after ∼38 Ma, likely in conjunction with re-invigoration of deepwater export from the North Atlantic. We also observe that Blake Nose bioSiO2 fluxes through the middle Eocene cooling interval (∼48 to 34 Ma) are similar to or higher than background fluxes throughout the late Paleocene–early Eocene interval (∼65 to 48 Ma) of intense greenhouse warmth. This observation is consistent with a temporally variable rather than constant silicate weathering feedback strength model for the Paleogene, which would instead predict that marine bioSiO2 burial should peak during periods of extreme warming.

Background We previously reported the Alopecia Areata Consensus of Experts study, which presented results of an international expert opinion on treatments for alopecia areata. Objective To report the results of the Alopecia Areata Consensus of Experts international expert opinion on diagnosis and laboratory evaluation for alopecia areata. Methods Fifty hair experts from 5 continents were invited to participate in a 3-round Delphi process. Consensus threshold was set at greater than or equal to 66%. Results Of 148 questions, expert consensus was achieved in 82 (55%). Round 1 consensus was achieved in 10 of 148 questions (7%). Round 2 achieved consensus in 47 of 77 questions (61%). The final face-to-face achieved consensus in 25 of 32 questions (78%). Consensus was greatest for laboratory evaluation (12 of 14 questions [86%]), followed by diagnosis (11 of 14 questions [79%]) of alopecia areata. Overall, etiopathogenesis achieved the least category consensus (31 of 68 questions [46%]). Limitations The study had low representation from Africa, South America, and Asia. Conclusion There is expert consensus on aspects of epidemiology, etiopathogenesis, clinical features, diagnosis, laboratory evaluation, and prognostic indicators of alopecia areata. The study also highlights areas where future clinical research could be directed to address unresolved hypotheses in alopecia areata patient care.

Dentoglobigerina is a diverse genus of planktonic foraminifera ranging from the Eocene to Recent. However, the ancestry of Dentoglobigerina has been controversial. A growing body of evidence indica...

Objective. Music has been shown to modulate pain, although the impact of music on specific aspects of nociceptive processing is less well understood. Using quantitative sensory testing (QST), we assessed the impact of a novel music app on specific aspects of nociceptive processing. Design. Within-subjects paired comparison of pain processing in control vs music condition. Setting. Human psychophysical laboratory. Subjects. Sixty healthy adult volunteers. Methods. Subjects were assessed for baseline anxiety, depression, and catastrophizing using validated questionnaires. QSTs measured included 1) pain threshold and tolerance to deep muscle pressure, 2) pain with mechanical pinprick, 3) temporal summation of pain (TSP) with a repeated pain stimulus, and 4) conditioned pain modulation (CPM) with a second painful stimulus. QSTs were performed in the absence and presence of music delivered through a music app. Results. We found an increase in pressure pain thresholds in both the forearm (P = 0.007) and trapezius (P = 0.002) with music, as well as a decrease in the amount of pinprick pain (P

Improved knowledge of the connection between striking variations in the abundance and coiling direction of the trochospiral planktic foraminiferal genus Morozovella and early Eocene carbon-cycle changes, is presented in this study as deriving from new data recorded from the Pacific Ocean (Shatsky Rise, Ocean Drilling Program Sites 1209, 1210). This location spans the Early Eocene Climatic Optimum (EECO; ~53-49 Ma), the interval when Earth surface temperatures and atmospheric pCO2 reached the maximum peak of entire Cenozoic (Zachos et al., 2001, Sciences; Anagnostou et al. 2016, Nature; Inglis et al., 2020 Clim. Past). A significative impact of the EECO on planktic foraminiferal assemblages has recently been recorded in previous works from the Atlantic Ocean, where a definitive marked decline in abundance, diversity, test-size and change in coiling direction of the mixed-layer symbiont-bearing genus Morozovella, took place within the first ~600 kyr of this interval (Luciani et al., 2016 Clim. Past; Luciani et al. 2017 Paleoceanogr.; Luciani et al., 2017 GloPlaCha; D’Onofrio et al., 2020 Geosciences; Luciani et al., 2021 GloPlaCha). As registered in Atlantic sites, in the tropical Pacific Ocean Sites 1209 and 1210, the morozovellids drop permanently their relative abundance at the carbon isotope excursion (CIE) known as J event (~53 Ma), which marks the EECO beginning. A second major change affected all the morphologically defined species of Morozovella (possibly criptic species) at the Atlantic Ocean, resulting in a switch from dominant dextral to sinistrally coiling preference, within ~200 kyr after the K/X event (~52.8 Ma). Although the coiling direction preference of Morozovella at Shatsky Rise changed from dominant dextral to dominant sinistral after the K/X event as well as in the Atlantic sites, here the switch occurred with a delay of ~200 kyr. The recorded modifications clearly reflect important changes in evolution or environment. These changes may include temperature increase and pH decrease that could have reduced the symbiotic relationship and induced calcification crisis. Searching for the driving causes of the observed variations, our data clearly demonstrate their wide geographic and possibly global character and the evident relationship between the environmental perturbations occurred in the mixed-layer at the EECO and the striking changes on planktic foraminiferal assemblages during the first ~800 kyr of this intriguing interval.

There is consensus since the last IPCC report that the rate of climate warming related to high CO2 pressure is generating a strength of the greenhouse state thus the comprehension of marine ecosystems resilience is a pressing humankind issue. The long-term response of the biota under elevated temperatures and CO2 concentrations remains uncertain because modern studies are limited in time. The geological archive offers the key opportunity to evaluate the resilience of planktic foraminifera on a long-term perspective. Planktic foraminifera are important marine calcifiers, regulating biogeochemical cycles, abundant in marine sediments since the Cretaceous, and largely adopted for paleoecological and paleoceanographic reconstructions as they are extremely sensitive to environmental parameters. The Early Eocene Climatic Optimum (EECO, ~ 53-49 Ma) is a crucial interval of Earth’ history to investigate as recording the maximum temperature and pCO2 of the entire Cenozoic (Zachos et al., 2001, Sciences; Anagnostou et al. 2016, Nature; Inglis et al., 2020 Clim. Past). Our recent research shows that the EECO markedly impacted the planktic foraminifera communities by inducing an important turnover as recorded from the latitudinally spaced Atlantic sites 1051, 125 and 1263. Specifically, the mixed-layer symbiont-bearing genus Morozovella, that dominated tropical-subtropical early Paleogene assemblages, abruptly and permanently declined its abundance (up to one-third), size, and diversity at the EECO beginning, close to the carbon isotope excursion known as the J event (~ 53 Ma) whereas the abundance and diversity of Acarinina markedly increased (Luciani et al., 2016 Clim. Past; Luciani et al. 2017 Paleoceanogr.; Luciani et al. 2017 GloPlaCha; D’Onofrio et al., 2020 Geosciences). In addition, the Morozovella morphospecies (or criptic species) display different coiling direction (the ability to add chambers in clock- or counter-clock wise) that was dominantly dextral below the EECO and becoming dominantly sinistral at the EECO, within ~ 200 kyr after the carbon isotope excursion known as K/X event (~ 52.8 Ma) (Luciani et al. 2021 GloPlaCha). Therefore, the sinistral morphotypes represent the main survivors at the expense of dextral forms, that were less resilient to the EECO stressors. Our stable carbon and oxygen data on dextral and sinistral morphotypes performed below and above the major coiling shift, show that sinistral morphotypes typically have lower δ13C values. The lower δ13C signatures of the sinistral specimens, suggests that they were less dependent on their photosymbiotic partnerships, possibly migrating slightly deeper in the mixed-layer. This strategy could have made them able to better tolerate the pressure occurring during the EECO. Our record strongly advises on a causal relationship to chemical-physical modifications in the surface waters, possibly to the temperature increase. Preliminary Mg/Ca derived paleotemperatures through (LA)-ICP-MS from Site 1263 reveal that Morozovella crater and M. subbotinae record a greater warming at the EECO than Acarinina coalingensis and A. soldadoensis. The higher rise in temperature recorded by morozovellids may explain the reduced symbiotic relationship, even though further geochemical analyses are in progress to explore the influence of other potential stressors such as pH decrease.

The Emirates Exploration Imager (EXI) on-board the Emirates Mars Mission (EMM) offers both regional and global imaging capabilities for studies of the Martian atmosphere. EXI is a framing camera with a field-of-view (FOV) that will easily capture the martian disk at the EMM science orbit periapsis. EXI provides 6 bandpasses nominally centered on 220, 260, 320, 437, 546, 635 nm using two telescopes (ultraviolet (UV) and visible(VIS)) with separate optics and detectors. Images of the full-disk are acquired with a resolution of 2–4 km per pixel, where the variation is driven by periapsis and apoapsis points of the orbit, respectively. By combining multiple observations within an orbit with planetary rotation, EXI is able to provide diurnal sampling over most of the planet on the scale of 10 days. As a result, the EXI dataset allows for the delineation of diurnal and seasonal timescales in the behavior of atmospheric constituents such as water ice clouds and ozone.This combination of temporal and spatial distinguishes EXI from somewhat similar imaging systems, including the Mars Color Imager (MARCI) onboard the Mars Reconnaissance Orbiter (MRO) (Malin et al. in Icarus 194(2):501–512, 2008) and the various cameras on-board the Hubble Space Telescope (HST; e.g., James et al. in J. Geophys. Res. 101(E8):18,883–18,890, 1996; Wolff et al. in J. Geophys. Res. 104(E4):9027–9042, 1999). The former, which has comparable spatial and spectral coverage, possesses a limited local time view (e.g., mid-afternoon). The latter, which provides full-disk imaging, has limited spatial resolution through most of the Martian year and is only able to provide (at most) a few observations per year given its role as a dedicated, queue-based astrophysical observatory. In addition to these unique attributes of the EXI observations, the similarities with other missions allows for the leveraging of both past and concurrent observations. For example, with MARCI, one can build on the ∼6 Mars years of daily global UV images as well as those taken concurrently with EXI.

ObjectiveMicroRNA (miRNA) are small endogenous regulatory RNA molecules that have emerged as potential therapeutic targets and biomarkers in autoimmunity. Here, we investigated serum miRNA levels in patients with psoriatic arthritis (PsA) and further assessed a serum miRNA signature in therapeutic responder versus nonresponder PsA patients.MethodsSerum samples were collected from healthy controls (HC; n = 20) and PsA patients (n = 31), and clinical demographics were obtained. To examine circulatory miRNA in serum from HC and PsA patients, a focused immunology miRNA panel was analyzed utilizing a miRNA Fireplex assay (FirePlex Bioworks Inc.). MiRNA expression was further assessed in responders versus nonresponders according to the European League Against Rheumatism response criteria.ResultsSix miRNA (miR-221-3p, miR-130a-3p, miR-146a-5p, miR-151-5p, miR-26a-5p, and miR-21-5p) were significantly higher in PsA compared to HC (all P < 0.05), with high specificity and sensitivity determined by receiver-operating characteristic curve analysis. Analysis of responder versus nonresponders demonstrated higher baseline levels of miR-221-3p, miR-130a-3p, miR-146a-5p, miR-151-5p, and miR-26a-5p were associated with therapeutic response.ConclusionThis study identified a 6-serum microRNA signature that could be attractive candidates as noninvasive markers for PsA and may help to elucidate the disease pathogenesis.

BackgroundRheumatoid (RA) and psoriatic arthritis (PsA) are common autoimmune and autoinflammatory diseases of unknown aetiology characterised by complex synovial pathology with a detrimental effect on the patient’s quality of life. Significant differences in pathophysiology may explain distinct clinical manifestations and account for differential responses to specific therapeutics. Recent implementation of single cell transcriptomic analysis of sorted synovial cells has revealed the diverse cellular landscape of the RA synovial stromal and immune cell compartments, however, a complete analysis of immune and stromal cells in tandem, for RA and PsA patient synovial tissue has not been performed.ObjectivesTo combine novel scRNA transcriptomic approaches and ex vivo assays in order to: identify differences in the cellular landscape of RA and PsA synovial tissue inflammation and immune – stromal cell interactions that drive pathology in RA and PsA.MethodsSingle cell transcriptomic profiling of 178,000 synovial tissue cells from 5 PsA and 4 RA patients, importantly, without prior sorting of immune and stromal cells. This approach enabled the generation of a unique cell atlas of intact synovial tissue identifying immune and stromal cell interactions. State of the art data integration and annotation techniques identified and characterised 18 stromal and 14 immune cell clusters. Bioinformatic examination of cell-cell communication via construction of receptor-ligand interaction networks with further in vitro validation of stromal and immune cell crosstalk through flow cytometric analysis, multiplex ELISA and mitochondrial and single cell metabolic profiling by multiphoton and florescent lifetime imaging microscopy, seahorse.ResultsFollowing quality control and data integration the PsA and RA cellular landscape was generated and nine mega clusters indicative of fibroblasts, endothelial cells, pericytes, macrophages, dendritic cells (DC), B cells, plasma cells, T cells and NKT consisting of several sub clusters were identified. Distinct points of transcriptomic deviation and convergence between RA and PsA were identified for each of the major cell types of the joint. Specifically, cell cycle and trajectory analysis revealed that only a fraction of synovial T cells are actively proliferating. Additionally, the differential usage of immunoglobulin light chains by memory and plasma cells indicates that plasma cells are potentially not derived from the local memory B cell pool of the synovial tissue. Importantly, we report distinct fibroblast and endothelial cell transcriptomes indicating differentially abundant subpopulations in RA and PsA characterised by distinct transcription factor usage and signalling pathway enrichment. Specifically transcriptomic imputation analysis revealed abundance of invasive FAPα+THY1+ regulated by transcription factor TEAD1 in RA compared to PsA synovial tissue. In order to identify potential cell-cell communication driving inflammation in RA and PsA, novel receptor–ligand interaction networks were generated and downstream of the receptor, target characterisation was performed. Herein we identify RA-specific synovial T cell-derived TGF-β and macrophage IL-1β synergy in driving the transcriptional profile of FAPα+THY1+ invasive synovial-fibroblasts, expanded in RA compared to PsA synovial tissue biopsies (Figure 1). Ex vivo treatment of RA patient synovial fibroblasts identified TGF-b and IL-1b synergy are a major driver of IL-6 production, fibroblast activation and adhesion molecule expression. Interestingly, the aforementioned proinflammatory changes of RA patient synovial fibroblasts were coupled with significant alterations in mitochondrial eccentricity and size and a marked metabolic adaptation towards a strongly glycolytic profile (Figure 1).Figure 1.ConclusionDisrupting specific immune and stromal cell interactions offers novel opportunities for targeted therapeutic intervention in RA and PsA.Disclosure of InterestsAchilleas Floudas: None declared, Conor Smith: None declared, Orla Tynan: None declared, Nuno Neto: None declared, Vinod Krishna Employee of: Janssen Pharmaceuticals, Sarah Wade: None declared, Megan Hanlon: None declared, Clare Cunningham: None declared, Viviana Marzaioli: None declared, Mary Canavan: None declared, Jean Fletcher: None declared, Suzanne Cole Employee of: Janssen Pharmaceuticals, Ling-Yang Hao Employee of: Janssen Pharmaceuticals, Sunil Nagpal Employee of: Janssen Pharmaceuticals, GSK, Michael Monaghan: None declared, Douglas Veale Consultant of: Janssen, Eli Lilly, Pfizer, Ursula Fearon Consultant of: Janssen, Eli Lilly, Pfizer.

[Abstract The East African Rift System (EARS) exerted a major influence on river drainage basins and regional climate of east Africa during the Cenozoic. Recent studies have highlighted an offshore branch of the EARS in the western Indian Ocean, where the Kerimbas Graben and the Davie Ridge represent its sea floor expression. To date, a clear picture of the impact and timing of this EARS offshore branch on the continental margin of the western Indian Ocean, and associated sediment dispersal pathways, is still missing. This study presents new evidence for four giant canyons along the northern portion of the Davie Ridge offshore Tanzania. Seismic and multibeam bathymetric data highlight that the southernmost three canyons are now inactive, supra‐elevated relative to the adjacent sea floor of the Kerimbas Graben and disconnected from the modern slope systems offshore the Rovuma and Rufiji River deltas. Regional correlation of dated seismic horizons, integrated with well data and sediment samples, proves that the tectonic activity driving the uplift of the Davie Ridge in this area has started during the middle‐upper Miocene and is still ongoing, as suggested by the presence of fault escarpments at the sea floor and by the location and magnitude of recent earthquakes. Our findings contribute to placing the Kerimbas Graben and the Davie Ridge offshore Tanzania in the regional geodynamic context of the western Indian Ocean and show how the tectonics of the offshore branch of the EARS modified the physiography of the margin, re‐routing the deep‐water drainage network since the middle Miocene. Future studies are needed to understand the influence of changing sea floor topography on the western Indian Ocean circulation and to evaluate the potential of the EARS offshore tectonics in generating tsunamigenic events., This study presents the discovery of four giant canyons along the northern portion of the Davie Ridge (western Indian Ocean). Three canyons are now inactive, supra‐elevated relative to the adjacent sea floor and disconnected from the modern slope systems offshore the Rovuma and Rufiji River deltas. The chronological constraints available suggest that the tectonic activity driving the uplift of the Davie Ridge in this area has started during the middle‐upper Miocene. Our findings contribute to placing the Kerimbas Graben and the Davie Ridge offshore Tanzania in the regional geodynamic context of the western Indian Ocean and show how the tectonics of the offshore branch of the EARS modified the physiography of the margin, re‐routing the deep‐water drainage network. ]

ObjectivesPsoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis. Janus Kinase inhibitors (JAKi) have emerged as an encouraging class of drugs for the treatment of PsA. Here, we compare the effect of four JAKi on primary PsA synovial fibroblasts (PsAFLS) activation, metabolic function, and invasive and migratory capacity.MethodsPrimary PsAFLS were isolated and cultured with JAKi (Peficitinib, Filgotinib, Baricitinib and Upadacitinib) in the presence of Oncostatin M (OSM). pSTAT3 expression in response to OSM was quantified by Western Blot analysis. Pro-inflammatory cytokines/chemokines were quantified by ELISA and cell migration by wound-repair scratch assays. Invasive capacity was examined using Matrigel™ invasion chambers and MMP multiplex MSD assays. PsAFLS bioenergetics was assessed using the Seahorse XFe Extracellular Flux Analyzer, which simultaneously quantifies two energetic pathways- glycolysis (ECAR) and oxidative phosphorylation (OCR). In parallel, inflammatory, invasive, and migratory genes were quantified by RT-PCR.ResultsOSM induces pSTAT3 expression in PsAFLS. OSM-induced secretion of MCP-1 and IL-6 was inhibited by all JAKi with Peficitinib, Baricitinib and Upadacitinib showing the greatest effect. In contrast, JAKi had no significant impact on IL-8 expression in response to OSM. PsAFLS cell invasion, migratory capacity and MMP1, 3, and 9 were suppressed following JAKi treatment, with Peficitinib showing the greatest effect. These functional effects were accompanied by a change in the cellular bioenergetic profile of PsAFLS, where JAKi significantly decreased glycolysis and the ECAR/OCR, resulting in a shift to a more quiescent phenotype, with Peficitinib demonstrating the most pronounced effect.ConclusionThis study demonstrates that JAK/STAT signalling mediates the complex interplay between inflammation and cellular metabolism in PsA pathogenesis. This inhibition shows effective suppression of inflammatory mechanisms that drive pathogenic functions of PsAFLS, further supporting the role of JAKi as a therapeutic target for the treatment of PsA.

This chapter informs readers of recent developments with open educational resources (OERs) as well as the various advantages and challenges to the use of open access materials and repositories. This chapter explores examples of OER usage for instruction and research and discusses digital and instructional media relevant to open pedagogy and the technology-enabled democratization of learning. Finally, the chapter concludes with suggestions for advocacy of greater open access to benefit national and international dissemination of knowledge and the increase of societal use.

BackgroundMicroRNAs (miRNAs) are small non-coding RNAs which have been implicated as potential biomarkers or therapeutic targets in autoimmune diseases. This study examines circulatory miRNAs in RA patients and further investigates if a serum miRNA signature precedes clinical manifestations of disease in arthralgia or “at-risk individuals”.MethodsSerum was collected from HC subjects (N = 20), RA patients (N = 50), and arthralgia subjects (N = 10), in addition to a subgroup of the RA patients post-methotrexate (MTX) (N = 18). The FirePlex miRNA Immunology-V2 panel was selected for multiplex analysis of 68 miRNAs in each sample. DNA intelligent analysis (DIANA)-mirPath and Ingenuity Pathway Analysis (IPA) software were used to predict pathways targeted by the dysregulated miRNAs.Results8 miRNA (miR-126-3p, let-7d-5p, miR-431-3p, miR-221-3p, miR-24-3p, miR-130a-3p, miR-339-5p, let-7i-5p) were significantly elevated in RA serum compared to HC (all p < 0.01) and 1 miRNA (miR-17-5p) was significantly lower in RA (p < 0.01). High specificity and sensitivity were determined by receiver operating characteristic (ROC) curve analysis. Both miR-339-5p and let-7i-5p were significantly reduced post-MTX (both p < 0.01). MiR-126-3p, let-7d-5p, miR-431-3p, miR-221-3p, miR-24-3p, miR-130a-3p were also significantly elevated in subjects “at risk” of developing RA (all p < 0.05) compared to HC. IPA analysis of this miRNA signature identified downstream targets including key transcription factors NF-κB, STAT-1, STAT-3, cytokines IL-1β, TNF-α, and matrix-metalloproteases all importantly associated with RA pathogenesis.ConclusionThis study identified six miRNAs that are altered in both RA and “at-risk individuals,” which potentially regulate key downstream pathways involved in regulating inflammation. These may have potential as predictive signature for disease onset and early progression.

Objective and Methods The transition of HIV from an acute, fatal illness to a chronic health condition has shifted the treatment needs of people living with HIV (PLWH). PLWH, including sexual minority men (SMM), are living longer and are subject to health concerns often associated with aging. A major health concern of older SMM living with HIV who report problematic substance use is chronic pain. This qualitative analysis of 15 one-on-one interviews with older SMM living with HIV and chronic pain aimed to characterize this population’s experiences with pain, engagement in HIV care, and problematic substance use. This study was conducted in a community health center in Boston, MA. We also solicited suggestions for preferred intervention strategies. Results Three main themes emerged from the interview transcripts: 1) the impact of chronic pain and pain treatment on engagement in HIV clinical care; 2) the impact of substance use on chronic pain; and 3) response to interventions to address chronic pain and substance use. Conclusions These findings underscore the need for interventions that address the structural, physical, and psychological barriers to engagement in medical and self-care that affect older SMM living with HIV and chronic pain.

Background Transcranial laser stimulation is a novel method of noninvasive brain stimulation found safe and effective for improving prefrontal cortex neurocognitive functions in healthy young adults. This method is different from electric and magnetic stimulation because it causes the photonic oxidation of cytochrome-c-oxidase, the rate-limiting enzyme for oxygen consumption and the major intracellular acceptor of photons from near-infrared light. This photobiomodulation effect promotes mitochondrial respiration, cerebrovascular oxygenation and neurocognitive function. Pilot studies suggest that transcranial photobiomodulation may also induce beneficial effects in aging individuals. Objectives Randomized, sham-controlled study to test photobiomodulation effects caused by laser stimulation on cytochrome-c-oxidase oxidation and hemoglobin oxygenation in the prefrontal cortex of 68 healthy younger and older adults, ages 18–85. Methods Broadband near-infrared spectroscopy was used for the noninvasive quantification of bilateral cortical changes in oxidized cytochrome-c-oxidase and hemoglobin oxygenation before, during and after 1064-nm wavelength laser (IR-A laser, area: 13.6 cm2, power density: 250 mW/cm2) or sham stimulation of the right anterior prefrontal cortex (Brodmann Area 10). Results As compared to sham control, there was a significant laser-induced increase in oxidized cytochrome-c-oxidase during laser stimulation, followed by a significant post-stimulation increase in oxygenated hemoglobin and a decrease in deoxygenated hemoglobin. Furthermore, there was a greater laser-induced effect on cytochrome-c-oxidase with increasing age, while laser-induced effects on cerebral hemodynamics decreased with increasing age. No adverse laser effects were found. Conclusion The findings support the use of transcranial photobiomodulation for cerebral oxygenation and alleviation of age-related decline in mitochondrial respiration. They justify further research on its therapeutic potential in neurologic and psychiatric diseases.

Faulting and earthquakes occur extensively along the flanks of the East African Rift System, including an offshore branch in the western Indian Ocean, resulting in remobilization of sediment in the form of landslides. To date, constraints on the occurrence of submarine landslides at margin scale are lacking, leaving unanswered a link between rifting and slope instability. Here, we show the first overview of landslide deposits in the post-Eocene stratigraphy of the Tanzania margin and we present the discovery of one of the biggest landslides on Earth: the Mafia mega-slide. The emplacement of multiple landslides, including the Mafia mega-slide, during the early-mid Miocene is coeval with cratonic rifting in Tanzania, indicating that plateau uplift and rifting in East Africa triggered large and potentially tsunamigenic landslides likely through earthquake activity and enhanced sediment supply. This study is a first step to evaluate the risk associated with submarine landslides in the region., The authors describe a huge submarine landslide deposit offshore Tanzania and highlight that large and potentially tsunamigenic landslide events are associated with plateau uplift and continental rifting in East Africa.

Ultraviolet light (UVL) room disinfection has emerged as an adjunct to manual cleaning of patient rooms. Two different no-touch UVL devices were implemented in 3 health system hospitals to reduce Clostridioides difficile infections (CDI). CDI rates at all 3 facilities remained unchanged following implementation of UVL disinfection. Preintervention CDI rates were generally low, and data from one hospital showed high compliance with manual cleaning, which may have limited the impact of UVL disinfection.

Objectives To investigate the functional role of miR-23a in synovial fibroblasts (SFC) activation in psoriatic arthritis (PsA). Methods Differential expression of the miR-23a-27a-24-2 cluster was identified by real-time quantitative PCR in PsA synovial tissue and peripheral blood mononuclear cells (PBMC) compared to osteoarthritis (OA) and correlated with disease activity. For regulation experiments, PsA synovial fibroblasts (SFC) were cultured with Toll-like receptor (TLR) ligands and pro-inflammatory cytokines. PsA SFC were transfected with a miR-23a inhibitor to assess the functional effect on migration, invasion and expression of pro-inflammatory meditators. The direct interaction between miR-23a and predicted target mRNA, phosphodiesterase 4B (PDE4B), was examined by luciferase reporter gene assay, with the expression and regulation confirmed by RT-PCR and western blot. A PDE4 inhibitor was used to analyse the function of PDE4B signalling in both miR-23a and Poly(I:C)-induced PsA SFC activation. Results Synovial tissue expression of miR-23a was lower in PsA compared to OA and correlated inversely with disease activity and synovitis. TLR activation via Poly(I:C) and LPS, but not Pam3CSK4, significantly decreased miR-23a expression, with no significant effect observed in reponse to stimulation with pro-inflammatory cytokines. Decreased miR-23a expression enhanced PsA SFC migration, invasion and secretion of IL-6, IL-8, MCP-1, RANTES and VEGF. We identified PDE4B as a direct target of miR-23a and demonstrated enhanced mRNA and protein expression of PDE4B in anti-miR-23a transfected PsA SFC. Poly(I:C) and/or miR-23a-induced migration and enhanced cytokine expression was suppressed by the blockade of PDE4 signalling. Conclusions In PsA, dysregulated miR-23a expression contributes to synovial inflammation through enhanced SFC activation, via PDE4B signalling, and identifies a novel anti-inflammatory mechanism of PDE4 blockade.

BackgroundWe have previously shown that children with Down’s syndrome-associated arthritis (DA) display a more aggressive form of inflammatory arthritis compared to that of Juvenile Idiopathic Arthritis (Shih et al., 2019). DA is associated with an increase in polyfunctional T-cells coexpressing TNF-α DA is associated with an increase in polyfunctional T-cells coexpressing TNF-fibroblasts (FLS) (Foley et al., 2019).ObjectivesIn this study we examine the effect of cytokine synergy on primary DA FLS function.MethodsPrimary DA FLS were cultured and stimulated with TNF-α (0.1 and 1ng/ml), IL-17A (20 and 50ng/ml), IFN-ɣ (10 and 50ng/ml) and GM-CSF (20 and 100ng/ml) or a combination of these cytokines and the following functional experiments performed. Chemokine and adhesion molecule cell surface expression were quantified by flow cytometry, in addition to quantification of leukocyte-DA-FLS adhesion assays. Gene and protein expression of proinflammatory and metabolic mediators were quantified by ELISA and RT-PCR. Furthermore, real-time metabolic activity in response to cytokine stimulation was assessed by measuring the two major energy pathways: glycolysis (ECAR) and oxidative phosphorylation (OCR), by the Seahorse XFe96 Analyser.ResultsWe examined the effects of T cell derived cytokines, TNF-α, IL-17A, IFN-γ and GM-CSF, alone and in combination on DA FLS function. TNF-α, IL-17A and IFN-γ induced IL-6, RANTES and MCP-1 production, with no effect observed for GM-CSF. Furthermore, TNF-α, IFN-ɣ and IL-17A increased leukocyte adhesion to DA FLS. TNF-α and IFN-ɣ induced cell surface expression of CXCR3, CXCR4, ICAM-1 and VCAM-1 on DA FLS. Next, we investigated the potential synergistic relationship that these cytokines could have on proinflammatory mediators. IL-17A and IFN-ɣ potentiated the effects TNF-α on IL-6 and MCP-1 secretion compared to stimulation alone. Furthermore, cytokine synergy significantly induced IL-6, IL-8, RANTES and LDHA mRNA expression compared to basal. IL-17A and IFN-αL-17A and IFN- eeased ts TNF-α on IL-6 and MCP-1 secretion compared to stimulation alone. Additionally, IFN the ECAR:OCR ratio demonstrating a shift in the metabolic profile of DA FLS to glycolysis. Overall DA FLS are transformed from a quiescent metabolic state to an energetic phenotype.ConclusionTNF-αNF-lusion:OCR ratio demonstrating a shift in the metabolhe aggressive phenotype of DA FLS through increased cytokine, adhesion molecule and chemokine expression, which is pathways for the treatment of DA.References[1]Foley, C. et al. (2019) ‘Increased T cell plasticity with dysregulation of T follicular helper, T peripheral helper and T regulatory cell responses in children with JIA and Down syndrome-associated arthritis’, Arthritis & Rheumatology, pp. 0–1. doi: 10.1002/art.41150.[2]Shih, Y. J. et al. (2019) ‘Enthesitis-related arthritis is the most common category of juvenile idiopathic arthritis in Taiwan and presents persistent active disease’, Pediatric Rheumatology. Pediatric Rheumatology. doi: 10.1186/s12969-019-0363-0.Disclosure of InterestsNone declared.

BackgroundRheumatoid Arthritis (RA) is a common autoimmune disease characterized by systemic polyarthritis affecting the joints, most notably of the hands and feet. A fundamental feature of RA is inflammation within the synovial joint due to neo-angiogenesis which facilitates an influx of immune cells and release of pro-inflammatory mediators.ObjectivesIn this study we investigate the effect of metabolic reprogramming on IL-1β regulation of stromal cell activation and invasiveness in RA.MethodsPrimary RA synovial fibroblasts (RAFLS) and human umbilical vein endothelial cells (HUVEC) were cultured with IL-1 β (2 ng/mL) alone or in combination with the metabolic inhibitor rapamycin (100nM). Pro-inflammatory cytokines IL-6, MCP-1 and Rantes were quantified by real-time PCR and ELISA. Cellular adhesion and network formation were quantified by adhesion binding assays and Matrigel invasion assays. pS6 (a surrogate marker of the mTOR pathway) was quantified by flow cytometry. Cellular bioenergetics was assessed using the Seahorse-XFe-technology and key glycolytic genes (HK2, PKM2, G6DP) were quantified by real-time PCR. YAP was measured by Western-Blot.ResultsIL-1β significantly induced secretion of IL-6 (pConclusionRapamycin inhibits IL-1β -induced pro-inflammatory mechanisms in key stromal cells involved in the pathogenesis of RA. Targeting metabolism may lead to new potential therapeutic or adjuvant strategies, particularly for those patients who have sub-optimal responses to current treatments.References[1]Kim EK, Min HK, Lee SY, Kim DS, Ryu JG, Na HS, Jung KA, Choi JW, Park SH, Cho ML. Metformin rescues rapamycin-induced mitochondrial dysfunction and attenuates rheumatoid arthritis with metabolic syndrome. Arthritis Res Ther. 2020 Apr 10;22(1):77. doi: 10.1186/s13075-020-02174-3. PMID: 32276645; PMCID: PMC7149912.Disclosure of InterestsNone declared

Objective To examine the effects of tofacitinib on metabolic activity, mitochondrial function, and proinflammatory mechanisms in rheumatoid arthritis (RA). Methods Ex vivo RA synovial explants and primary RA synovial fibroblasts (RASFs) were cultured with 1 μM tofacitinib. RASF bioenergetics were assessed using an XF24 analyzer, and key metabolic genes were assessed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Mitochondrial function was assessed using specific cell fluorescent probes and by mitochondrial gene arrays. Mitochondrial mutagenesis was quantified using a mitochondrial random mutation capture assay, and lipid peroxidation was quantified by enzyme-linked immunosorbent assay (ELISA). The effect of tofacitinib on spontaneous release of proinflammatory mediators from RA whole tissue synovial explants was quantified by ELISAs/MSD multiplex assays, and metabolic markers were quantified by RT-PCR. Finally, RASF invasion, matrix degradation, and synovial outgrowths were assessed by transwell invasion/Matrigel outgrowth assays and ELISA. Results Tofacitinib significantly decreased mitochondrial membrane potential, mitochondrial mass, and reactive oxygen species production by RASFs and differentially regulated key mitochondrial genes. Tofacitinib significantly increased oxidative phosphorylation, ATP production, and the maximal respiratory capacity and the respiratory reserve in RASFs, an effect paralleled by a decrease in glycolysis and the genes for the key glycolytic enzymes hexokinase 2 (HK2), glycogen synthase kinase 3α (GSK-3α), lactate dehydrogenase A, and hypoxia-inducible factor 1α. Tofacitinib inhibited the effect of oncostatin M (OSM) on interleukin-6 (IL-6) and monocyte chemotactic protein 1 and reversed the effects of OSM on RASF cellular metabolism. Using RA whole tissue synovial explants, we found that tofacitinib inhibited the key metabolic genes for glucose transporter 1, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, 3'-phosphoinositide-dependent protein kinase 1, HK2, and GSK-3α, the proinflammatory mediators IL-6, IL-8, IL-1β, intercellular adhesion molecule 1, vascular endothelial growth factor, and TIE-2, and RASF outgrowth from synovial explants, RASF invasion, and matrix metalloproteinase 1 activity. Conclusion This study demonstrates that JAK/STAT signaling mediates the complex interplay between inflammation and cellular metabolism in RA pathogenesis.

Regional anaesthesia is widely used in modern anaesthetic practice for perioperative and postoperative analgesia. In the operating theatre, regional anaesthesia is used both on its own and in combination with other techniques (general anaesthesia and sedation). Regional anaesthesia is now a core skill set in anaesthetic training. This article provides a basic outline of regional anaesthesia for surgeons and other non-anaesthetic staff working with anaesthetists, reviewing preparation, consent, basic and specialist equipment, central neuraxial blocks (spinal, epidural and caudal), trunk blocks, upper limb blocks (interscalene, supraclavicular, infraclavicular and axillary) and lower limb blocks (femoral, fascia iliaca, sciatic, popliteal and ankle). It also discusses the pharmacology of the agents used and common complications.