Search

Changes in chondrocyte gene expression can contribute to the development of osteoarthritis (OA), and so recognition of the regulative processes during chondrogenesis can lead to a better understanding of OA. microRNAs (miRNAs) are key regulators of gene expression in chondrocytes/OA, and we have used a combined experimental, bioinformatic, and systems biology approach to explore the multiple miRNA–mRNA interactions that regulate chondrogenesis. A longitudinal chondrogenesis bioinformatic analysis identified paralogues miR-199a-5p and miR-199b-5p as pro-chondrogenic regulators. Experimental work in human cells demonstrated alteration of miR-199a-5p or miR-199b-5p expression led to significant inverse modulation of key chondrogenic genes and extracellular matrix production. miR-199a/b-5p targets FZD6, ITGA3 and CAV1 were identified by inhibition experiments and verified as direct targets by luciferase assay. The experimental work was used to generate and parameterise a multi-miRNA 14-day chondrogenesis kinetic model to be used as a repository for the experimental work and as a resource for further investigation of this system. This is the first multi-miRNA model of a chondrogenesis-based system, and highlights the complex relationships between regulatory miRNAs, and their target mRNAs.

Abstract CAR T-cell therapy has transformed relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukaemia (B-ALL) management and outcomes, but following CAR T infusion, interventions are often needed. In a UK multicentre study, we retrospectively evaluated tisagenlecleucel outcomes in all eligible patients, analysing overall survival (OS) and event-free survival (EFS) with standard and stringent definitions, the latter including measurable residual disease (MRD) emergence and further anti-leukaemic therapy. Both intention-to-treat and infused cohorts were considered. We collected data on feasibility of delivery, manufacture, toxicity, cause of therapy failure and followed patients until death from any cause. Of 142 eligible patients, 125 received tisagenlecleucel, 115/125 (92%) achieved complete remission (CR/CRi). Severe cytokine release syndrome and neurotoxicity occurred in 16/123 (13%) and 10/123 (8.1%), procedural mortality was 3/126 (2.4%). The 2-year intent to treat OS and EFS were 65.2% (95%CI 57.2–74.2%) and 46.5% (95%CI 37.6–57.6%), 2-year intent to treat stringent EFS was 35.6% (95%CI 28.1–44.9%). Median OS was not reached. Sixty-two responding patients experienced CAR T failure by the stringent event definition. Post failure, 1-year OS and standard EFS were 61.2% (95%CI 49.3–75.8) and 55.3% (95%CI 43.6–70.2). Investigation of CAR T-cell therapy for B-ALL delivered on a country-wide basis, including following patients beyond therapy failure, provides clinicians with robust outcome measures. Previously, outcomes post CAR T-cell therapy failure were under-reported. Our data show that patients can be successfully salvaged in this context with good short-term survival.

Climate change-related challenges faced by forest managers are ecological, economic, and social in nature. While several past assessments have looked at the climate-related perceptions and needs of foresters working in rural contexts, urban foresters are not often included in these assessments. Examining foresters’ risk perceptions, adaptation interests and intentions, and need for information/support in rural and urban contexts side-by-side reveals unique opportunities for learning across the rural-to-urban gradient. Through two surveys targeting both rural and urban foresters, we have identified key learning opportunities that support climate-adaptive forest management.Our analysis shows that many foresters are seeking to maintain current forest conditions or restore forest conditions following a disruption or change, though some see value in transitioning forests to be more resistant and resilient to future climates. We also show a difference in confidence between urban and rural foresters when it comes to addressing climate change through specific adaptation strategies. Based on our findings, we propose facilitated learning opportunities across the rural-to-urban gradient. This would allow urban foresters to learn from rural foresters on topics such as establishment and maintenance of long-term, large, ecologically complex forested areas within cities. Rural foresters could gain insights from their urban counterparts on planting strategies and other approaches that are common in urban settings but novel in rural settings, including stock sourcing and species selection.To better enable foresters to implement climate adaptation strategies, we suggest: (1) facilitating learning across the rural-to-urban gradient, (2) public engagement trainings and opportunities targeting foresters, (3) workforce development programing, and (4) programs that limit the financial risk that foresters, landowners, and municipalities face when applying forest adaptation strategies to rural or urban lands.

AT 2019azh is a H+He tidal disruption event (TDE) with one of the most extensive ultraviolet and optical data sets available to date. We present our photometric and spectroscopic observations of this event starting several weeks before and out to approximately 2 yr after the g -band's peak brightness and combine them with public photometric data. This extensive data set robustly reveals a change in the light-curve slope and a possible bump in the rising light curve of a TDE for the first time, which may indicate more than one dominant emission mechanism contributing to the pre-peak light curve. Indeed, we find that the MOSFiT -derived parameters of AT 2019azh, which assume reprocessed accretion as the sole source of emission, are not entirely self-consistent. We further confirm the relation seen in previous TDEs whereby the redder emission peaks later than the bluer emission. The post-peak bolometric light curve of AT 2019azh is better described by an exponential decline than by the canonical t ^−5/3 (and in fact any) power-law decline. We find a possible mid-infrared excess around the peak optical luminosity, but cannot determine its origin. In addition, we provide the earliest measurements of the H α emission-line evolution and find no significant time delay between the peak of the V -band light curve and that of the H α luminosity. These results can be used to constrain future models of TDE line formation and emission mechanisms in general. More pre-peak 1–2 days cadence observations of TDEs are required to determine whether the characteristics observed here are common among TDEs. More importantly, detailed emission models are needed to fully exploit such observations for understanding the emission physics of TDEs.