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RAS–p110α signalling in macrophages is required for effective inflammatory response and resolution of inflammation
No full textMacrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses
Rapid water permeation by aramid foldamer nanochannels with hydrophobic interiors.
No full textAquaporins are natural proteins that rapidly transport water across cell membranes, maintaining homeostasis, whilst strictly excluding salt. This has inspired their use in water purification and desalination, a critical emerging need. However, stability, scalability, and cost have prevented their widespread adoption in water purification membrane technologies. As such, attention has turned to the use of artificial water channels, with pore functionalized polymers and macrocycles providing a powerful alternative. Whilst impressive rates of transport have been achieved, the combination of a scalable, high-yielding synthesis and efficient transport has not yet been reported. Herein, we report such a system, with densely functionalized channel interiors, synthesized by high-yielding living polymerization with low polydispersities, showing high salt exclusion, and excellent water transport rates. Our aramid foldamers create artificial water channels with hydrophobic interiors, and single-channel water permeability rates of up to 108 water molecules per second per channel, approaching the range of natural Aquaporins (c. 109). We show that water transport rates closely correspond to the helical length, with the polymer which most closely matches bilayer thickness showing optimal efficacy, as supported by molecular dynamics simulations. Our work provides a basis for the scalable synthesis of next-generation artificial water channels
'They're creepy creatures with human-like features': children's experiences of visual hallucinations in Charles Bonnet syndrome-a qualitative study.
No full textOBJECTIVE: Charles Bonnet syndrome (CBS) refers to the presence of visual hallucinations occurring secondary to visual impairment. The aim of this study was to understand the phenomenology of CBS in children and assess the emotional impact and support needs of patients and their families. DESIGN: Semistructured qualitative interview study. SETTING: UK. PARTICIPANTS: Children (7-15 years) with an inherited retinal disease living with CBS and their parents. RESULTS: 10 participants were recruited from six families (dyadic interviews n=4; parent-only interviews n=2). Thematic analysis identified five superordinate themes relating to experiences of CBS: (1) diagnosis journey, (2) hallucination phenomenology, (3) impact of hallucinations, (4) understanding and managing hallucinations and (5) experiences of support. The impact of CBS was broad and heterogenous, causing significant disruption to patients' daily life. Limited awareness led to parents expressing largely negative healthcare experiences. Overall, the extent of knowledge and understanding of CBS was an indicator of successful self-management of the condition. CONCLUSIONS: The journey towards understanding and managing CBS for both parents and children is challenging. Although coping strategies can lead to improved adjustment, visual hallucinations compounded the difficulty of living with a chronic visual impairment. Healthcare providers have an integral role in ensuring patients and families are effectively supported to allay fears and promote psychological well-being
The CSF transcriptome in adults with pneumococcal meningitis reveals compartmentalised host inflammatory responses associated with mortality.
No full textPneumococcal meningitis (PM) has persistently poor clinical outcomes, especially in sub-Saharan Africa. To better characterise the inflammatory response and identify factors associated with mortality we compared paired peripheral blood and cerebrospinal fluid (CSF) transcriptomes before the initiation of antibiotics in Malawian adults with proven PM. Blood transcriptional profiles were obtained in 28 patients with PM, with simultaneous paired with CSF profiles available for 13 patients. 15/28 (52%) patients died. Comparison of the transcriptome between CSF and blood compartments showed upregulation of 2293 differentially expressed genes in CSF and 909 in blood; enriched pathways in CSF included inflammasome activity and neutrophil migration/activation, contrasting with enrichment for pathways including platelet and endothelial activation, cell cycle, cytokine release and oxidative stress in the blood transcriptome. Comparison of CSF profiles between survivors and non-survivors revealed 1829 differentially expressed genes. Non-survivor CSF was enriched for multiple innate inflammatory pathways, including IL-17A and Type 1 interferons and proteolysis. In contrast, minimal transcriptomic differences between outcome groups were detected in blood. Inflammation in PM is characterised by compartmentalised responses in blood and CSF. Poorer outcomes are associated with an dysregulated innate immune host response to S. pneumoniae in the CSF compartment
Discovery and validation of a novel class of necroptosis inhibitors targeting RIPK1.
No full textNecroptosis is a form of programmed cell death that, when dysregulated, is associated with cancer and inflammatory and neurodegenerative diseases. Here, starting from hits identified from a phenotypic high-throughput screen for inhibitors of necroptosis, we synthesized a library of compounds containing a 7-phenylquinoline motif and validated their anti-necroptotic activity in a novel live-cell assay. Based on these data, we designed an optimized photoaffinity probe for target engagement studies and through biochemical and cell-based assays established receptor-interacting kinase 1 (RIPK1) as the cellular target, with inhibition of necroptosis arising from the prevention of RIPK1 autophosphorylation and activation. X-ray crystallography and mass spectrometry revealed that these compounds bind at the hinge region of the active conformation of RIPK1, establishing them as type I kinase inhibitors. In addition, we demonstrated in vitro synergy with type III kinase inhibitors, such as necrostatin-1 and found that lead compounds protected mice against acute inflammation in necroptosis models in vivo. Overall, we present a novel pharmacophore for inhibition of human RIPK1, a key protein involved in necroptosis, and provide a photoaffinity probe to explore RIPK1 target engagement in cells
Toward the clinical translation of implantable brain-computer interfaces for motor impairment: Research trends and outcome measures.
No full textImplantable brain-computer interfaces (iBCIs) decode neural signals to control external effectors, offering potential to restore function in individuals with severe motor impairments, such as loss of limb function or speech. This systematic review examines the evolution of iBCI research and key bottlenecks to clinical translation, particularly the absence of standardized, clinically meaningful outcome measures. A comprehensive search of MEDLINE, Embase, and CINAHL identifies 112 studies, nearly half (49.1%) published since 2020. Eighty unique iBCI participants were identified, providing the most up-to-date estimate of global users. Research remains concentrated in the United States (83%), with growing contributions from Europe, China, and Australia. Electrocorticography (ECoG)-based devices increasingly emerge alongside micro-electrode arrays. iBCI devices are now being used to control a broader range of effectors, including robotic prosthetics and digital technologies. Although most (69.6%) studies reported outcome measures prospectively, these primarily related to decoding (69.6%) and task performance (62.5%), with only 17.9% assessing clinical outcomes. When cassessed, clinical outcomes were highly heterogeneous due to varied approaches across target populations. iBCIs show potential to restore functional independence at scale. However, challenges remain around cross-subject generalization, scalable implantation, and outcome standardization. Novel measures should be developed collaboratively with engineers, clinicians, and individuals with lived experience of motor impairment
PPAR-δ orchestrates a prometastatic metabolic response to microenvironmental cues in pancreatic cancer.
No full textThe pronounced desmoplastic response in pancreatic ductal adenocarcinoma (PDAC) contributes to the development of a microenvironment depleted of oxygen and nutrients. To survive in this hostile environment, PDAC cells employ various adaptive mechanisms that may represent therapeutic targets. Here, we showed that nutrient starvation and microenvironmental signals commonly present in PDAC tumors activate PPAR-δ to rewire cellular metabolism and promote invasive and metastatic properties both in vitro and in vivo. Mild mitochondrial inhibition induced by low-dose etomoxir or signals from tumor-associated macrophages altered the lipidome and triggered the downstream transcriptional program of PPAR-δ. Specifically, PPAR-δ reduced mitochondrial oxygen consumption and boosted the glycolytic capacity by altering the ratio of MYC and PGC1A expression, two key regulators of pancreatic cancer metabolism. Notably, genetic or pharmacological inhibition of PPAR-δ prevented this metabolic rewiring and suppressed both invasiveness in vitro and metastasis in vivo. These findings establish PPAR-δ as a central driver of metabolic reprogramming in response to starvation and tumor microenvironmental cues that promotes a pro-metastatic phenotype in PDAC, suggesting that PPAR-δ inhibition could serve as a therapeutic strategy to combat PDAC progression
Spatial Organisation of Tumour cDC1 States Correlates with Effector and Stem-Like CD8+ T Cells Location.
No full textCD8+ T cells are central to targeting and eliminating cancer cells. Their function is critically supported by type 1 conventional dendritic cells (cDC1s), which both prime antigen-specific CD8+ T cells in tumour-draining lymph nodes (tdLNs) and sustain primed CD8+ T cells within tumours. Despite their importance, the spatiotemporal organisation of cDC1s within tumours and their diverse functional roles remain poorly understood. Here, we use scRNAseq and unbiased spatial analysis to construct a detailed map of cDC1 states and distribution within immunogenic mouse tumours during CD8+ T-cell-mediated rejection. We reveal two distinct cDC1 activation states characterised by differential expression of genes linked to anti-tumour immunity, including Cxcl9 and Il12b. Strikingly, Il12b-expressing cDC1s are CCR7+ and enriched at tumour borders, where they closely associate with stem-like TCF1+ CD8+ T cells. In contrast, CCR7- Cxcl9-expressing cDC1s are preferentially found within the tumour parenchyma alongside effector CD8+ T cells. Analysis of a published dataset of human tumours similarly reveals a spatial association between CCR7+ cDC1 and stem-like TCF1+ CD8+ T cells. These findings uncover a highly spatially coordinated interaction between cDC1s and CD8+ T cells within tumours, shedding light on the intricate cellular dynamics that underpin effective anti-tumour immunity
WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain acute myeloid leukaemia growth.
No full textThe lack of curative therapies for acute myeloid leukaemia (AML) remains an ongoing challenge despite recent advances in the understanding of the molecular basis of the disease. Here we identify the WNK1-OXSR1/STK39 pathway as a previously uncharacterised dependency in AML. We show that genetic depletion and pharmacological inhibition of WNK1 or its downstream phosphorylation targets OXSR1 and STK39 strongly reduce cell proliferation and induce apoptosis in leukaemia cells in vitro and in vivo. Furthermore, we show that the WNK1-OXSR1/STK39 pathway controls mTORC1 signalling via regulating amino acid uptake through a mechanism involving the phosphorylation of amino acid transporters, such as SLC38A2. Our findings underscore an important role of the WNK1-OXSR1/STK39 pathway in regulating amino acid uptake and driving AML progression
Blood and urine early treatment response biomarkers in HIV-associated disseminated tuberculosis
No full textBackground: Treatment response biomarkers are needed in the care of patients hospitalised with HIV-associated tuberculosis (TB).Objectives: We describe the changes in bacillary load during early treatment using quantitative and semi-quantitative measures of Mycobacterium tuberculosis in blood and urine.Method: We collected serial blood and urine samples at multiple timepoints in consenting adult patients with HIV and positive urine lipoarabinomannan (LAM), admitted to Mitchells Plain Hospital, Cape Town. Blood and urine Xpert Ultra, mycobacterial blood culture and urine LAM were performed. Survival analysis and mixed-effects modelling were used to determine time to a negative test, and to give the predicted probability of a positive test at the different timepoints.Results: Sixteen participants, predominantly male (63%), with median age 39 years (interquartile range [IQR] 36–43), and CD4 count 27 cells/mm3 (IQR 8–83) were included. At day 14, urine LAM, urine Xpert Ultra and blood Xpert Ultra remained positive in between 75% and 86% of the participants. A mixed-effects model predicted a decline in ordinal values of urine Xpert Ultra (cycle threshold), blood Xpert Ultra (cycle threshold) and blood culture (time-to-positivity) in response to anti-TB treatment. Conversely, urine LAM grade intensity increased over the 14 days.Conclusion: M. tuberculosis DNA was detectable in urine and blood in decreasing quantity up to 14 days of standard treatment in patients with HIV-associated TB. Urine Alere LAM showed an increasing grade intensity during this period. Further research in larger groups and extended periods are needed to assess relation to clinical outcomes