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Nutrients activate distinct patterns of small-intestinal enteric neurons.
No full textThe ability to detect and respond appropriately to ingested nutrients is essential for an organism's survival and to ensure its metabolic demands are met. Nutrient signals from the gut lumen trigger local intestinal reflexes in the enteric nervous system (ENS) to facilitate digestion and absorption1-4, but the precise cellular pathways that are involved in the initial neuronal sensory process remain unclear. The extent to which the ENS is capable of discerning different luminal chemicals is also unknown. Here we use calcium imaging to identify specific enteric pathways that are activated in response to luminal nutrients applied to mouse jejunum. Notably, we show that different nutrients activate neurochemically defined ensembles of myenteric and submucosal neurons. Furthermore, we find that enteric neurons are not directly sensitive to nutrients but detect different luminal chemicals through the epithelium, mainly via a serotonin signalling pathway. Finally, our data reveal a spatial distribution of luminal information along the radial axis of the intestine, whereby some signals that originate from the villus epithelium are transmitted first to the myenteric plexus, and then back to the submucosal plexus, which is closer to the lumen
Sensing of extracellular l-proline availability by the integrated stress response determines the outcome of cell competition.
No full textCell competition is a conserved fitness quality control that eliminates cells that are less fit than their neighbors. How winner cells induce the elimination of losers is poorly understood. We tackle this question by studying the onset of embryonic differentiation in mice, where cell competition eliminates 35% of embryonic cells. These loser cells have mitochondrial dysfunction, which we show causes amino acid deprivation and activation of the integrated stress response (ISR), a pathway essential for their survival. We demonstrate that l-proline is a key amino acid sensed by the ISR and that proline represses the ISR and drives their elimination. These results indicate that cell competition acts as a previously unidentified tissue-sparing mechanism, regulated by the availability of extracellular amino acids, that allows for the elimination of dysfunctional cells when amino acids are plentiful but ensures their survival in nutrient-poor environments
The role of extracellular matrix viscoelasticity in development and disease.
No full textFor several decades, research has studied the influence of the extracellular matrix (ECM) mechanical properties in cell response, primarily emphasising its elasticity as the main determinant of cell and tissue behaviour. However, the ECM is not purely elastic; it is viscoelastic. ECM viscoelasticity has now emerged as a major regulator of collective cell dynamics. This review highlights recent findings on the role of ECM viscoelasticity in development and pathology
Impact of metformin on HBV replication: No evidence of suppression in vitro.
No full textBACKGROUND: Outcomes of chronic Hepatitis B (CHB) infection have been increasingly associated with various metabolic syndromes, including metabolic-dysfunction associated steatotic liver disease (MASLD), with a potential for impact on liver disease progression. There is some evidence that metformin, a widely used anti-diabetic drug, may reduce hepatocellular carcinoma (HCC) incidence in people living with Hepatitis B Virus (HBV), but with little to no evidence of impact on the virus itself in vivo. However, previous in vitro studies suggest metformin may have a direct impact on HBV replication, although the mechanism remains unclear. OBJECTIVES: We aimed to investigate the impact of metformin on HBV replication in vitro. STUDY DESIGN: Hepatocyte cell lines constitutively expressing HBV (HepAD38) were treated once or thrice with escalating doses of metformin, using lamivudine and water as controls. We monitored cellular cytotoxicity as well as HBV biomarkers (HBeAg, HBsAg, HBV DNA and RNA) throughout the assay. RESULTS: We did not observe any impact of metformin on HBV replication after a single dose or three repeated treatments. CONCLUSIONS: In HepAD38 cells, HBV replication is not impacted by metformin treatment. This contrasts with prior in vitro data but is in line with clinical evidence that suggests metformin acts through an influence on liver disease progression rather than a direct antiviral impact on HBV itself
Spatiotemporal dynamics of the oropharyngeal microbiome in a cohort of Ivorian school children.
No full textThe respiratory tract harbours microorganisms of the normal host microbiota which are also capable of causing invasive disease. Among these, Neisseria meningitidis a commensal bacterium of the oropharynx can cause meningitis, a disease with epidemic potential. The oral microbiome plays a crucial role in maintaining respiratory health. An imbalance in its composition is associated with increased risk of invasive disease. The main objective of this study was to evaluate changes in the spatio-temporal dynamics of the oropharyngeal microbiota considering meningococcal carriage in a cohort of 8-12-year-old school children within (Korhogo) and outside (Abidjan) of the meningitis belt of Côte d'Ivoire. A significant geographic difference in the oropharyngeal microbiome was identified between the two study sites in terms of bacterial abundance and diversity (p < 0.001), with greater diversity in children in Abidjan than in Korhogo. Meningococcal carriage was low in the cohort with eight Neisseria carriers identified in Korhogo (3.64%) including one Neisseria meningitidis (0.45%). No Neisseria were detected in Abidjan indicating geographical differences in carriage (p = 0.006). Negative correlations were also found between Neisseria abundance and humidity. Meningococcal carriage was very low during the study; however, Neisseria carriage differed between the two study areas, with a higher frequency in children in Korhogo. Analysis of the oropharyngeal microbiome showed significant differences between children followed in Abidjan and Korhogo with higher microbial diversity in Abidjan, which is generally associated with better health status. Significant correlations between Neisseria or other pathogens carriage and climatic variables (Temperature, Relative humidity, and Wind speed) were also demonstrated, indicating an important role of climate in the carriage of these bacteria; an important element to note in the current context of climate change
GPU-accelerated bone image analysis in BoneJ
No full textPoster presented as part of the Crick BioImage Analysis Symposium 2025.Permission has been given by authors to upload to Crick Figshare.Copyright remains with the original authors.</p
LCMS files for the manuscript <b><i>Mycobacterium tuberculosis</i></b><b> overcomes phosphate starvation by extensively remodelling its lipidome with phosphorus-free lipids.</b>
No full textLCMS files generated during the work Mycobacterium tuberculosis overcomes phosphate starvation by extensively remodelling its lipidome with phosphorus-free lipids.200812_RG200123 is the polar metabolite dataset, experiment 1 of 2WT 1,2,3,4,5,6,7,8delglpQ1 17,18,19,20,21,22210212_RG201202 is the polar metabolite dataset, experiment 2 of 2.WT 37,38,39,40,41,42delglpQ1 43,44,45,46,47,48delglpQ1::glpQ1_Pimyc 62,63,64,65,66,67210219_RG201202 is the standard phosphate lipidomics dataset, experiment 1of 2WT 1,2,3,4,6delglpQ1 7,8,9,10,11,12delglpQ1::glpQ1_Pimyc 26,27,28,29210823_RG210423 is the standard lipidomics dataset, experiment 2 of 2.WT 2,3,4,5,6delglpQ1 7,8,10,11,12delglpQ1::glpQ1_Pimyc 25,26,27,28,29220107_RG211125 is the zero vs 25mM phosphate lipidomics dataset 1 of 2WT zero Pi: 1,2,3,4,5,6delglpQ1 zero Pi: 7,8,9,10,11,12delglpQ1::glpQ1_Pimyc zero Pi: 13,14,15,16,17,18delglpq1::glpq1_Pimyc 25mM Pi: 31, 32,33,34,35220307_RG220201 is the zero vs 25mM phosphate lipidomics dataset 2 of 2WT zero Pi: 1,2,3,4,5,6delglpQ1 zero Pi: 7,8,9,10,11.delglpQ1::glpQ1_Pimyc zero Pi: 13,14,15,16,17,18delglpq1::glpq1_Pimyc 25mM Pi: 31,32,33,34,35,36</p
Add in a virus: four cases of severe Kawasaki disease and concurrent adenovirus infection
No full textBackground
Kawasaki disease is an idiopathic systemic vasculitis which predominantly occurs in young children. Approximately one third of children with Kawasaki disease have a concurrent acute infection. Several cases of severe and complicated Kawasaki disease in the setting of concurrent adenovirus infection have been described in the literature.
Case presentations
Four children, between the ages of 9 months and 2 ½ years, presented to two centres in South Africa between October 2023 and March 2024 with simultaneous adenovirus infection and Kawasaki disease. All four cases fulfilled American Heart Association 2017 diagnostic criteria for typical Kawasaki disease. Adenovirus infection was confirmed by polymerase chain reaction testing of nasopharyngeal aspirate specimens and, in one case, was further confirmed on pleural fluid analysis. A unifying feature of these four cases was marked severity of Kawasaki disease. All four cases were complicated by macrophage activation syndrome. Two patients exhibited IVIG resistance, defined by recrudescent fever more than 36 h after initial IVIG therapy, and two children developed coronary artery abnormalities. These children were primarily managed with IVIG therapy. Two patients received multiple IVIG doses due to IVIG resistance. All four patients received adjuvant steroid therapy, which was indicated for macrophage activation syndrome. All four children were discharged after several weeks. Disease resolution was confirmed at follow up in three of four cases; one patient was lost to follow up.
Conclusions
These cases are illustrative of the challenges of distinguishing between acute infections and Kawasaki disease, and managing cases with concurrent infection. We postulate that adenovirus infection may trigger immune dysregulation in at-risk children, resulting in a hyperinflammatory syndrome which is clinically consistent with Kawasaki disease and macrophage activation syndrome
Causes, associated exposures, and outcomes of cirrhosis and hepatocellular carcinoma in Malawi: an observational cohort and case-control study.
No full textBACKGROUND: African countries have the highest age-standardised mortality from liver disease. We studied patients with cirrhosis and hepatocellular carcinoma in Malawi to ascertain the causes, associated exposures, and outcomes after discharge, and identify opportunities for intervention strategies. METHODS: In this case-control cohort study, we recruited patients aged 16 years or older who met the study definitions for cirrhosis or hepatocellular carcinoma from the Queen Elizabeth Central Hospital in Blantyre, Malawi. In the cirrhosis group, we excluded patients with a liver stiffness greater than 12 kPa if a cause of potential false elevation of liver stiffness was identified and a liver ultrasound did not show signs of cirrhosis; people with extrapulmonary tuberculosis or other non-hepatic causes of ascites; and pregnant people. In the hepatocellular carcinoma group, we excluded those with an extrahepatic malignancy or ultrasound features consistent with liver metastases, pregnant people, and indeterminate lesions as determined by consultant radiologists on serial ultrasounds. Research nurses identified potential participants on medical and surgical wards, the medical outpatient clinic, and endoscopy unit, using systematic case notes review and clinician referral during weekdays. Patients were followed up for 6 months. A community sample was recruited from the catchment area of the hospital to estimate the general population prevalence of diseases and exposures potentially associated with liver disease. For hepatitis B and C, we conducted a serological survey in individuals aged 16 years or older who were randomly selected from a census, and we randomly selected a proportion of individuals who were HBsAg positive or HBsAg negative to estimate the general population prevalence of HIV, alcohol, smoking, diabetes, hepatitis D and E, and autoimmune hepatitis serological markers. We estimated population attributable fractions (PAFs) for cirrhosis and hepatocellular carcinoma using community controls and the serological survey. PAFs were estimated from logistic regression models adjusted for age and sex, using the Bruzzi method with percentile bootstrap confidence intervals. FINDINGS: Between Nov 1, 2017, and April 30, 2019, we prospectively screened 708 patients and enrolled 138 diagnosed with cirrhosis and 78 diagnosed with hepatocellular carcinoma. Patients had a median age of 40 years (IQR 35-51), 134 (62%) were male, and 82 (38%) were female. In those with hepatocellular carcinoma, median tumour size was 13·2cm (10·2-17·3) and median survival was 40 days (95% CI 30-51). The community sample comprised 3258 individuals with hepatitis B and 1661 with hepatitis C identified from the serological survey, and 120 individuals negative for HBsAg and 94 people who were HBsAg positive from the serological survey to estimate the general population prevalence of HIV, alcohol, smoking, diabetes, hepatitis D and E, and autoimmune hepatitis serological markers. At 6 months, 83 (60%) of 130 patients with cirrhosis and six (8%) of 78 patients with hepatocellular carcinoma were still alive. Hepatitis B was the main attributable cause of cirrhosis (PAF 25·3% [17·5-33·3]) and hepatocellular carcinoma (73·1% [62·6-82·9]). HIV was the second leading attributable exposure associated with cirrhosis (22·2% [12·2-32·2]) and hepatocellular carcinoma (18·0% [4·8-30·9]); the association persisted after adjusting for hepatitis B virus co-infection. For hepatocellular carcinoma (but not cirrhosis), smoking (23·6% [8·9 to 37·2]) and alcohol (14·5 [-0·2 to 28·4]) were secondary attributable exposures. Autoimmune hepatitis (five [4%] patients), primary biliary cholangitis (four [3%] patients), and hepatitis C (two [1%] patients) were uncommon causes of cirrhosis, and no patients in either group had hepatitis D or E viraemia. INTERPRETATION: Hepatitis B is the leading cause of cirrhosis and hepatocellular carcinoma in Malawi. HIV was diagnosed at a much higher rate among patients with cirrhosis and hepatocellular carcinoma than community controls; it is uncertain whether the relationship is causal or influenced by confounding. Alcohol and smoking are modifiable exposures associated with hepatocellular carcinoma. Hepatocellular carcinoma and cirrhosis are diagnosed at an advanced stage, with a poor prognosis. Community screen-and-treat programmes for hepatitis B could substantially reduce liver-related mortality in this region. FUNDING: Wellcome Trust, Bill and Melinda Gates Foundation, and German Federal Ministry of Economic Cooperation and Development
The confluence of HIV-1 and HIV-2: Implications for disease progression and insights for therapy.
No full textTwo distinct types of human immunodeficiency virus (HIV), namely, HIV-1 and HIV-2 exist. HIV-1 is responsible for the global pandemic and has an aggressive pathogenesis. On the contrary, HIV-2 is not only less aggressive but also confined to West and Central African regions. Even after four decades of HIV research, a scalable cure or effective vaccine against HIV remains elusive. Consequently, the concept of a functional cure or vaccine, targeting to limit disease progression, allowing sufficient time for the immune response to clear the virus, has gained traction. Efforts to identify new therapeutic targets for development of a functional cure have focused on elite controllers, that is, individuals who naturally control HIV-1 infection in the absence of antiretroviral therapy. However, little progress has been associated with these efforts perhaps due to the scarcity of elite controllers, who make up only 0.15% of HIV-1 infected population globally. A distinct but largely unexplored subset of HIV patients comprise HIV-1 and HIV-2 dually infected individuals. This group of patients naturally presents with an attenuated disease progression phenotype akin to natural controllers. In this review, we discuss the attenuated disease progression phenomenon in dually infected individuals and offer potential explanations for this unanticipated observation. Additionally, we propose potential therapeutic and/or vaccine strategies that could leverage interactions of HIV-1 and HIV-2. Such strategies are likely to inform alternative therapeutics. A thorough understanding of the mechanism underlying the attenuated disease progression phenotype in HIV dually infected individuals is crucial for the design of a functional cure