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Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of esophageal cancer.
No full textCDKN2A is a tumor suppressor located in chromosome 9p21 and frequently lost in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). How CDKN2A and other 9p21 gene co-deletions affect EAC evolution remains understudied. We explored the effects of 9p21 loss in EACs and cancer progressor and non-progressor BEs with matched genomic, transcriptomic and clinical data. Despite its cancer driver role, CDKN2A loss in BE prevents EAC initiation by counterselecting subsequent TP53 alterations. 9p21 gene co-deletions predict poor patient survival in EAC but not BE through context-dependent effects on cell cycle, oxidative phosphorylation and interferon response. Immune quantifications using bulk transcriptome, RNAscope and high-dimensional tissue imaging showed that IFNE loss reduces immune infiltration in BE, but not EAC. Mechanistically, CDKN2A loss suppresses the maintenance of squamous epithelium, contributing to a more aggressive phenotype. Our study demonstrates context-dependent roles of cancer genes during disease evolution, with consequences for cancer detection and patient management
The bat influenza A virus subtype H18N11 induces nanoscale MHCII clustering upon host cell attachment.
No full textPrior to the discovery of bat influenza A virus (IAV) subtypes H17N10 and H18N11, all IAVs were thought to bind sialic acid residues via hemagglutinin (HA) to mediate attachment and subsequent viral entry. However, H17 and H18 engage a proteinaceous receptor: the major histocompatibility complex class II (MHCII). The mechanistic details of this hitherto unknown protein-mediated entry are not understood. Given that conventional IAVs rely on multivalent binding to sialylated glycans, we hypothesized that bat HA similarly interacts with multiple MHCII molecules. Using photoactivated localization microscopy (PALM) on fixed and live cells, we demonstrate that bat IAV particles attach to pre-existing MHCII clusters and induce a further increase in cluster size upon binding. To measure the impact of viral attachment on the dynamics of MHCII, we employ an "inverse attachment" approach, immobilizing viral particles on coverslips before seeding live MHCII-expressing cells on top. Single-molecule tracking reveals that the mobility of MHCII is indeed slowed down in viral proximity leading to a local enrichment of MHCII molecules beneath the viral particle. These findings suggest that viral attachment induces MHCII clustering, a process similar to the MHCII dynamics observed during the formation of an immunological synapse
Cardiometabolic biomarkers and systemic inflammation in US adolescents and young adults with latent tuberculosis infection: a population-based cohort study
No full textBackground
Mycobacterium tuberculosis (M.tb) infection in adults increases incident type 2 diabetes and atherosclerotic cardiovascular disease risk. It is unknown if this cardiometabolic detriment occurs in the young. We investigated whether young persons with latent tuberculosis infection (LTBI) have worse cardiometabolic health than uninfected peers.
Methods
Peripubescent adolescents (12-15 years old) and older adolescents/young adults (16-30 years old) were assessed for LTBI by tuberculin skin testing (induration ≥10mm). Outcomes included fasting plasma glucose (FPG), HbA1c, c-peptide, NTproBNP, hs-Troponin T, CRP, ferritin, diabetes/prediabetes (FPG ≥5.6 mmol/L and/or HbA1c ≥5.7%) and homeostatic model of insulin resistance (HOMA2-IR). LTBI cases were propensity score-matched 1:4 with TB-uninfected controls on sociodemographics to estimate adjusted median (adjMedian), mean differences (adjMD), and odds ratios (adjOR) of cardiometabolic indices.
Results
Seventy-five LTBI cases were matched with 300 TB uninfected peers. Among older participants, LTBI associated with higher inflammation [adjMedian (IQR) CRP: 0.22 (0.05, 0.34) vs. 0.11 (0.04, 0.35) mg/dL; p=0.027; ferritin: 55.0 (25.1, 90.3) vs. 41.1 (29.5, 136.2) ng/mL; p=0.047], but not among peripubescent adolescents. No meaningful differences were observed in FPG [adjMD (95%CI): -0.05 (-0.22, 0.12) mmol/L; p=0.57], HbA1c [0.0 (-0.17, 0.17) %; p=0.98] or diabetes/prediabetes prevalence [adjOR (95%CI): 0.9 (0.29, 2.29); p=0.85], insulin secretion/resistance, NTproBNP, or hs-Troponin T by LTBI status.
Conclusion
Older adolescents and young adults with LTBI had higher inflammation than those without LTBI while cardiometabolic profiles were similar. Unlike adults, M.tb infection in young people may not be associated with cardiometabolic derangement, though the longterm consequences of chronic inflammation require further study
Mechanotransduction as a therapeutic target for brain tumours
No full textDespite decades of research, treatment options for many paediatric and adult brain tumours remain inadequate. Mechanotransduction, a process by which cells convert mechanical cues into biochemical signals, resulting in the activation of signalling cascades, is crucial in the progression of aggressive brain tumours such as glioblastoma (GBM). In GBM, a stiffened extracellular matrix accompanies the aberrant expression of mechanosensitive ion channels, including Piezo and transient receptor potential (TRP) channels, impacting brain tumour progression and therapeutic response. Thus, targeting these ion channels and associated signalling pathways may provide effective adjuvant therapy. Focused ultrasound (FUS) is an emerging technology being explored in diagnostic and therapeutic applications within oncology and has the potential to non-invasively modulate mechanosensitive pathways. Here, we discuss recent findings, highlighting how mechanobiology is altered in brain tumours, the potential of mechanosensitive ion channels as therapeutic targets and perspectives on using FUS to exploit aberrant brain tumour mechanobiology to provide non-invasive adjuvant therapy. At the intersection of cancer cell biology and biomedical engineering, this review offers a perspective on leveraging mechanotransduction for therapeutic advances in brain tumours
Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia.
No full textT-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy commonly driven by NOTCH1 activating mutations. A concomitant feature associated with NOTCH1 mutations is heightened oxidative metabolism enabling the exponential proliferation of T-ALL blasts. As such, targeting mitochondrial metabolism in T-ALL is an attractive therapeutic avenue. Related to this, canagliflozin (cana), is an FDA-approved sodium glucose co-transporter 2 inhibitor with known off-target effects on complex I and glutamate dehydrogenase, but its potential anti-leukaemic effects remain unexplored. Here, we show that cana possesses potent anti-leukaemic effects underpinned by proliferative defects, cell cycle disruption and apoptosis. These anti-leukaemic effects driven by cana, are attributed to a perturbed tricarboxylic acid (TCA) cycle and mitochondrial metabolism, and elevated mitochondrial ROS. Proteomic analysis revealed that cana treatment resulted in a compensatory increase in the expression of ATF4 targets, including upregulation of serine biosynthesis pathway and one-carbon metabolism enzymes. As such, restriction of serine and glycine synergized with cana treatment, further enhancing its anti-leukaemic effects. Collectively, our study reveals a cana-driven metabolic vulnerability that can be further exploited via dietary manipulation to treat T-ALL
Functional specialisation of multisensory temporal integration in the mouse superior colliculus.
No full textOur perception of the world depends on the brain's capacity to integrate information from multiple senses, with timing differences serving as crucial cues for binding or segregating cross-modal signals. The superior colliculus (SC) is a central hub for such integration, yet the contributions of its distinct regions remain poorly understood. Here we show, from recordings of over 5000 neurons in awake mice, that multisensory neurons reliably encode audiovisual delays through nonlinear integration of auditory and visual inputs. This nonlinearity enhances the precision of delay representation, with posterior-medial SC populations representing the peripheral sensory field showing superior temporal discriminability. Connectivity analyses reveal stronger coupling in the medial SC and function-specific recurrent networks, with multisensory neurons receiving about half of their local input from other multisensory neurons. Together, these results demonstrate how nonlinear integration, regional specialisation, and network architecture combine to support robust sensory binding and accurate encoding of temporal multisensory information
Clinical trials for Hepatitis Delta Virus in the WHO African region: A neglected virus among neglected viruses.
No full textOBJECTIVES: We set out to evaluate the extent to which Hepatitis Delta Virus (HDV) Clinical Trials (CT) include populations from the World Health Organisation (WHO) African region, aiming to highlight inequities and advocate for global investment in inclusive HDV research. METHODS: We screened the clinicaltrial.gov and the WHO International Clinical Trials Registry Platform (ICTRP) repositories for 'Hepatitis Delta virus' and 'HDV' related CT. Datasets were merged using R v.4.2.1. We classified studies according to location and associated WHO region. RESULTS: We identified a total of 47 CT on HDV, mainly conducted in Europe (69.3%), Western Pacific (19.6%) and the Americas (8.5%). Despite the highest estimated anti-HDV seroprevalence in the general population, there were no CT registered in the WHO African region. CT are still predominantly done in the regions of initial drug discovery, as seen with bulevirtide (Europe) and lonafarnib (Americas). CONCLUSION: HDV-focused CT are needed in the WHO African region, as the region with the highest disease burden, and unique genotypes (5-8); to evaluate efficacy of novel anti-HDV compounds and to ensure that new treatments can be distributed and deployed as they become available
Protocol for rapid 5-plex 3D imaging and single-cell analysis of immune responses in whole murine lymph nodes.
No full textLymph nodes orchestrate adaptive immune responses, with germinal centers enabling affinity maturation and plasma cell formation. Here, we present a protocol for rapid, high-resolution, multicolor 3D imaging of whole immunized mouse lymph nodes. We describe steps for immunization, lymph node harvesting, fixation, permeabilization, staining, and clearing. We cover image acquisition using a light sheet fluorescence microscope and analysis using the Imaris software. This protocol allows the quantification of germinal center B cells, plasma cells, and follicular T cells at single-cell resolution
Making sense of oxygen sensing.
No full textHomeostatic control of cellular oxygen availability is a crucial feature of all eukaryotic life, and central to this process is the ability to sense oxygen across a broad range of concentrations and time scales. Much of our understanding of the molecular mechanisms underpinning oxygen sensing has been obtained using cell culture models, yet the biophysical properties of oxygen combined with the complex nature of cellular O2 consumption can make the interpretation of such data difficult. In this commentary, we have outlined some of the main problems encountered in measuring and manipulating cell monolayer oxygenation in vitro, and contextualised them using both historical and contemporary examples
PEtab.jl: advancing the efficiency and utility of dynamic modelling.
No full textSUMMARY: Dynamic models represent a powerful tool for studying complex biological processes, ranging from cell signalling to cell differentiation. Building such models often requires computationally demanding modelling workflows, such as model exploration and parameter estimation. We developed two Julia-based tools: SBMLImporter.jl, an SBML importer, and PEtab.jl, an importer for parameter estimation problems in the PEtab format, designed to streamline modelling processes. These tools leverage Julia's high-performance computing capabilities, including symbolic pre-processing and advanced ODE solvers. PEtab.jl aims to be a Julia-accessible toolbox that supports the entire modelling pipeline from parameter estimation to identifiability analysis. AVAILABILITY AND IMPLEMENTATION: SBMLImporter.jl and PEtab.jl are implemented in the Julia programming language. Both packages are available on GitHub (github.com/sebapersson/SBMLImporter.jl and github.com/sebapersson/PEtab.jl) as officially registered Julia packages, installable via the Julia package manager. Each package is continously tested and supported on Linux, macOS, and Windows. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online