Biology subjects

Tiniakos, D.

Publications and source records attributed to Tiniakos, D..

5 recordsLinked to original sources

bioRxiv2025

STExplorer: Navigating the Micro-Geography of Spatial Omics Data

Spatial transcriptomics (ST) has the potential to provide unprecedented insights into gene expression across tissue architecture, but existing analytical methods often overlook the full complexity of the spatial dimension. We present STExplorer, an R package that adapts well-established computational geography (CG) methods to explore the micro-geography of spatial omics data. By incorporating techniques like Geographically Weighted Principal Component Analysis (GWPCA), Fuzzy Geographically Weighted Clustering (FGWC), Geographically Weighted Regression (GWR), and analyses of observation Spatial Autocorrelation (SA), STExplorer enables the uncovering of spatially resolved patterns that capture the spatial heterogeneity of biological data. STExplorer provides a complete suite of functions for spatial analyses and visualisations, supporting deeper biological understanding and inference. Built on the Bioconductor ecosystem, the package integrates with SpatialFeatureExperiment objects, ensuring compatibility with existing pipelines. It includes preprocessing capabilities such as data import, quality control, gene count normalisation, and variable gene selection, alongside tools for downstream analysis and detailed visualisations that quantify and map spatial heterogeneity and relationships. We demonstrate the utility of STExplorer through applications to spatial transcriptomics datasets, revealing that spatially varying gene expression and relationships are often masked by standard analyses. By bridging bioinformatics and CG, STExplorer provides a novel and informed approach to spatial transcriptomics analysis, with robust tools to address spatial heterogeneity and its associated underlying biology, thereby advancing our understanding of complex tissue biology without reinventing the wheel.

bioinformatics↗

bioRxiv2025

Morpho-functional timeline of progressive cystic fibrosis pancreatic exocrine and endocrine pathology derived from semi-quantitative scoring and AI-driven quantitativeimage analysis

Cystic fibrosis (CF) is associated with pancreatic exocrine insufficiency (PEI) early in life and diabetes in up to 50% of adults. The underlying CF-related sequential changes within the pancreas associated with exocrine and endocrine insufficiency remain incompletely understood due to scarcity of available human tissue, protracted disease course and absence of established robust and reproducible analytical approaches. This study aimed to develop and apply a systematic analysis cross-sectionally to CF pancreatic tissue samples from donors over a wide age range to construct a timeline related to the main exocrine and endocrine changes underlying progressive disease. Based on a histopathological semi-quantitative scoring system and AI-driven quantitative image analysis pancreatic changes were individually evaluated and classified according to three patterns: fibrotic; fibrotic and lipotic; and lipoatrophic. This systematic evaluation was applied to 29 CF and 58 control donors without pancreatic disease. Rapid loss of acinar tissue with virtually complete absence by the age of 7 years was confirmed, mirrored by fatty tissue replacement - changes underlying PEI and likely preceding progression towards diabetes. Ductal blockage by thickened secretions was associated with increasing ductal dilatation accompanied by peri-ductal fibrosis, followed by ductal loss with involution of associated fibrosis in parallel with increasing adipocyte proportional area (PA). Remaining ducts were relatively small surrounded by residual fibrosis. Islets became increasingly clustered initially surrounded by activated pancreatic stellate cells (PSCs) and fibrosis and then disorganised by interposing fibrotic tissue between endocrine cell regions and surrounded by residual collagen stranding in a lipoatrophic pancreas. Overall islet mass was not significantly reduced but {beta}-cell PA was significantly reduced from birth without further loss over time. We concluded that the natural history of pancreatic CF progresses inexorably from peri-ductal fibrosis to global fat replacement with relatively well-maintained islet mass but PSC-associated fibrotic islet remodelling circumstantially implicated in {beta}-cell failure.

pathology↗

bioRxiv2024

Compromised chronic efficacy of a Glucokinase Activator AZD1656 in mouse models for common human GCKR variants

Glucokinase activators (GKAs) have been developed as blood glucose lowering drugs for type 2 diabetes. Despite good short-term efficacy, several GKAs showed a decline in efficacy chronically during clinical trials. The underlying mechanisms remain incompletely understood. We tested the hypothesis that deficiency in the liver glucokinase regulatory protein (GKRP) as occurs with common human GCKR variants affects chronic GKA efficacy. We used a Gckr-P446L mouse model for the GCKR exonic rs1260326 (P446L) variant and the Gckr-del/wt mouse to model transcriptional deficiency to test for chronic efficacy of the GKA, AZD1656 in GKRP-deficient states. In the Gckr-P446L mouse, the blood glucose lowering efficacy of AZD1656 (3 mg/kg body wt) after 2 weeks was independent of genotype. However after 19 weeks, efficacy was maintained in wild-type but declined in the LL genotype, in conjunction with raised hepatic glucokinase activity and without raised liver lipids. Sustained blood glucose lowering efficacy in wild-type mice was associated with qualitatively similar but more modest changes in the liver transcriptome compared with the P446L genotype, consistent with GKA therapy representing a more modest glucokinase excess than the P446L genotype. Chronic treatment with AZD1656 in the Gckr-del/wt mouse was associated with raised liver triglyceride and hepatocyte microvesicular steatosis. The results show that in mouse models of liver GKRP deficiency in conjunction with functional liver glucokinase excess as occurs in association with common human GCKR variants, GKRP-deficiency predisposes to declining efficacy of the GKA in lowering blood glucose and to GKA induced elevation in liver lipids.

pharmacology and toxicology↗

bioRxiv2020

Macrophage Scavenger Receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the exact mechanisms remain incompletely understood. Here we demonstrate that macrophage scavenger receptor 1 (MSR1, CD204) expression is associated with the occurrence of hepatic lipid-laden foamy macrophages and correlates with the degree of steatosis and steatohepatitis in a cohort of 170 NAFLD patients. Mice lacking Msr1 are protected against high fat-cholesterol diet (HFD)-induced metabolic disorder, showing fewer hepatic lipid-laden foamy macrophages, less hepatic inflammation, improved dyslipidemia and glucose tolerance, while showing a change in hepatic lipid metabolism. We show that MSR1 induces a pro-inflammatory response via the JNK signaling pathway upon triggering by saturated fatty acids. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNFa. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and ex vivo human liver slices resulted in the prevention of foamy macrophage formation and liver inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate transaminase levels in a cohort of over 400,000 patients. Taken together, our data suggest a critical role for MSR1 in lipid homeostasis and a potential therapeutic target for the treatment of NAFLD. One Sentence SummaryThe immunometabolic role of MSR1 in human NAFLD.

immunology↗

bioRxiv2018

Regulation of checkpoint kinase signalling and tumorigenesis by the NF-κB regulated gene, CLSPN

Inhibition of the tumour promoting activities of NF-{kappa}B by cell signalling pathways has been proposed as a natural mechanism to limit the development of cancer. However, there has been a lack of evidence for these effects in vivo. Here we report that RelAT505A mice, where a CHK1 targeted Thr505 phosphosite is mutated to alanine, display earlier onset of MYC driven lymphoma than wild type littermates. We describe a positive feedback loop in which the NF-{kappa}B subunits RelA and c-Rel, in a manner dependent upon RelA Thr505 phosphorylation, drive the expression of the ATR checkpoint kinase regulator Claspin in response to DNA replication stress in cancer cells. This in turn is required for maintenance of CHK1 activity. Loss of a single allele of the Clspn gene in mice is sufficient to drive earlier tumorigenesis and low levels of CLSPN mRNA expression are associated with worse survival in some forms of human cancer. We propose that loss of this pathway early in tumorigenesis promotes cancer development through increased genomic instability. However, in malignant cancer cells it can help promote their addiction to the checkpoint kinase signalling required for the maintenance of genomic integrity. Importantly, disruption of this pathway leads to resistance of cells to treatment with CHK1 inhibitors. Claspin expression could therefore act as a biomarker for responsiveness of patients to CHK1 inhibitors and provide a potential pathway for the development of tumour resistance.

cancer biology↗