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Miranda, A.

Publications and source records attributed to Miranda, A..

At least 19 recordsLinked to original sources

MillionTrees: A global benchmark for tree detection across geography, sensor, and annotation geometry

Airborne tree monitoring using remotely sensed data, combined with the growth of computer vision models for object detection and segmentation, can facilitate broad scale assessment of tree health, ecology and ecosystem function. However, datasets for airborne tree detection have been largely limited to a single geography, resolution, or annotation approach, making it difficult to develop general models and benchmark their utility for broad applications. We compile existing and newly published annotation datasets to create a comprehensive dataset for training and evaluating airborne tree detection in RGB imagery. The MillionTrees dataset has over a million individual trees from a broad range of forest types, tree species, and geographic locations. In addition, it has six million weakly supervised annotations from a range of sources including airborne LiDAR and photogrammetry, arborist surveys, and simulated landscapes. An evaluation standard is provided to facilitate rapid model development. We benchmark several existing tree detection algorithms and demonstrate that while current open-source models do not generalize across the diverse datasets in the benchmark, training on MillionTrees improves both within-domain and out-of-domain performance. Held-out validation datasets using ground truth derived from terrestrial LiDAR paired with overhead RGB show that overfitting to test data is common and hyperparameter tuning is an underappreciated challenge towards a global zero shot tree detection method. We discuss the limitations of the currently available data for airborne RGB tree detection, how to create more robust evaluation data and the need for better understanding of the uncertainty and utility of tree detection from airborne remote sensing.

ecology↗

CD44-CD206 axis drives dendritic cell loss and immunosuppression in immaturely glycosylated bladder tumours

Antigen-presenting-cell dysfunction drives immune exclusion, but how tumour glycans disable these cells remains incompletely defined. Immature O-glycosylation, marked by Tn and sialyl-Tn antigens, drives myeloid dysfunction in bladder cancer. Transcriptomics and human tumour profiling linked this state to reduced representation of antigen-presenting myeloid cells and attenuated lymphoid-effector programmes. In glycoengineered models, immature O-glycans promoted immunoregulatory macrophage phenotypes and contact-dependent death of monocyte-derived dendritic cells (moDCs), while surviving cells showed impaired maturation and T-cell activation. Tumour-cell CD44 standard isoform was required for DC death, which was accompanied by inflammasome-associated proteins and gasdermin D cleavage, consistent with pyroptosis. Receptor-discovery approaches converged on CD206, which bound immaturely glycosylated CD44. CD206 blockade restored DC viability. In immunocompetent mice, immature glycosylation accelerated tumour growth and depleted conventional DCs, whereas CD206 blockade restrained tumour progression and restored local and nodal myeloid and lymphoid immunity. These findings identify CD44-CD206 as a targetable glycoimmune checkpoint that promotes immune exclusion.

immunology↗

ZNF687 couples bone marrow myeloid progenitor dynamics toosteoclastogenesis in severe Paget's disease of bone

Pagets disease of bone (PDB) is a late-onset skeletal disorder characterized by excessive osteoclast-mediated bone remodelling and disorganized bone deposition. The P937R mutation in the ZNF687 gene causes a severe form of PDB complicated by giant cell tumour transformation. Although ZNF687 has been implicated in osteoclastogenesis, whether it regulates upstream haematopoietic progenitor dynamics and bone marrow myeloid output remains unclear. Using a constitutive Zfp687 knock-out mouse model, we showed that Zfp687 loss causes postnatal growth restriction, reduced bone marrow cellularity, impaired osteoclast differentiation in vitro and in vivo, and increased trabecular bone mass during adulthood. Flow cytometry revealed a marked reduction in osteoclast progenitors and macrophages in Zfp687-deficient bone marrow, whereas the pagetic P937R mutation promoted the expansion of the same myeloid populations in the Zfp687P937R knock-in mouse model. Single-cell RNA sequencing of bone marrow-derived c-Kit+ haematopoietic progenitors further demonstrated that Zfp687 loss selectively disrupted the myeloid progenitor compartment. This analysis identified 22 transcriptionally distinct populations and revealed a significant depletion of the early cycling granulocyte-monocyte progenitor cluster, without evidence of a global block in myeloid differentiation. Mechanistically, Zfp687 deficiency impaired the Brd4-c-Myc-NFATc1 axis in osteoclastogenic precursors and reduced Csf1 expression in bone marrow stromal and osteoblastic cells, linking intrinsic transcriptional competence to niche-derived M-CSF support. In pagetic patient iPSCs-derived haematopoietic progenitors, the P937R mutation enhanced clonogenic haematopoietic output, accelerated colony formation, and promoted the expansion of primitive/multipotent colony-forming progenitors, leading to hypercellular myeloid colonies. Together, our findings establish ZNF687 as a regulator of haematopoietic progenitor dynamics that couples bone marrow myeloid output to osteoclastogenesis, providing a progenitor-level mechanism for severe ZNF687-related PDB.

cancer biology↗

Multimodal Hypersampling of the adult human heart resolves tissue-specific cell states and disease-associated variants

Cardiovascular diseases often arise in anatomically specialised regions of the heart that remain poorly represented in existing single-cell and spatial atlas references. Here we profiled 28 regions of the adult human heart from 36 donors, combining paired single-nucleus RNA and chromatin accessibility assays with spatial transcriptomics. The resulting atlas integrates 1,059,175 expression profiles and 452,614 chromatin accessibility profiles, and defines spatial niches across the heart. In cardiac valves, we identify a valve fibroblast-macrophage niche that is polarised to the non-fibrosa surface and expands with age. Aortic stenosis genetic risk was enriched in inflammatory regulatory programmes of the Valve Fibroblast Immune cell state. In pulmonary veins, we define PITX2+ Myocardial Sleeve Cells, a region-restricted cardiomyocyte population in which a fine-mapped 4q25 atrial fibrillation variant intersects a cell type-specific open chromatin region. In coronary arteries, we resolve a RUNX1-marked synthetic smooth muscle layer in the subintima that provides a molecular identity for diffuse intimal thickening, a constitutive feature of the healthy vessel wall and a substrate for atherosclerosis, and show by perturbation in human smooth muscle cells that RUNX1 promotes cell-cycle entry while restraining inflammatory cytokine gene expression. Finally, allele-specific accessibility together with deep learning models fine-tuned to predict regulatory activity from DNA sequence identify cell type-specific regulatory effects at GWAS loci for atrial fibrillation, coronary artery disease and calcific aortic valve stenosis, including a variant whose Valve Fibroblast-specific effect on the polyamine transporter ATP13A3 is opposite in direction to the effect seen in bulk-tissue eQTL references that lack valve cells. Together with these cardiac sequence models and CardioSleuth, an AI-powered exploration engine for cardiac regulatory effects, this atlas links cardiac anatomy, gene regulation and disease genetics at single-cell resolution. By placing genetic risk in its precise cellular and anatomical context, it provides a foundation for mechanistic disease understanding, cell-state-specific therapeutic target nomination, and improved interpretation of inherited cardiovascular risk to inform future therapy and management.

Cell Biology↗

CD276 Immature Glycosylation Drives Colorectal Cancer Aggressiveness and T-cell Mediated Immune Escape

Colorectal cancer (CRC) progression is fueled by immune evasion, yet the underlying molecular mechanisms remain to be fully characterized. CD276 (B7-H3), an immune checkpoint glycoprotein frequently overexpressed in aggressive tumours, is extensively modified by glycosylation, a process known to regulate protein stability, localization, and immune interactions. However, its glycosylation-dependent functions in CRC remain unclear. This study shows that poor-prognosis CRC tumours exhibit dysregulated glycogene expression, leading to an immature O-glycosylation phenotype that enhances malignancy. Using C1GALT1 knockout CRC cells, which recapitulate the cancer glycocalyx, it was demonstrated that this glycosylation shift promotes proliferation and invasion. We further identify CD276 as a metastasis-associated glycoprotein whose function is shaped by O-glycan modifications. Mechanistically, immature O-glycosylation of CD276 enhances invasion, suppresses T-cell activation, and induces an immunosuppressive cytokine milieu, reinforcing its role in tumour immune escape. These findings establish CD276 as a glycosylation-dependent immune checkpoint and a promising therapeutic target to overcome immune evasion in CRC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/668091v1_ufig1.gif" ALT="Figure 1"> View larger version (101K): org.highwire.dtl.DTLVardef@2af030org.highwire.dtl.DTLVardef@fee9a8org.highwire.dtl.DTLVardef@19e1c49org.highwire.dtl.DTLVardef@152fd73_HPS_FORMAT_FIGEXP M_FIG C_FIG Table of ContentsColorectal cancer (CRC) progression is closely linked to immune evasion, yet the molecular mechanisms underlying this process remain poorly understood. This study identifies CD276 (B7-H3) as a glycosylation-driven regulator of CRC aggressiveness and demonstrates how O-glycosylation remodeling promotes tumour immune escape. These findings establish CD276 as a potential therapeutic target and highlight the role of glycoproteoform-specific immune modulation in cancer progression.

cancer biology↗

Preclinical evaluation of CHDI-009R for quantification of mutant huntingtin aggregates

Huntingtons disease (HD) is a neurodegenerative disorder caused by an expanded trinucleotide repeat in the huntingtin gene (HTT) that subsequently leads to aggregation of the mutant huntingtin (mHTT) protein. Thus, lowering mHTT is a key therapeutic approach used by several candidate therapeutics currently under investigation. Visualization of the efficiency of these therapeutics through in vivo mHTT quantification rises in importance. For positron emission tomography (PET) imaging of mHTT aggregates, it is critical to characterize the in vivo kinetic profile of newly identified mHTT binders to assess their translational application. Here, we report the evaluation of [11C]CHDI-009R, a PET imaging radioligand with higher affinity and selectivity for mHTT aggregates than previously reported radioligands, in the heterozygous (HET) zQ175DN mouse model of HD and wild-type (WT) littermates at 9 and 3 months of age. [11C]CHDI-009R displayed high stability in plasma and brain, which was reflected in brain kinetics as demonstrated by rapid uptake followed by relatively slow elimination. Kinetic modeling and volume of distribution VT (IDIF) indicated the radioligands ability to quantify mHTT aggregation at 9 months of age with clear genotype differentiation (p<0.0001). [11C]CHDI-009R showed an excellent test-retest reliability in 9-month-old mice (intraclass correlation coefficient: 0.62 - 0.79). A phenotypic difference in mHTT aggregates was also observed in 3-month-old mice in several brain structures (p<0.05) and was confirmed with [3H]CHDI-009R autoradiography. Overall, this study suggests [11C]CHDI-009R is a promising radioligand for the detection of cerebral mHTT aggregates in a mouse model of HD and supports its advance to clinical evaluation.

neuroscience↗

Prognostically favorable immune responses to ovarian cancer are distinguished by self-reactive intra-epithelial plasma cells

Tumor-infiltrating B cells (TIL-Bs) are strongly associated with patient survival; however, the underlying mechanisms are poorly understood. Using integrated single-cell and spatial biology approaches, we defined at clonal resolution the molecular phenotypes, tumor reactivity patterns, and microenvironmental locations of TIL-Bs in high-grade serous ovarian cancer (HGSC). Prognostic benefit was associated with a TIL-B-rich tumor microenvironment with marked infiltration of malignant epithelium by plasma cells (PCs). PCs spanned five molecular phenotypes; exhibited high rates of somatic hypermutation and clonal expansion; and expressed predominantly IgG1 antibodies recognizing broadly expressed nuclear, cytoplasmic, and cell surface self-antigens. Many PC-derived antibodies were polyreactive. Self- and poly-reactive TIL-Bs penetrated tumor epithelium and stroma and expressed interferon-stimulated genes, indicating strong in situ activation. The self- and poly-reactive nature of TIL-B responses, reminiscent of autoimmune disease, may provide a means for the immune system to combat tumor heterogeneity and could potentially be harnessed for more effective immunotherapy.

cancer biology↗

Targeting lysosomal damage is a new therapeutic perspective for Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD), a muscle degenerative disease affecting young boys, arises from the loss of dystrophin. Current gene therapy approaches aim to restore a shortened form of dystrophin (microdystrophin) via Adeno-Associated Vector (AAV) delivery, but clinical studies show limited efficacy, emphasizing the need for improved strategies such as combined therapies. In this study, we identified lysosomal perturbations in the myofibers of DMD patients and animal models, an overlooked mechanism of cellular damage in muscular dystrophies. These were notably marked by the upregulation and recruitment of Galectin-3, a known biomarker of lysosomal membrane permeabilization, to damaged lysosomes, alongside alterations in lysosome number, morphology, and activation of endolysosomal damage response. Importantly, microdystrophin therapy in Dmdmdx mice fails to fully correct these damages. However, combining it with trehalose, a lysosome-protective disaccharide, significantly improves outcome, enhancing muscle function, histology and transcriptome. These findings highlight lysosomal damage as a novel mechanism in DMD pathogenesis and suggest that combining trehalose with gene therapy could enhance therapeutic efficacy. TeaserLysosomal damage contributes to DMD pathology and is an interesting therapeutic target worth considering for current and future approaches.

physiology↗

GlycoAvatars: Bead-Coated Membrane Models for Studying the Cancer-Immune Cells Interactome

Immature O-glycosylation of plasma membrane proteins, characterized by the presence of glycosites with a single GalNAc residue (the Tn antigen) rather than more extended and complex glycans, is a prominent feature of many advanced solid tumors across different origins and aetiologies. This form of glycosylation has been strongly associated with poor prognosis and is known to play a crucial role in the progression of the disease. Notably, it has been directly implicated in the crosstalk with the immune system, inducing tolerogenic phenotypes in both innate and adaptive immune cells. Despite this, the specific receptors involved in these interactions remain largely unidentified. To address this gap, we propose a novel high-throughput proteomics assisted strategy for characterizing the glycan interactome using plasma membrane-derived glycoprotein coated magnetic beads. Glycoproteins were isolated from plasma membranes of glycoengineered cell models with immature glycosylation and were then cloaked on the surface of magnetic beads, creating simplified cell "GlycoAvatars." These GlycoAvatars were primarily employed to characterize the interactome between gastric and colorectal cancer cell lines and immune cells (dendritic cells and macrophages), providing a tool for identifying potentially relevant molecular nodes in glycan-mediated immune synapses, foreseeing their application in deciphering tumor-immune interactions.

biochemistry↗

Preclinical validation and kinetic modelling of the SV2A PET ligand UCB-J in mice

Synaptic vesicle protein 2A (SV2A) is ubiquitously expressed in presynaptic terminals where it functions as a neurotransmission regulator protein. Synaptopathy has been reported during healthy ageing and in a variety of neurodegenerative diseases. Positron emission tomography (PET) imaging of SV2A can be used to evaluate synaptic density. The PET ligand [11C]UCB-J has high binding affinity and selectivity for SV2A but has a short physical half-life due to the 11C isotope. Here we report the characterization and validation of its 18F-labeled equivalent, [18F]UCB-J, in terms of specificity, reproducibility and stability in C57BL/6J mice. Plasma analysis revealed at least one polar radiometabolite. Kinetic modelling was performed using a population-based metabolite corrected image-derived input function (IDIF). [18F]UCB-J showed relatively fast kinetics and a reliable measure of the IDIF-based volume of distribution (VT(IDIF)). [18F]UCB-J specificity for SV2A was confirmed through a levetiracetam blocking assay (50 to 200 mg/kg). Reproducibility of the VT(IDIF) was determined through test-retest analysis, revealing significant correlation (r2=0.773, p<0.0001). Time-stability analyses indicate a scan duration of 60 min to be sufficient to obtain a reliable VT(IDIF). In conclusion, [18F]UCB-J is a selective SV2A ligand with optimal kinetics in mice. Further investigation is warranted for (pre)clinical applicability of [18F]UCB-J in synaptopathies.

neuroscience↗

Preclinical evaluation of the novel CHDI-650 PET ligand for non-invasive quantification of mutant huntingtin aggregates in Huntington's disease

PurposePositron emission tomography (PET) imaging of mutant huntingtin (mHTT) aggregates is a potential tool to monitor disease progression as well as the efficacy of candidate therapeutic interventions for Huntingtons disease (HD). To date, the focus has been mainly on the investigation of 11C radioligands; however, favourable 18F radiotracers will facilitate future clinical translation. This work aimed at characterising the novel [18F]CHDI-650 PET radiotracer using a combination of in vivo and in vitro approaches in a mouse model of HD. MethodsAfter characterising [18F]CHDI-650 using in vitro autoradiography, we assessed in vivo plasma and brain radiotracer stability as well as kinetics through dynamic PET imaging in the heterozygous (HET) zQ175DN mouse model of HD and wild-type (WT) littermates at 9 months of age. Additionally, we performed a head-to-head comparison study at 3 months with the previously published [11C]CHDI-180R radioligand. ResultsPlasma and brain radiometabolite profiles indicated a suitable metabolic profile for in vivo imaging of [18F]CHDI-650. Both in vitro autoradiography and in vivo [18F]CHDI-650 PET imaging at 9 months of age demonstrated a significant genotype effect (p<0.0001) despite the poor test-retest reliability. [18F]CHDI-650 PET imaging at 3 months of age displayed higher differentiation between genotypes when compared to [11C]CHDI-180R. ConclusionOverall, [18F]CHDI-650 allows for discrimination between HET and WT zQ175DN mice at 9 and 3 months of age. [18F]CHDI-650 represents the first suitable 18F radioligand to image mHTT aggregates in mice and its clinical evaluation is underway.

neuroscience↗

Multilevel Plasticity and Altered Glycosylation Drive Aggressiveness in Hypoxic and Glucose-Deprived Bladder Cancer Cells

Bladder tumours with aggressive characteristics often present with microenvironmental niches marked by low oxygen levels (hypoxia) and limited glucose supply due to inadequate vascularization. The molecular mechanisms facilitating cellular adaptation to these stimuli remain largely elusive. Employing a multi-omics approach, we discovered that hypoxic and glucose- deprived cancer cells enter a quiescent state supported by mitophagy, fatty acid {beta}-oxidation, and amino acid catabolism, concurrently enhancing their invasive capabilities. Reoxygenation and glucose restoration efficiently reversed cell quiescence without affecting cellular viability, highlighting significant molecular plasticity in adapting to microenvironmental challenges. Furthermore, cancer cells exhibited substantial perturbation of protein O-glycosylation, leading to simplified glycophenotypes with shorter glycosidic chains. Exploiting glycoengineered cell models, we established that immature glycosylation contributes to reduced cell proliferation and increased invasion. Our findings collectively indicate that hypoxia and glucose deprivation trigger cancer aggressiveness, reflecting an adaptive escape mechanism underpinned by altered metabolism and protein glycosylation, providing grounds for clinical intervention.

biochemistry↗

Ovipin: a chicken eggs antibiotic agent

The intensive and indiscriminate use of antibiotic has increased cases of microorganisms resistance and becoming a worldwide public health problem. In the last years, from natural sources such as hens egg, have received special attention in the discovery of new bioactive compounds. This study aims to identify and characterize a new peptide from chicken egg of Gallus gallus domesticus. The chicken egg was subjected the extraction acid, the supernatant was prefractionated in Sep- Pak column and fractionated peptide by reverse-phase high-performance liquid chromatography (RP-HPLC). The antimicrobial activity of the fractions were evaluated through liquid growth inhibition assays. The molecular weight and amino acid sequence was determined by mass spectrometry (MS/MS), the characaterization performed by bioinformatics analysis with Peaks(R) tool and comparision with the NCBI and UniProt-SwisProt database. The physicochemical parameters of the samples were evaluated with online programs. One fraction named Ovipin peptide, showed antimicrobial activity against Gram-positive bacteria (Micrococcus luteus - MIC 1.94 {micro}M) and Filamentous fungus (Aspergillus niger - MIC 31.01 {micro}M). The minimum inhibitory concentration against Cryptococcus neoformans VNI (WM 148) Yeast was 15.51 {micro}M, this microorganism an opportunistic yeast and mainly binds in immunosuppressed or immunocompromissed people. Ovipin is a hydrophoic peptide and not cause significant hemolytic effect against human erythrocytes. Ovipin primary sequence is YVSPVAIVKGLNIPL and a molecular weight of 1,581.94 Da. Ovipin shows 100% and 93.3%, respectively, sequence similarity with the fragments Apolipoprotein B of Gallus gallus and Apolipoprotein B of five others species of Aves. Our data suggest that Ovipin peptide could be a potential therapeutic candidate to be used an alternative against infections developed by resistant microorganisms, mainly in the fight against Cryptococcus neoformans opportunistic yeast.

microbiology↗

Glycoproteogenomics characterizes the CD44 splicing code driving bladder cancer invasion

Bladder cancer (BC) management demands the introduction of novel molecular targets for precision medicine. Cell surface glycoprotein CD44 has been widely studied as a potential biomarker of BC aggressiveness and cancer stem cells. However, significant alternative splicing and multiple glycosylation generate a myriad of glycoproteoforms with potentially distinct functional roles. The lack of tools for precise molecular characterization has led to conflicting results, delaying clinical applications. Addressing these limitations, we have interrogated the transcriptome of a large BC patient cohort for splicing signatures. Remarkable CD44 heterogeneity was observed, as well as associations between short CD44 standard splicing isoform (CD44s), invasion and poor prognosis. In parallel, immunoassays showed that targeting short O-glycoforms could hold the key to improve CD44 cancer specificity. This prompted the development of a glycoproteogenomics approach, building on the integration of transcriptomics-customized datasets and glycomics for protein annotation from nanoLC-ESI-MS/MS experiments. The concept was applied to invasive human BC cell lines, glycoengineered cells, and tumor tissues, enabling unequivocal CD44s identification. Finally, we confirmed the link between CD44s and invasion in vitro by siRNA knockdown, supporting findings from BC tissues. The key role played by short-chain O-glycans in CD44-mediated invasion was also demonstrated through glycoengineered cell models. Overall, CD44s emerged as biomarker of poor prognosis and CD44-Tn/STn as promising molecular signatures for targeted interventions. This study materializes the concept of glycoproteogenomics and provides a key vision to address the cancer splicing code at the protein level, which may now be expanded to better understand CD44 functional role in health and disease. Significance StatementThe biological role of CD44, a cell membrane glycoprotein involved in most cancer hallmarks and widely explored in BC, is intimately linked to its protein isoforms. mRNA alternative splicing generates several closely related polypeptide sequences, which have so far been inferred from transcripts analysis, in the absence of workflows for unequivocal protein annotation. Dense O-glycosylation is also key for protein function and may exponentiate the number of proteoforms, rendering CD44 molecular characterization a daunting enterprise. Here, we integrated multiple molecular information (RNA, proteins, glycans) for definitive CD44 characterization by mass spectrometry, materializing the concept of glycoproteogenomics. BC specific glycoproteoforms linked to invasion have been identified, holding potential for precise cancer targeting. The approach may be transferable to other tumors, paving the way for precision oncology.

cancer biology↗

A novel imaging ligand as a biomarker for mutant huntingtin-lowering in Huntington's disease

Huntingtons disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (PolyQ) tract. While several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, no method is currently available to visualize mHTT levels in the living brain. Here we demonstrate the development of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11C ([11C]CHDI-180R) enables non-invasive monitoring of mHTT pathology in the brain and can track region-and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression. We further show that therapeutic agents that lower mHTT in the striatum have a functional restorative effect that can be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.

neuroscience↗

Open Targets Genetics: An open approach to systematically prioritize causal variants and genes at all published GWAS trait-associated loci

Genome-wide association studies (GWAS) have identified many variants robustly associated with complex traits but identifying the gene(s) mediating such associations is a major challenge. Here we present an open resource that provides systematic fine-mapping and protein-coding gene prioritization across 133,441 published human GWAS loci. We integrate diverse data sources, including genetics (from GWAS Catalog and UK Biobank) as well as transcriptomic, proteomic and epigenomic data across many tissues and cell types. We also provide systematic disease-disease and disease-molecular trait colocalization results across 92 cell types and tissues and identify 729 loci fine-mapped to a single coding causal variant and colocalized with a single gene. We trained a machine learning model using the fine mapped genetics and functional genomics data using 445 gold standard curated GWAS loci to distinguish causal genes from background genes at the same loci, outperforming a naive distance based model. Genes prioritized by our model are enriched for known approved drug targets (OR = 8.1, 95% CI: [5.7, 11.5]). These results will be regularly updated and are publicly available through a web portal, Open Targets Genetics (OTG, http://genetics.opentargets.org), enabling users to easily prioritize genes at disease-associated loci and assess their potential as drug targets.

genetics↗

Simultaneous 3D super-resolution fluorescence microscopy and atomic force microscopy: combined SIM and AFM platform for cell imaging

Correlating data from different microscopy techniques holds the potential to discover new facets of signaling events in cellular biology. Here we report for the first time a hardware set-up capable of achieving simultaneous imaging of spatially correlated super-resolution fluorescence microscopy and atomic force microscopy, a feat only obtained until now by fluorescence microscopy set-ups with spatial resolution restricted to the Abbe resolution limit. We hereby remove the need to perform independent measurement and subsequent data averaging required to eliminate cell-to-cell variation in observed signals. We detail system integration, demonstrate system performance and report imaging of sub-resolution fluorescent beads and genome-engineered human bone osteosarcoma epithelial cells.

cell biology↗

Cancer stemness, intratumoral heterogeneity, and immune response across cancers

Regulatory programs that control the function of stem cells are active in cancer and confer properties that promote progression and therapy resistance. However, the impact of a stem cell-like tumor phenotype (\"sternness\") on the immunological properties of cancer has not been systematically explored. Using gene expression-based metrics, we evaluate the association of stemness with immune cell infiltration and genomic, transcriptomic, and clinical parameters across 21 solid cancers. We find pervasive negative associations between cancer stemness and anticancer immunity. This occurs despite high stemness cancers exhibiting increased mutation load, cancer-testis antigen expression, and intratumoral heterogeneity. Stemness was also strongly associated with cell-intrinsic suppression of endogenous retroviral expression and type I interferon signaling and increased expression of several therapeutically accessible signaling pathways. Thus, stemness is not only a fundamental process in cancer progression but may represent a unifying mechanism linking antigenicity, intratumoral heterogeneity, and immune suppression across cancers.

cancer biology↗