Biology subjects

Das, S.

Publications and source records attributed to Das, S..

At least 271 records · Page 15Linked to original sources

bioRxiv2022

The crosstalk between microbial sensors ELMO1 and NOD2 shape intestinal immune responses

Microbial sensors play an essential role in maintaining cellular homeostasis. Our knowledge is limited on how microbial sensing helps in differential immune response and its link to inflammatory diseases. Recently, we have shown that cytosolic sensor ELMO1 (Engulfment and Cell Motility Protein-1) binds to effectors from pathogenic bacteria and controls intestinal inflammation. Here, we show that ELMO1 interacts with another sensor, NOD2 (Nucleotide-binding oligomerization domain-containing protein 2), that recognizes bacterial cell wall component muramyl dipeptide (MDP). The polymorphism of NOD2 is linked to Crohns disease (CD) pathogenesis. Interestingly, we found that overexpression of ELMO1 and mutant NOD2 (L1007fs) were not able to clear the CD-associated adherent invasive E. coli (AIEC-LF82). To understand the interplay of microbial sensing of ELMO1-NOD2 in epithelial cells and macrophages, we used enteroid-derived monolayers (EDMs) from ELMO1 and NOD2 KO mice and ELMO1 and NOD2-depleted murine macrophage cell lines. The infection of murine EDMs with AIEC-LF82 showed higher bacterial load in ELMO1-KO, NOD2 KO EDMs, and ELMO1 KO EDMs treated with NOD2 inhibitors. The murine macrophage cells showed that the downregulation of ELMO1 and NOD2 is associated with impaired bacterial clearance that is linked to reduced pro-inflammatory cytokines and reactive oxygen species. Our results indicated that the crosstalk between microbial sensors in enteric infection and inflammatory diseases impacts the fate of the bacterial load and disease pathogenesis.

microbiology↗

bioRxiv2022

Machine Learning Identifies Signatures of Macrophage Reactivity and Tolerance that Predict Disease Outcomes

Single-cell transcriptomic studies have greatly improved organ-specific insights into macrophage polarization states are essential for the initiation and resolution of inflammation in all tissues; however, such insights are yet to translate into therapies that can predictably alter macrophage fate. Using machine learning algorithms on human macrophages, here we reveal the continuum of polarization states that is shared across diverse contexts. A path, comprised of 338 genes accurately identified both physiologic and pathologic spectra of "reactivity" and "tolerance", and remained relevant across tissues, organs, species and immune cells (> 12,500 diverse datasets). This 338-gene signature identified macrophage polarization states at single-cell resolution, in physiology and across diverse human diseases, and in murine pre-clinical disease models. The signature consistently outperformed conventional signatures in the degree of transcriptome-proteome overlap, and in detecting disease states; it also prognosticated outcomes across diverse acute and chronic diseases, e.g., sepsis, liver fibrosis, aging and cancers. Crowd-sourced genetic and pharmacologic studies confirmed that model-rationalized interventions trigger predictable macrophage fates. These findings provide a formal and universally relevant definition of macrophage states and a predictive framework (http://hegemon.ucsd.edu/SMaRT) for the scientific community to develop macrophage-targeted precision diagnostics and therapeutics. One Sentence SummarySignatures of macrophage reactivity and tolerance (SMaRT) predict disease outcomes

systems biology↗

bioRxiv2022

Neutrophils reprograms the bone marrow to impair T-cell immunity during tuberculosis

Mycobacterium tuberculosis (Mtb) infection induces persistent influx of neutrophils that associates with poor bacterial control and clinical outcome from tuberculosis (TB). Although implicated in TB pathology, the mechanism by which these cells contribute to pathogenesis is poorly understood. Using Cell-DIVE multiplexed immunofluorescence imaging and spatial analysis of inflammatory TB lesions, we demonstrated that persistent neutrophil infiltration affects the spatiotemporal organization of T-lymphocytes and impairs their function. Instead of directly suppressing T-cells, neutrophils produce granulocyte colony stimulating factor (CSF3/G-CSF) that collaborates with type I interferon (IFN-I) to promote a granulocyte-skewed hematopoiesis impacting T-lymphocyte production. Importantly, neutrophil-intrinsic IFN-I receptor 1 (IFNAR1) is both necessary and sufficient to promote pathologic granulopoiesis. Finally, inhibition of IFNAR1-signaling alone mitigates immunopathogenesis by restoring hematopoietic equilibrium. Collectively, our work uncovers a potential immunevasion strategy by which virulent Mtb strains induce IFN-I to generate pathogen-permissive neutrophils that produce G-CSF and sustain pathogenic hematopoiesis to impair T-cell immunity during TB.

immunology↗

bioRxiv2022

Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid beta aggregates in vivo in a mouse model of Alzheimer's disease

BackgroundReactive oxidative stress is a critical player in the amyloid beta (A{beta}) toxicity that contributes to neurodegeneration in Alzheimers disease (AD). Mitochondrial damage, observed in AD, is one of the main sources of reactive oxygen species. Although A{beta} causes neuronal mitochondria-associated reactive oxidative stress in vitro, this has never been directly observed in the in vivo living brain. Here, we tested whether A{beta} plaques and soluble oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether the neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants. MethodsWe expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease, and performed intravital multiphoton microscopy of neuronal mitochondria and A{beta} plaques. ResultsFor the first time, we demonstrated by direct observation exacerbated mitochondrial oxidative stress in neurons after both A{beta} plaque deposition and direct application of soluble oligomeric A{beta} onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. ConclusionsConsidering these results, mitochondria-targeted compounds hold promise as neuroprotective drugs for the prevention and/or treatment of AD.

neuroscience↗

bioRxiv2022

Glioma-BioDP: Database for Visualization of Molecular Profiles to Improve Prognosis of Brain Cancer

Cancer researchers often seek user-friendly interactive tools for validation, exploration, analysis, and visualization of molecular profiles in cancer patient samples. To aid researchers working on both low-and high-grade gliomas, we developed Glioma-BioDP, a web tool for exploration and visualization of RNA and protein expression profiles of interest in these tumor types. Glioma-BioDP is an extended version of our earlier published tool GBM-BioDP. In this version we have included expression data from both the low-and high-grade glioma patient samples from The Cancer Genome Atlas and enabled querying by mRNA, microRNA, and protein level expression data from Illumina HiSeq and RPPA platforms respectively. Glioma-BioDP enables users to explore the association of genes, proteins, and miRNA expression with molecular and/or histological subtypes of gliomas, surgical resection status and survival. The prognostic significance and visualization of the selected expression profiles can be explored using interactive utilities provided. This tool also enables potential validation and generation of new hypotheses of novel therapies impacting gliomas that aid in personalization of treatment for optimum outcomes. AvailabilityGlioma-BioDP web tool with user manual is available from: https://glioma-biodp.nci.nih.gov Contact: uma@mail.nih.gov

cancer biology↗

bioRxiv2022

Denaturation resistant P2 tetramer imports fatty acids from human serum into intraerythrocytic Plasmodium falciparum

The initiation of asymmetric karyokinesis of intraerythrocytic Plasmodium falciparum (Pf) begins without dismantling the nuclear envelope showing the hallmark feature of closed mitosis (1-10). In Pf, karyokinesis precedes cytokinesis and cell body formation (6, 8-10). Regulation at the beginning of nuclear division either through checkpoints or by importing serum components was largely unknown. At the trophozoite stage, PfP2 tetramer trafficked to the infected erythrocyte (IE) surface and the inaccessibility of IE surface PfP2 to its bonafide ligand led to the arrest of nuclear division (11-13). Here we show that PfP2 tetramer localization on the IE surface and the beginning of nuclear division are concomitant in nature. Synthetically induced denaturation resistant PfP2 tetramer interacts with human serum fatty acids and phospholipids for its import into IEs at the beginning of karyokinesis. In the natively folded denaturation resistant PfP2 tetramer cage, the Cys-Cys redox switch regulates the binding and subsequent release of fatty acids on the IE surface. This mechanistic insight of fatty acids import inside IEs using synthetically induced denaturation resistant PfP2 tetramer provides an unique drug screening platform for novel small molecule screening against malaria.

molecular biology↗

bioRxiv2022

Spatially Resolved Metabolites in Stable and Vulnerable Human Atherosclerotic Plaques Identified by Mass Spectrometry Imaging

Impairments in carbohydrate, lipid, and amino acid metabolism drive features of plaque instability. However, where these impairments occur within the atheroma remains largely unknown. Therefore, we sought to characterize the spatial distribution of metabolites within stable and unstable atherosclerosis in both the fibrous cap and necrotic core. Atherosclerotic tissue specimens were scored based on the Stary classification scale and subdivided into stable and unstable atheromas. After performing mass spectrometry imaging (MSI) on these samples, we identified over 850 metabolite-related peaks. Using MetaboScape, METASPACE, and HMDB, we confidently annotated 170 of these metabolites and found over 60 of these were different between stable and unstable atheroma. We then integrated these results with an RNA-sequencing dataset comparing stable and unstable human atherosclerosis. Upon integrating our MSI results with the RNA-seq dataset, we discovered that pathways related to lipid metabolism and long-chain fatty acids were enriched in stable plaques, whereas reactive oxygen species, aromatic amino acid, and tryptophan metabolism were increased in unstable plaques. Acylcarnitines and acylglycines were increased in stable plaques whereas tryptophan metabolites were enriched in unstable plaques. Evaluating spatial differences in stable plaques revealed lactic acid in the necrotic core, whereas pyruvic acid was elevated in the fibrous cap. In unstable plaques, 5-hydroxyindole-acetic acid was enriched in the fibrous cap. Our work herein represents the first step to defining an atlas of metabolic pathways involved in plaque destabilization in human atherosclerosis. We anticipate this will be a valuable resource and open new avenues of research in cardiovascular disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/494038v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@111368org.highwire.dtl.DTLVardef@1112d99org.highwire.dtl.DTLVardef@c8cdb2org.highwire.dtl.DTLVardef@13895d6_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2022

The "LINC" in between Δ40p53-miRNA axis in the regulation of cellular processes

Previous research has shown that {Delta}40p53, the translational isoform of p53, can inhibit cell growth independently of p53 by regulating microRNAs. Here, we explored the role of {Delta}40p53 in regulating the long non-coding RNA-microRNA-cellular process axis, specifically focusing on LINC00176. Interestingly, LINC00176 levels were predominantly affected by the overexpression/stress-mediated induction and knockdown of {Delta}40p53 rather than p53 levels. Additional assays revealed that {Delta}40p53 transactivates LINC00176 transcriptionally and could also regulate its stability. RNA immunoprecipitation experiments revealed that LINC00176 sequesters several putative microRNA targets, which could further titrate several mRNA targets involved in different cellular processes. To understand the downstream effects of this regulation, we ectopically overexpressed and knocked down LINC00176 in HCT116 p53-/- (harboring only {Delta}40p53) cells, which affected their proliferation, cell viability, and expression of epithelial markers. Our results provide essential insights into the pivotal role of {Delta}40p53 in regulating the novel LINC00176 RNA-microRNA-mRNA axis independent of FL-p53 and in maintaining cellular homeostasis.

cancer biology↗

bioRxiv2022

Green emitting carbon quantum dots (GCQDs) to probe endocytic pathways in cells; for tissue and in vivo bioimaging

Small sized, carbon-based organic nanoparticles have recently gained attention due their advantage of biocompatibility, photostability and biological non-toxicity as compared to their inorganic counterparts. Herein, a new class of small (5-8 nm), green emitting fluorescent carbon quantum dots (GCQDs) were synthesized using organic substrates like citric acid and ascorbic acid in aqueous solvent containing water and ethanol. The very small size and bright green photoluminescence prompted their use for both in vitro and in vivo bioimaging. GCQDs were uptaken via clathrin mediated pathways in mouse kidney and liver primary cells. Similarly, they showed active uptake and distribution in the zebrafish embryo model system. The optical tunability and surface modification properties of these GCQDs provide a platform to be explored for them to emerge as a new class of targeted bioimaging entities, as well as tools for biomedical applications.

bioengineering↗

bioRxiv2022

Topological Data Analysis of Human Brain Networks Through Order Statistics

Understanding the topological characteristics of the brain network across a population is central to understanding brain functions. The abstraction of human connectome as a graph has been pivotal in gaining insights on the topological features of the brain network. The development of group-level statistical inference procedures in brain graphs while accounting for the heterogeneity and randomness still remains a difficult task. In this study, we develop a robust statistical framework based on persistent homology using the order statistics for analyzing brain networks. The use of order statistics greatly simplifies the computation of the persistent barcodes. We validate the proposed methods using comprehensive simulation studies and subsequently apply to the resting-state functional magnetic resonance images. We conclude a statistically significant topological difference between the male and female brain networks. Author summaryWe fit a random graph model to the brain network and compute the expected persistent barcodes using order statistics. This novel approach significantly simplifies the computation of expected persistent barcodes, which otherwise requires complex theoretical constructs. Subsequently, the proposed statistical framework is used to discriminate if two groups of brain networks are topologically different. The method is applied in determining the sexual dimorphism in the shape of resting-state functional magnetic resonance images.

neuroscience↗

bioRxiv2022

CK2 signaling from TOLLIP-dependent perinuclear endosomes is an essential feature of KRAS mutant cancers

Oncogenic RAS induces perinuclear translocation of the effector kinases ERK and CK2 and their scaffold, KSR1, forming endosomal signaling hubs termed perinuclear signaling centers (PSCs). PSCs are present in all cancer cell lines and tissues examined, suggesting that subcellular compartmentalization of oncogenic kinases drives tumorigenesis. However, the mechanism of perinuclear targeting, whether this location affects kinase substrate specificity, and the importance of PSCs in cancer are unclear. Here we show that the endosomal adaptor, TOLLIP, specifically tethers RAB11A+ signaling endosomes containing CK2 and KSR1 to the perinuclear ER. A predicted {beta}-hairpin fold in TOLLIP mediates binding to the KSR1 CA5 pseudo-kinase domain, recruiting CK2/KSR1 complexes to perinuclear endosomes. TOLLIP is essential for proliferation/survival of tumor cells carrying KRAS and NRAS mutations but not HRAS, BRAF, ERBB or PTEN lesions, or non-transformed cells. KRasG12D-induced lung lesions in Tollip-/- mice displayed reduced numbers of carcinomatous lesions, implicating TOLLIP in malignant progression. TOLLIP-dependent perinuclear CK2 was shown to phosphorylate discrete substrates, including proteins involved in translation and ribosome biogenesis such as RIOK1. Thus, TOLLIP is a key RAS pathway signaling adaptor in K/NRAS tumors whose inhibition is a specific vulnerability of these cancers.

cancer biology↗

bioRxiv2022

Engineering Proprioceptive Implants via Surgical and Regenerative Approaches: Preliminary Interpretations

The periodontal ligaments are a group of specialized connective tissue fibres with vascular and neural elements that essentially attach a tooth to the alveolar bone. Endosseous dental implant replacing a lost tooth, gets ankylosed to the alveolar bone without intervening periodontal fibres (osseointegration). Hence, proprioception, one of the most important function of periodontal ligament is not elicited by commercial dental implants currently in use. To salvage the flaw, in our proof-of-principle trial in rabbits, biodegradable nanofibres were coiled around the additive manufactured (AM) customized titanium implants. Further, human dental pulp stem cells (DPSCs), adult mesenchymal stem cells of neuro-ectodermal origin, were seeded on the nanofibrous coated, orthotopically placed 3D-printed titanium implants and were induced to differentiate into neural cell lineages. The invivo anchoring mechanism of these biodegradable neuro-supportive scaffold coated implants could probably be "proprioceptive osseointegration" instead of defaults events leading to normal "osseointegration" and could exhibit features similar to periodontium, having possible anastomosis between the severed nerve terminals present in the wall of the extraction socket relaying to/from brain and newly differentiated neural cells present in the regenerated neo-tissue complex, gradually replacing the biodegradable scaffold and may eventually results in the development of proprioceptive osseointegrated root-form endosseous dental implants in near future.

bioengineering↗

bioRxiv2022

Evolution of Delta variant by non-Spike signature co-appearing mutations: trailblazer of COVID-19 disease outcome

The high transmissibility and infectivity of a SARS-CoV-2 variant is usually ascribed to the Spike mutations, while emerging non-spike mutations might be a serious threat to the current Spike-recombinant vaccines. In addition to mutations in structural Spike glycoprotein, rapid accumulation of mutations across non-structural genes is leading to continuous virus evolution, altering its pathogenicity. We performed whole genome sequencing of SARS-CoV-2 positive samples collected from different clinical groups from eastern India, during the second pandemic wave (April-May, 2021). In addition to the several common spike mutations in Delta variant, two mutually explicit signature constellations of non-spike co-appearing mutations were identified, driving symptomatic and asymptomatic infections. We attempted to correlate these unique signatures of non-Spike co-appearing mutations to COVID-19 disease outcome. Results revealed that the Delta strains harboring a unique constellation of 9 non-spike co-appearing mutations could be the wheeler and dealer of symptomatic infection, even post vaccination. The strains predominantly driving asymptomatic infection possessed 7 non-spike co-appearing mutations, which were mutually exclusive in contrast to the set of mutations causing symptomatic disease. Phylodynamic analysis depicted high probability of emergence of these unique sub-clusters within India, with subsequent spread worldwide. Interestingly, some mutations of this signature were selected in Omicron and IHU variants, which suggest that gradual accumulation of such co-existing mutations may lead to emergence of more "vaccine-evading variants" in future. Hence, unfaltering genome sequencing and tracking of non-Spike mutations might be significant in formulation of any future vaccines against emerging SARS-CoV-2 variants that might evade the current vaccine-induced immunity.

genomics↗

bioRxiv2022

The interplay between lncRNAs, RNA-binding proteins and viral genome during SARS-CoV-2 infection reveals strong connections with regulatory events involved in RNA metabolism and immune response.

Viral infections are complex processes based on an intricate network of molecular interactions. The infectious agent hijacks components of the cellular machinery for its profit, circumventing the natural defense mechanisms triggered by the infected cell. The successful completion of the replicative viral cycle within a cell depends on the function of viral components versus the cellular defenses. Non-coding RNAs (ncRNAs) are important cellular modulators, either promoting or preventing the progression of viral infections. Among these ncRNAs, the long non-coding RNA (lncRNA) family is especially relevant due to their intrinsic functional properties and ubiquitous biological roles. Specific lncRNAs have been recently characterized as modulators of the cellular response during infection of human host cells by single stranded RNA viruses. However, the role of host lncRNAs in the infection by human RNA coronaviruses such as SARS-CoV-2 remains uncharacterized. In the present work, we have performed a transcriptomic study of a cohort of patients with different SARS-CoV-2 viral load. Our results revealed the existence of a SARS-CoV-2 infection-dependent pattern of transcriptional up-regulation in which specific lncRNAs are an integral component. To determine the role of these lncRNAs, we performed a functional correlation analysis complemented with the study of the validated interactions between lncRNAs and RNA-binding proteins (RBPs). This combination of in silico functional association studies and experimental evidence allowed us to identify a lncRNA signature composed of six elements - NRIR, BISPR, MIR155HG, FMR1-IT1, USP30-AS1, and U62317.2 - associated with the regulation of SARS-CoV-2 infection. We propose a competition mechanism between the viral RNA genome and the regulatory lncRNAs in the sequestering of specific RBPs that modulates the interferon response and the regulation of RNA surveillance by nonsense-mediated decay (NMD). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/485903v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@4368c9org.highwire.dtl.DTLVardef@1948201org.highwire.dtl.DTLVardef@e31fd9org.highwire.dtl.DTLVardef@1400805_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstractModel of interactions among lncRNA and cognate RNA-binding proteins in SARS-CoV-2 infection. According to our model, the viral genome can establish direct interactions with three core proteins (DDX3X, UPF1 and IGF2BP2) involved in mRNA metabolism and regulation of the interferon response, which are also components of a SARS-CoV-2 lncRNA-centered regulatory network. The competition between viral RNA and lncRNAs could act as a counteracting factor for the normal function of homeostatic lncRNA-centered regulatory networks, contributing to viral progression and replication. Black arrows depict physical interactions between network components; red arrows represent functional relationships.

bioinformatics↗

bioRxiv2022

Targeting an evolutionarily conserved "E-L-L" motif in the spike protein to develop a small molecule fusion inhibitor against SARS-CoV-2

As newer variants of SARS-CoV-2 continue to pose major threats to global human health and economy, identifying novel druggable antiviral targets is the key towards sustenance. Here, we identify an evolutionary conserved "E-L-L" motif present within the HR2 domain of all human and non-human coronavirus spike (S) proteins that play a crucial role in stabilizing the post-fusion six-helix bundle (6-HB) structure and thus, fusion-mediated viral entry. Mutations within this motif reduce the fusogenicity of the S protein without affecting its stability or membrane localization. We found that posaconazole, an FDA-approved drug, binds to this "E-L-L" motif resulting in effective inhibition of SARS-CoV-2 infection in cells. While posaconazole exhibits high efficacy towards blocking S protein-mediated viral entry, mutations within the "E-L-L" motif rendered the protein completely resistant to the drug, establishing its specificity towards this motif. Our data demonstrate that posaconazole restricts early stages of infection through specific inhibition of membrane fusion and viral genome release into the host cell and is equally effective towards all major variants of concerns of SARS-CoV-2 including beta, kappa, delta, and omicron. Together, we show that this conserved essential "E-L-L" motif is an ideal target for the development of prophylactic and therapeutic interventions against SARS-CoV-2.

biochemistry↗

bioRxiv2022

An affinity-matured DLL4 ligand for broad-spectrum activation and inhibition of Notch signaling

The Notch pathway regulates cell fate decisions and is an emerging target for regenerative and cancer therapies. Recombinant Notch ligands are attractive candidates for modulating Notch signaling; however, their intrinsically low receptor-binding affinity restricts their utility in biomedical applications. To overcome this limitation, we evolved variants of the ligand Delta-like 4 (DLL4) with enhanced affinity and cross-reactivity. A consensus variant with maximized binding affinity, DeltaMAX, engages human and murine Notch receptors with 500- to 1000-fold increased affinity compared to wild-type human DLL4. DeltaMAX also potently activates human Notch in plate-bound, bead-bound, and cellular formats. When administered as a soluble decoy, DeltaMAX inhibits Notch activation in response to either Delta-like (DLL) or Jagged (Jag) ligands, highlighting its utility as both an agonist and antagonist. Finally, we demonstrate that DeltaMAX stimulates increased proliferation and expression of effector mediators in primary activated human T cells. Taken together, our data defines DeltaMAX as a versatile biotechnological tool for broad-spectrum activation or inhibition of Notch signaling.

bioengineering↗

bioRxiv2022

An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model

Hematopoietic stem and progenitor cells (HSPCs) can lead to the establishment of a long-lasting microglia-like progeny in the brain of properly myeloablated hosts. We exploited this approach to treat the severe CLN1 neurodegenerative disorder, which is the most aggressive form of neuronal ceroid lipofuscinoses, due to deficiency of palmitoyl-protein thioesterase 1 (hPPT1). We here provide first evidence that: i) transplantation of wild type HSPCs exerts a partial but long-lasting mitigation of the symptoms; ii) transplantation of HSPCs over-expressing hPPT1 by lentiviral gene transfer enhances therapeutic benefit as compared to wild type cell transplant, with first demonstration of such a dose-effect benefit for a purely neurodegenerative condition like CLN1 disease; iii) transplantation of hPPT1 over-expressing HSPCs by a novel intracerebroventricular (ICV) approach is sufficient to transiently ameliorate CLN1 disease symptomatology in the absence of hematopoietic tissue engraftment of the transduced cells; and iv) the combinatorial transplantation of transduced HSPCs intravenously and ICV results in the most robust therapeutic benefit among the tested approaches on both pre-symptomatic as well as symptomatic animals. Overall, these findings provide first evidence of the efficacy and feasibility of this novel approach to treat CLN1 disease and possibly other neurodegenerative conditions, paving the way for its future clinical application.

neuroscience↗

bioRxiv2022

PSMA-bearing extracellular vesicles secreted from prostate cancer convert the microenvironment to a tumor-supporting, pro-angiogenic state.

Extracellular vesicles (EV) are comprised of vesicles budding from cell membranes and smaller intracellular vesicles shed by cells. EV play a role in remodeling the tumor microenvironment (TME) and support tumor progression. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein with a carboxypeptidase function, frequently associated with poor clinical prognosis in prostate cancer (PCa). We previously identified an oncogenic PSMA signaling function in prostate cancer. Others demonstrated that EV isolated from the plasma of patients with high-grade PCa carry PSMA, but so far no pathophysiological effect has been associated with PSMA-bearing EV. Here we demonstrate that EV from PCa cells are able to transfer PSMA and its functionality to cells in the TME. The consequence of that EV-mediated PSMA transfer is an acute to long-term increased secretion of vascular endothelial growth factor-A (VEGF-A), angiogenin, pro-angiogenic and pro-lymphangiogenic mediators and increased 4E binding protein 1 (4EBP-1) phosphorylation in tumors. We compare EV from PCa cells with or without PSMA expression to address the role of PSMA-bearing EV in promoting pro-tumoral changes in the TME using classical molecular biology and novel molecular imaging approaches.

cancer biology↗