Biology subjects

Fernandes, R.

Publications and source records attributed to Fernandes, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Combined inhibition of AIF/CHCHD4 interaction and GLS1 to exploit metabolic vulnerabilities in pediatric osteosarcoma

Osteosarcoma is a malignant bone tumor with a high risk of metastatic relapse and poor outcomes due to primary and acquired chemoresistance. This highlights the medical need to develop effective targeted approaches to overcome chemoresistance. Recent studies have revealed the roles of metabolic reprogramming and mitochondria-nucleus crosstalk in osteosarcoma progression, indicating the potential of these cellular processes as therapeutic targets. The complex formed by mitochondrial apoptosis-inducing factor (AIF) and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) orchestrates the import and oxidative folding of cysteine-rich, nuclear-encoded proteins, thereby regulating key mitochondrial functions and metabolism. Here, we identified mitoxantrone as an inhibitor of the AIF/CHCHD4 mitochondrial import machinery and revealed a new mitoxantrone-induced metabolic vulnerability in some osteosarcoma cell line models, characterized by intracellular glutamine accumulation and an increase in nucleotide synthesis. As a result, synergy was found between mitoxantrone and the glutaminase inhibitor telaglenastat in both in vitro and in vivo osteosarcoma models. Collectively, our findings position the AIF/CHCHD4 complex as a druggable therapeutic target and provide a combination strategy for mitoxantrone/telaglenastat treatment to overcome metabolic adaptations and chemoresistance in osteosarcoma. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/716303v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1229e58org.highwire.dtl.DTLVardef@1c9af45org.highwire.dtl.DTLVardef@120d2borg.highwire.dtl.DTLVardef@11e8216_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Multi-omics analysis of TNBC organoids identifies phosphorylation of the membrane trafficking machinery as a key event associated with FER-mediated invasion

Triple Negative Breast Cancer (TNBC) is characterised by unfavourable outcome due to the combination of its metastatic propensity, chemo-refractory behaviour and the lack of effective targeted interventions. Expression of the feline sarcoma-related (FER) kinase constitutes an independent prognostic factor that correlates with poor patient survival. FER promotes invasive behaviour in TNBC cells by regulating endosomal sorting and recycling (ESR) of adhesion proteins. Yet, the ESR machinery supporting invasion in TNBC, particularly within 3D environments, remains poorly understood. Here, we used FER-expressing TNBC patient-derived xenograft organoids (PDXOs) and MDA-MB-231 cells to identify the membrane trafficking machinery promoting invasion. Using a combination of proteomics, phospho-proteomics, and single cell RNA-sequencing, we show that the invasion of FER-expressing PDXO cells in collagen-I is mainly associated with the differential phosphorylation of membrane trafficking regulators, including SEC16A and a marked increase in Rab4-positive tubules. SEC16A depletion impairs cell invasion and reduces the number of focal adhesions and Rab4-positive tubules. Importantly, FER regulates SEC16A levels and localization, specifically in TNBC. Altogether, we identified SEC16A as a key player in FER-driven TNBC invasion, highlighting the membrane trafficking machinery as a promising target for the development of new therapeutic strategies.

cancer biology↗

bioRxiv2025

Uncovering structural determinants of peptide recognition by public and private T-cell receptors

Public T cell receptors (TCRs) recurrently emerge across individuals in response to common pathogens, yet the structural and biophysical basis distinguishing public from private clonotypes remains incompletely defined. Here, we combine epitope mapping, single-cell TCR sequencing, and single-particle cryo-electron microscopy to dissect CD8+ T cell responses to the immunodominant SARS-CoV-2 ORF3a(207-215) epitope presented by HLA-A*01:01. Among responding clonotypes, we identify a shared public TCR (TCRpub) and an individual-specific private TCR (TCRpriv) that use nearly identical TRBV5-1 {beta} chains but distinct chains. Both clonotypes exhibit comparable micromolar affinity and functional avidity, yet their structures reveal different antigen-recognition modes. We determined cryo-EM structures of the TCRpub and TCRpriv in complex with ORF3a(207-215)/ HLA-A*01:01 at [~]3 [A] resolution. Despite targeting the same epitope, the two receptors engaged the peptide-MHC complex with distinct CDR-loop orientations and contact footprints: TCRpub engages the peptide through a peptide-centric AGDL CDR3{beta} motif and focuses interactions on the MHC 2-helix, whereas TCRpriv distributes contacts across both MHC -helices via a canonical CDR3{beta} configuration. These findings illustrate how near-identical {beta} chains can yield divergent recognition strategies to recognise the same pMHC ligand through alternative -chain pairing. More broadly, this work establishes cryo-EM as a robust approach for resolving physiological-affinity TCR/pMHC complexes, providing mechanistic insight into how public TCRs emerge and persist in antiviral immunity.

immunology↗

bioRxiv2025

Chromatin signalling pathways and FANCE amplification affect ATR inhibitor sensitivity in metastatic breast cancer

Metastatic breast cancer remains incurable, as many patients develop therapy resistance. Loss of ATM/p53 increases reliance on the ATR pathway, positioning ATR inhibitors (ATRi) as promising therapeutics. However, targeting a single pathway often leads to resistance due to tumour heterogeneity or alternative signalling mechanisms. Here, we combine chromatin-enrichment proteomics and phospho-proteomics with genome sequencing data in the ATRi-sensitive triple negative breast cancer (TNBC) cell line MDA-MB-453 to map adaptive responses to the ATR inhibitor AZD6738. We identify chromatin-associated activation of survival pathways, including AKT1, RPTOR (mTORC1), CDK4/5, and OGFR, alongside hyperphosphorylation of MKI67, SAFB2, and CHD4, indicating ATRi sensitivity. Complementary siRNA screening of DNA damage response (DDR) genes reveals that amplification of Fanconi anaemia (FA) pathway gene FANCE increases sensitivity to AZD6738. Analysis of breast cancer datasets highlights frequent FANCE amplification in metastatic patients, particularly in circulating tumour cells. Strikingly, pharmacological inhibition of the FA pathway (UBE2T/FANCL-IN-1) synergises with AZD6738. Together, our findings define adaptive resistance mechanisms to ATR inhibition and nominate FA pathway blockade as a rational combination strategy. Overall, our work provides fundamental insight into the complexity of DDR in metastatic breast cancer and offers a platform for mechanistic investigation, which can be exploited in cancer therapy.

cancer biology↗

bioRxiv2025

Distribution patterns of invasive alien plant species in mainland Portugal

Understanding the distribution and diversity of invasive alien species is increasingly vital to meet legal requirements and guide effective management. Portugal currently hosts a large number of invasive alien plant species, with significant environmental and socio-economic impacts. However, the distribution of most of these species in the territory and the factors driving their spread and diversity remain largely unexplored. To address this, we present the first atlas of invasive plants in mainland Portugal. A total of 96 terrestrial and aquatic invasive plants are represented, encompassing all species listed under Portuguese national legislation and the European Unions list of invasive species of concern. Occurrence data were collected from a broad array of sources, including national and international biodiversity observation databases, citizen science data, literature, and data collections owned by managers and researchers, totaling approximately 85,000 records (mean = 879 {+/-} 1,757 per species). Each species was characterized based on multiple distributional parameters, and a k-means analysis was used to group species with similar distribution patterns. The richness of invasive plants was mapped at the municipality level, and the drivers of their spatial variation were investigated using a comprehensive set of 30 variables representing multiple environmental and human factors. Results show that invasive plants occur in all mainland Portuguese municipalities, but with high variability. Four main patterns of distribution were identified: species that are primarily located along the coast (e.g., Acacia saligna), and a gradient of species with narrow (e.g., Reynoutria japonica), moderate (e.g., Ipomoea indica), and wide distribution ranges (e.g., Cortaderia selloana). Species richness was significantly higher in coastal and larger municipalities, particularly those closer to major urban centers and with a higher density of power lines. Our results provide the first comprehensive assessment of the distribution of invasive alien plants in mainland Portugal, establishing a much-needed baseline for future invasion prevention and management efforts.

ecology↗

bioRxiv2025

Bioindicator-based mapping of peatland potential in the Western Mediterranean-Atlantic Realm

Ecosystems with a naturally accumulated peat layer at the surface and wetlands with or without a peat layer dominated by a vegetation that may produce peat (hereafter peatlands for simplicity) are critical assets in global change due to their large carbon content storage capacity and essential ecosystem services. A Global Peatland Assessment was initiated during the UNFCCC COP22; however, many countries still lack accurate peatland maps. This is particularly concerning in the Western Mediterranean, where these ecosystems are frequently overlooked or misclassified. To help address this issue, we developed predictive distribution models for vascular plant and bryophyte species typical of peatland-type systems in the Western Mediterranean. We identified 28 indicator mire-typical plant taxa and created a database using filtered data from six different data sources, including our own field surveys. Thirteen high-resolution spatial predictor variables, covering topographic, soil, and hydroclimatic factors, were selected to reflect potential relationships with species presence. For each species, a potential distribution model was built using MaxEnt software. The resulting potential-distribution maps were cross-validated, and models with an AUC score of [≥]0.75 were classified into suitable or unsuitable areas. The species richness map aligned well with areas known to support peatlands. The indicator species-based mapping also suggests a broad potential for yet unrecorded peatlands in the Western Mediterranean, including small areas, particularly along the western and southwestern sandy coastlines and in the southern mountains.

ecology↗

bioRxiv2025

Engineered flavonoid disrupts mitochondrial AIF/CHCHD4 complex for targeted cancer therapy

Oncogenic metabolism depends on multifaceted mechanisms, including bidirectional inter-organelle communication between mitochondria and the nucleus, facilitating cellular adaptation at the transcriptomic, proteomic, and metabolomic levels. The mitochondrial protein complex composed of apoptosis-inducing factor (AIF) and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) is essential for this mitochondrio-nuclear communication. The AIF/CHCHD4 complex mediates the mitochondrial import of cysteine-enriched nuclear gene-encoded proteins, thereby adapting the mitochondrial proteome to cellular energy demands. We report the discovery of M30-E05, an engineered flavonoid that binds to the NADH pocket of AIF, preventing its dimerization and disrupting the AIF/CHCHD4 complex. Molecular docking and gel electrophoresis analysis of mitochondrial AIF/CHCHD4 substrates expression confirm this mechanism. In cancer cells, M30-E05 reduces the expression of nuclear gene-encoded mitochondrial proteins such as AIF, CHCHD4, COX17, and MICU1. In addition, M30-E05 fragments the mitochondrial network and impairs mitochondrial respiration, causing profound alterations, particularly in lipid and aminoacid metabolism, as revealed by kinetic measurements of oxygen consumption and mass spectrometric metabolomics. Importantly, M30-E05 significantly reduces the viability of a human adult and pediatric osteosarcoma cancer cell panel, including those from patient-derived xenografts (PDX) of osteosarcomas, and induces apoptosis. When orally administered for two weeks to immunodeficient NSG mice, M30-E05 inhibited tumor growth in a subcutaneous PDX xenograft model without apparent toxicity. We anticipate that M30-E05, as a first-in-class metabolic inhibitor, could serve as the lead compound for a new class of targeted antineoplastic agents. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/642976v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1b1add9org.highwire.dtl.DTLVardef@cac7corg.highwire.dtl.DTLVardef@101c9corg.highwire.dtl.DTLVardef@1c6845f_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

Tunneling CARs: Increasing CAR T tumor infiltration through the overexpression of MMP7 and SPP1

Chimeric antigen receptor T cell (CART) therapy has demonstrated remarkable efficacy in hematologic malignancies but has struggled to achieve comparable success in solid tumors. A key obstacle is the extracellular matrix (ECM) in solid tumors, which significantly impedes CART cell infiltration. In clinical trials, neuroblastoma (NB) has shown responsiveness to GD2-directed CART therapy, however, the failure of GD2.CARTs to effectively clear bulky disease - characterized by dense ECM - highlights the critical challenge of infiltration. In this study, we demonstrate that GD2.CARTs exhibit a unique infiltration-restriction compared to other CARTs and endogenous T cells. A separate analysis of clinical datasets identified MMP7 and SPP1 (OPN) as candidate genes to improve the infiltration of GD2.CARTs as these were upregulated in tumor-infiltrating leukocytes. MMP-7 and OPN overexpression enhanced CART extravasation (p < .001) and interstitial movement (p < .05) in ECM-dense environments in vitro. Overexpression of either OPN (p < .0001) or MMP-7 (p < .001) improved tumor infiltration in a xenograft model of NB. This resulted in improved tumor control (94% reduction in tumor burden, p < .05) and a survival extension in OPN-GD2.CART treated mice compared to unmodified GD2.CARTs (median of 148 days, p < .05). OPN overexpression did not increase off-target infiltration into healthy tissues or promote tumor metastasis, highlighting its potential for safe therapeutic application. Our study provides a framework for further exploration of gene modifications to improve CART infiltration and efficacy in solid tumors and identifies SPP1 as a candidate gene to improve GD2.CART treatment of bulky tumors.

immunology↗

bioRxiv2023

Introducing Isotopia: a stable isotope database for Classical Antiquity

We present Isotopia, an open-access database compiling over 36,000 stable isotope measurements ({delta}13C, {delta}15N, {delta}18O, {delta}34S, 87Sr/86Sr, 206Pb/204Pb, 207Pb/204Pb, 208Pb/204Pb, 207Pb/206Pb, and 208Pb/206Pb) on human, animal, and plant bioarchaeological remains dating to Classical Antiquity (approximately 800 BCE - 500 CE). These were recovered from different European regions, particularly from the Mediterranean. Isotopia provides a comprehensive characterisation of the isotopic data, encompassing various historical, archaeological, biological, and environmental variables. Isotopia is a resource for meta-analytical research of past human activities and paleoenvironments. The database highlights data gaps in isotopic classical archaeology, such as the limited number of isotopic measurements available for plants and animals, limited number of studies on spatial mobility, and spatial heterogeneity of isotopic research. As such, we emphasise the necessity to address and fill these gaps in order to unlock the reuse potential of this database.

paleontology↗

bioRxiv2023

Proximity proteomics reveals UCH-L1 as an essential regulator of NLRP3 mediated IL-1β production in human macrophages and microglia

Activation of the NACHT, LRR family pyrin domain containing 3 (NLRP3) inflammasome complex is an essential innate immune signalling mechanism. To reveal how human NLRP3 inflammasome assembly and activation are controlled, in particular by components of the ubiquitin system, proximity labelling, affinity purification and RNAi screening approaches were performed. Our study provides an intricate time-resolved molecular map of different phases of NLRP3 inflammasome activation. Also, we show that ubiquitin C-terminal hydrolase 1 (UCH-L1) interacts with the NACHT domain of NLRP3. Downregulation of UCH-L1 decreases pro-IL-1{beta} levels. UCH-L1 chemical inhibition with small molecules interfered with NLRP3 puncta formation and ASC oligomerization, leading to altered IL-1{beta} cleavage and secretion, particularly in microglia cells, which exhibited elevated UCH-L1 expression as compared to monocytes/macrophages. Altogether, we profiled NLRP3 inflammasome activation dynamics and highlight UCH-L1 as an important modulator of NLRP3-mediated IL-1{beta} production, suggesting that a pharmacological inhibitor of UCH-L1 may decrease inflammation-associated pathologies.

biochemistry↗

bioRxiv2023

Recent land use and land cover pressures on Iberian peatlands

Iberian peatlands have been severely affected by land use and land cover (LULC) changes. Despite these pressures, some peatlands persist in the region, although their susceptibility to LULC change remains poorly understood. This study presents the most detailed and extensive distribution data for Iberian peatlands to date and analyzes the dynamics and drivers of LULC in Iberian peatlands and their surrounding areas. We compiled peatland records from various sources and used Corine Land Cover Change layers to determine LULC shifts for 1990, 2000, 2006, 2012, and 2018. Environmental and socioeconomic variables were used to create Boosted Regression Tree models explaining spatial variations in the mean percentage of changed area. Analysis of 270 peatland locations in the Iberian Peninsula revealed that forests and seminatural areas constituted over 80% of the peatlands surroundings. Agricultural areas expanded the most, except between 2006 and 2012 when the artificial areas showed more gains. While most areas experienced an average change of 0%-9.51% of the total area, between 1990 and 2018, lowland peatlands (littoral and sublittoral) suffered more intense changes (9.51% to 38.43%). Our models showed that only elevation and agricultural area density were relevant predictors of spatial distribution changes. Upland Iberian peatlands showed lower susceptibility to LULC changes, while lowland peatlands underwent remarkable transformations. This study substantially expands previous knowledge about the distribution and conservation needs of these ecosystems in the Iberian Peninsula, especially those in littoral and sublittoral lowlands.

ecology↗

bioRxiv2022

A robust deep learning platform to predict CD8+ T-cell epitopes

T-cells play a crucial role in the adaptive immune system by inducing an anti-tumour response, defending against pathogens, and maintaining tolerance against self-antigens, which has sparked interest in the development of T-cell-based vaccines and immunotherapies. Because screening antigens driving the T-cell response is currently low-throughput and laborious, computational methods for predicting CD8+ T-cell epitopes have emerged. However, most immunogenicity algorithms struggle to learn features of peptide immunogenicity from small datasets, suffer from HLA bias and are unable to reliably predict pathology-specific CD8+ T-cell epitopes. Therefore, we developed TRAP (T-cell recognition potential of HLA-I presented peptides), a robust deep learning platform for predicting CD8+ T-cell epitopes from MHC-I presented pathogenic and self-peptides. TRAP uses transfer learning, deep learning architecture and MHC binding information to make context-specific predictions of CD8+ T-cell epitopes. TRAP also detects low-confidence predictions for peptides that differ significantly from those in the training datasets to abstain from making incorrect predictions. To estimate the immunogenicity of pathogenic peptides with low-confidence predictions, we further developed a novel metric, RSAT (relative similarity to autoantigens and tumour-associated antigens), as a complementary to dissimilarity to self from cancer studies. We used TRAP to identify epitopes from glioblastoma patients as well as SARS-CoV-2 peptides, and it outperformed other algorithms in both cancer and pathogenic settings. Thus, this study presents a novel computational platform for accurately predicting CD8+ T-cell epitopes to foster a better understanding of antigen-specific T-cell response and the development of effective clinical therapeutics. HighlightsO_LIHLA bias and out-of-distribution problem are causes of poor performance of current state-of-the-art algorithms C_LIO_LITransfer learning, deep learning architecture, context-specific and HLA-generalised approaches improve CD8+ T-cell epitope prediction C_LIO_LITRAP reports degree of correctness to improve reliability of the prediction C_LIO_LIA novel metric termed RSAT estimates immunogenicity of pathogenic peptides, as a complementary to dissimilarity to self from cancer studies C_LI

bioinformatics↗

bioRxiv2022

Triangulation reduces the polygon of error for the history of Transeurasian

In a recent study we used an interdisciplinary approach combining linguistics, archaeology and genetics to analyse the Transeurasian languages1. Our analysis concluded that the early dispersals of these languages were driven by agriculture. A preprint published on this server presents objections to the Transeurasian hypothesis and its association with farming dispersals2. However, close inspection of that text reveals numerous misinterpretations and inconsistencies. In the interest of furthering scientific debate over Transeurasian language and population history, we address the critiques, revising datasets and fine-tuning approaches. The linguistic critique questions the quantity and quality of our datasets. Here we show that the number of surviving cognate sets for Transeurasian is in line with that for well-established language families. In addition, we find that Tian et al.s failure to reject a core of regularly corresponding cognates in the basic vocabulary creates ground for a consensus about the genealogical relatability of the Transeurasian languages. The archaeological critique attempts a re-analysis of one Bayesian test using re-scored data only for northern China. Over half of the suggested re-scorings contain inconsistencies and it is not explained why the re-analysis retains the original data for sites outside northern China, comprising almost 60% of the total. More importantly, the sweeping claim that there is no evidence supporting the prehistoric migrations analysed in our study is not backed by any discussion of the archaeological record. With respect to genetics, the preprint claims a re-analysis showing that the data do not conclusively support the farming-driven dispersal of Turkic, Mongolian, and Tungusic, nor the two-wave spread of farming to Korea. In fact, the only genetic re-analysis presented is limited to samples from Korea and Japan and does not contradict our original conservative modelling of Neolithic individuals with Hongshan and our Bronze Age ones with Upper Xiajiadian. In sum, in bringing multiple lines of evidence together through triangulation, we gained a more balanced and richer understanding of Transeurasian dispersals than each discipline could provide individually. Our research doubtless leaves room for improvement but we remain confident that triangulation did not fail, but rather brought us a step closer to understanding the history of the Transeurasian languages.

evolutionary biology↗

bioRxiv2022

Neuronal temperature perception induces specific defenses that enable C. elegans to cope with the enhanced reactivity of hydrogen peroxide at high temperature

Hydrogen peroxide is the most common reactive chemical that organisms face on the microbial battlefield. The rate with which hydrogen peroxide damages biomolecules required for life increases with temperature, yet little is known about how organisms cope with this temperature-dependent threat. Here, we show that Caenorhabditis elegans nematodes use temperature information perceived by sensory neurons to cope with the temperature-dependent threat of hydrogen peroxide produced by the pathogenic bacterium Enterococcus faecium. These nematodes preemptively induce the expression of specific hydrogen peroxide defenses in response to perception of high temperature by a pair of sensory neurons. These neurons communicate temperature information to target tissues expressing those defenses via an insulin/IGF1 hormone. This strategy, which we call "enhancer sensing," is the first example of a multicellular organism inducing their defenses to a chemical when they sense an inherent enhancer of the reactivity of that chemical.

neuroscience↗

bioRxiv2021

Presenting the Compendium Isotoporum Medii Aevi (CIMA) and Bayesian Case Studies

AO_SCPLOWBSTRACTC_SCPLOWThe Compendium Isotoporum Medii Aevi (CIMA) gathers more than 50 000 isotopic measurements for bioarchaeological samples located within Europe and its margins dating between AD 500-1500. This volume of isotopic data, together with collected supporting information, offers multiple research opportunities. This is illustrated here using novel Bayesian modelling methods on selected case studies to reconstruct medieval human lifeways (i.e. human subsistence, spatial mobility), animal management practices, and paleo-environmental conditions. We also discuss how the integration of isotopic data with other types of archaeological and historical data can improve our knowledge of historical developments throughout medieval Europe.

paleontology↗

bioRxiv2021

Age-Related Type I Collagen Modifications Reveal Tissue-Defining Differences Between Ligament and Tendon

Tendons and ligaments tend to be pooled into a single category as dense elastic bands of collagenous connective tissue. They do have many similar properties, for example both tissues are flexible cords of fibrous tissue that join bone to either muscle or bone. Tendons and ligaments are both prone to degenerate and rupture with only limited capacity to heal, however; healing outcomes for tendons are often faster than ligament injuries. Type I collagen constitutes about 80% of the dry weight of tendons and ligaments and is principally responsible for the core strength of each tissue. Collagen synthesis is a complex process with multiple steps and numerous post-translational modifications including proline and lysine hydroxylation, hydroxylysine glycosylation and covalent cross-linking. The chemistry, placement and quantity of intramolecular and intermolecular cross-links are believed to be key contributors to the tissue-specific variations in material strength and biological properties of collagens. As tendons and ligaments grow and develop, the collagen cross-links are known to chemically mature, strengthen and change in profile. Accordingly, changes in cross-linking and other post-translational modifications are likely associated with tissue development and degeneration. Using mass spectrometry, we have compared tendon and ligaments from fetal and adult bovine knee joints to investigate changes in collagen post-translational properties. Although hydroxylation levels at the type I collagen helical cross-linking lysine residues were similar in all adult tissues, ligaments had significantly higher levels of glycosylation at these sites compared to tendon. Differences in lysine hydroxylation were also found between the tissues at the telopeptide cross-linking sites. Total collagen cross-linking analysis, including mature trivalent cross-links and immature divalent cross-links, revealed unique cross-linking profiles between tendon and ligament tissues. Tendons were found to have a significantly higher frequency of smaller diameter collagen fibrils compared with ligament, which we propose is a consequence of the unique cross-linking profile of each tissue. Understanding the specific molecular characteristics that define and distinguish these specialized tissues will be important for designing improved orthopedic treatment approaches.

biochemistry↗

bioRxiv2021

The proteome of remyelination is different from that of developmental myelination

Loss of myelin underlies the pathology of several neurological disorders of diverse etiology. CNS remyelination by adult oligodendrocyte progenitor cells (OPCs) can occur but it differs from developmental myelination carried out by neonatal OPCs. We asked whether the myelin proteome of remyelinated regions is changed. We compared the myelin proteome formed during development to the remyelination proteome attained after lysolecithin-induced demyelination in the mouse spinal cord. Mass-spectrometry analysis of iTRAQ labelled myelin protein lysates showed that the proteome of remyelination is different from that of developmental myelination, leading to profound changes in myelin protein content. Aside from known mediators of oligodendrocyte differentiation, we found proteome alterations included modulators of metabolism, cell signaling and actin cytoskeleton dynamics. Downregulating one candidate (FSCN1/Fascin1) was sufficient to partially hamper oligodendrocytes in-vitro. In summary, we identify the difference in the proteome of remyelinating oligodendrocytes as a novel potential contributor to the pathophysiology of demyelinating disorders, thus providing new potential therapeutic targets for future studies.

neuroscience↗

bioRxiv2021

Anti-GD2 antibody disrupts GD2:Siglec-7 interactions and synergizes with CD47 blockade to mediate tumor eradication

The disialoganglioside GD2 is consistently overexpressed in neuroblastoma and osteosarcoma, and is variably expressed in other sarcomas, gliomas, neuroendocrine tumors, and epithelial cancers. Anti-GD2 antibodies have improved the survival rates of patients with neuroblastoma only when administered as part of intense chemotherapy-based cytotoxic regimens, which are associated with debilitating late effects including hearing loss, growth retardation, and secondary leukemias. Despite broad expression of GD2 on osteosarcoma, anti-GD2 antibody has not mediated significant antitumor activity in that disease or any other GD2+ cancers. CD47 is a checkpoint molecule overexpressed on tumor cells that inhibits macrophage activity, and CD47 blockade has demonstrated promising clinical activity in early human trials. We investigated whether anti-CD47 antibody could enhance the efficacy of anti-GD2 antibody in neuroblastoma and other GD2+ malignancies. We demonstrate substantial synergy of these two agents, resulting in the recruitment of tumor associated macrophages (TAMs) to mediate robust and durable anti-tumor responses. The responses are driven by GD2-specific factors that reorient the balance of macrophage activity towards phagocytosis of tumor cells, including disruption of a newly described GD2:Siglec-7 axis. These results demonstrate the unique synergy of combining anti-GD2 with anti-CD47, which has the potential to significantly enhance outcomes for children with neuroblastoma and osteosarcoma and will soon be investigated in a first-in-human clinical trial.

immunology↗