Biology subjects

Bailey, A.

Publications and source records attributed to Bailey, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Ethanol withdrawal induces temporally distinct alterations in oxytocinergic, opioidergic, glutamatergic and neuroimmune systems associated with recognition memory deficits

Alcohol use disorder is associated with persistent neuroadaptations and cognitive impairments, particularly during withdrawal, yet the temporal dynamics and interactions between these processes remain poorly understood. In the present study, we investigated time-dependent alterations in the oxytocin receptor (OTR), -opioid receptor (MOPr), metabotropic glutamate receptor 5 (mGlu5R), and translocator protein (TSPO) following chronic ethanol exposure and withdrawal, and their relationship to behavioral impairments. Male C57BL/6J mice were exposed to a 10-day escalating-dose ethanol liquid diet paradigm followed by 1, 4, or 7 days of withdrawal. Motor coordination and recognition memory were assessed using rotarod and novel object recognition tests, and receptor binding was quantified using autoradiography across multiple brain regions. Chronic ethanol exposure induced motor deficits that persisted during early withdrawal, whereas recognition memory impairments emerged after 7 days of withdrawal. Ethanol exposure and withdrawal produced region- and time-dependent alterations across all systems examined, with increased OTR binding in septal regions and transient reductions in basomedial amygdala OTR binding during intermediate withdrawal that normalized following prolonged withdrawal, transient increases in MOPr binding in striatal regions at 4 days of withdrawal, increased mGlu5R binding in the nucleus accumbens core, basolateral amygdala, and hippocampus, and early transient increases in TSPO binding indicative of neuroimmune activation. Notably, mGlu5R binding in the caudate-putamen and amygdala was associated with recognition memory deficits in a withdrawal stage-dependent manner. Bioinformatic analysis of human postmortem hippocampal transcriptomic datasets from individuals with alcohol use disorder revealed no consistent changes in GRM5 expression, suggesting that mGlu5R dysregulation may be driven by post-transcriptional mechanisms. These findings demonstrate that ethanol withdrawal is characterized by temporally distinct neuroadaptations across multiple systems and identify mGlu5R as a key correlate of withdrawal-associated memory impairment, highlighting its potential as a translational therapeutic target.

pharmacology and toxicology↗

bioRxiv2026

Identification of pre-existing ubiquitous neoantigen-reactive tumor-infiltrating T-cells in a patient with metastatic pancreatic neuroendocrine tumor

BackgroundMutation-derived neoantigens, typically identified in primary tumors, are emerging therapeutic targets for personalized cancer vaccines and adoptive T-cell therapies. However, clinical efficacy of neoantigen-directed therapies in patients with metastatic disease remains limited, partly due to inter-site genetic heterogeneity. We investigated whether ubiquitous neoantigens-derived from mutations shared across all tumor sites-could provide more effective, durable targets, particularly in patients undergoing resection of metastatic lesions. MethodsWhole-exome and RNA sequencing were performed on 14 tumor samples (primary and 13 synchronous nodal metastases) from a treatment-naive patient with pancreatic neuroendocrine tumor (PNET). Ubiquitous mutations were identified bioinformatically, and their immunogenicity assessed using in-vitro stimulation of autologous peripheral blood mononuclear cells followed by IFN-{gamma} ELISpot assay. Neoantigen-specific T-cell clonotypes were further identified by HLA-tetramer staining and single-cell RNA/TCR sequencing. Neoantigen-reactive clonotypes identified in peripheral blood were tracked across multiple metastatic sites using bulk TCR{beta} repertoire sequencing. ResultsAmong 1,195 non-synonymous mutations detected, eight were shared across all 14 tumor sites. Of these, one encoded a neoantigen that elicited a reproducible IFN-{gamma} ELISpot response in peripheral blood, confirming its immunogenicity. Further, we identified the corresponding neoantigen-reactive TCR clonotypes in blood. Comparison with bulk TCR{beta} repertoires from eight metastatic sites showed that these clonotypes were present in every site analyzed, with evidence of local clonal expansion. ConclusionThis study provides direct evidence that a single ubiquitous mutation-derived neoantigen can generate systemic T-cell responses and clonotype expansion across multiple metastatic sites in a TMB-low, TIL-low tumor. Our findings support incorporating mutation-sharing status across metastases as a key criterion for neoantigen selection in cancer vaccines and adoptive T-cell therapies. This approach could inform the design of neoantigen-directed immunotherapies in metastatic PNET and potentially other metastatic solid tumors. What is already known on this topicNeoantigen-directed therapies, such as personalized cancer vaccines or adoptive T-cell transfer, can induce anti-tumor responses but have shown limited success in metastatic disease. One major barrier is genetic heterogeneity between tumor sites, suggesting that targeting ubiquitous mutations-those shared across all tumor sites-may improve the efficacy of such therapies. What this study addsIn one patient with metastatic pancreatic neuroendocrine tumor involving 13 lymph nodes, we identified eight ubiquitous mutations, one of which generated a detectable neoantigen-specific T-cell response in blood. The corresponding T-cell clonotypes were found across all metastatic sites analyzed and showed evidence of clonal expansion, providing direct evidence of systemic and local recognition of a shared neoantigen in a TMB-low/TIL-low cancer. How this study might affect research, practice or policyThese findings support incorporating mutation sharing across metastases as a key criterion in neoantigen selection for cancer vaccines and adoptive T-cell therapies. This strategy could enhance the relevance and durability of neoantigen- directed approaches in patients with metastatic disease.

immunology↗

bioRxiv2026

Re-analysis of Transcriptomic and Proteomic Data Using Multi-Omics Approaches Identifies Biomarkers of Diabetes-Associated Complications in an INS Mutant Pig Model

Mutant Insulin Induced Diabetes of Youth (MIDY) is an established porcine model caused by the INSC94Y mutation, which results in misfolded insulin, leading to severe {beta}-cell loss and hyperglycemia. Understanding disease pathophysiology is critical for identifying biomarkers and therapeutic targets, and animal models play a key role in this process. In this study, we re-analyzed published transcriptomic and proteomic data from the MIDY model using advanced multi-omics approaches and our in-house SurfacOmics tool. This integrative analysis identified ADAMTS17 as a novel biomarker, suggesting a potential association in diabetes-associated immune dysfunction and delayed wound healing through ECM-immune interplay.

bioinformatics↗

bioRxiv2026

A novel qPCR assay to detect the presence of Anopheles gambiae complex mosquitoes

BackgroundAnopheles mosquitoes vector pathogens responsible for more than 600,000 human deaths annually. Ecological studies of these insects are important to guide effective vector-control campaigns and to understand their broader ecological consequences. Molecular ecology methods, particularly qPCR, provide a valuable tool in such studies. By detecting trace DNA of a taxon of interest within mixed or environmental samples, qPCR can facilitate identification of prey taxa of interest in the diets of consumers. However, no protocol for the detection of An. gambiae complex mosquitoes in dietary samples has been available. MethodsWe introduce a new set of qPCR primers (Agam_CO1_F1 and Agam_CO1_R1) and a probe-based assay for detection of Anopheles gambiae-complex mosquitoes, even with short reads common in dietary and environmental samples. The primers were tested in vitro for their specificity and sensitivity, and in silico using Primer-BLAST to assess potential off-target amplification. ResultsThe qPCR primers amplified An. gambiae DNA even at low starting concentrations (5 copies {micro}l-1). The primers did not amplify any non-target DNA in either the in vitro or in silico tests, but consistently amplified An. gambiae complex DNA. The primers can therefore provide reliable tests for the presence or absence of An. gambiae complex in dietary or eDNA samples. ConclusionsThe new qPCR primers should allow advances in research into mosquito ecology by allowing detection of even trace amounts of An. gambiae DNA in dietary and environmental samples. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC="FIGDIR/small/707393v1_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@1fcce3corg.highwire.dtl.DTLVardef@47e5f5org.highwire.dtl.DTLVardef@4a7063org.highwire.dtl.DTLVardef@1188d60_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2026

Tilted striatofugal balance and beneficial effects of facilitating mGlu4 receptor activity in the Fmr1-/- mouse model of Fragile X Syndrome

Fragile X Syndrome (FXS) is the leading monogenic cause of autism spectrum disorder (ASD). To date, no approved pharmacological treatment alleviates social impairments in patients with FXS. Since D1 and D2 dopamine receptor-expressing striatal projection neurons (SPNs) were shown to regulate ASD-sensitive behaviors, we explored whether the balance of activity between D1- and D2-SPNs would be biased in the Fmr1-/- mouse model of FXS. We evaluated striatal function in Fmr1-/- and Fmr1+/+ mice under pharmacological challenge and performed RNAscope(R) in situ hybridization following social interaction to assess the activity of SPNs in the nucleus accumbens (NAc) and dorsal striatum (DS). We evidenced a decrease in D1-SPN activity, biasing the D1/D2-SPN balance towards an excessive weight of D2-SPN outputs. We then evaluated the effects of compounds that repress D2-SPN activity on behavioral impairments in Fmr1-/- mice. Systemically facilitating mGlu4 or blocking A2A receptor activity relieved behavioral deficits in this model. Finally, we tested the hypothesis that a tilt of the D1/D2-SPN balance in Fmr1-/- mice may contribute to their social deficit by facilitating mGlu4 activity directly in the projection site of NAc D2-SPNs. Social interaction in Fmr1-/- mice was fully rescued by photopharmacological activation of mGlu4 in the ventral pallidum (VP), where NAc D2-SPNs project. This result supports our hypothesis of excessive D2-SPN outputs and highlights the contribution of the VP in controlling social behavior. In conclusion, pharmacological compounds that repress D2-SPN activity demonstrate a promising therapeutic potential to relieve ASD-like deficits in FXS.

neuroscience↗

bioRxiv2025

TAp73 mediates anti-tumor immunity through regulation of lipid metabolism in the lung tumor microenvironment

While immunotherapy has become the standard of care for lung adenocarcinoma (LUAD) patients without actionable genomic alterations, only a subset of patients benefits from a long-lasting response to immunotherapy. Activation of p53-related signals has emerged as a potential mediator of the lung tumor microenvironment (TME). Given that mutant-p53 interacts with p73 extensively and TAp73-deficient mice develop LUAD, we engineered a mouse model with conditional deletion of TAp73 to understand the interactions of the p53 family in the TME and in metabolic pathways that impact anti-tumor immunity. We demonstrated that TAp73 exerts a tumor-suppressive role in KrasG12D-driven LUAD by regulating lipid metabolism in the TME. We identified a TAp73-driven transcriptional signature involving genes in the arachidonic acid metabolism pathway operational in tumor-associated macrophages that favors T-cell activation and thus anti-tumor immunity. Similar transcriptional changes are seen in macrophages from LUAD patients with p53 mutations and in association with response to immunotherapy. SIGNIFICANCEThere is a need to understand how the LUAD TME impacts patient response to immunotherapy. We identified a transcriptional program enacted by TAp73 in tumor alveolar macrophages that supports T-cell activation. Transcriptional and metabolomic data from LUAD patients supports the relevance of this program in response to immune checkpoint inhibition.

cancer biology↗

bioRxiv2025

Characterising a species-rich and understudied tropical insect fauna using DNA barcoding

BackgroundWest Africa has high biodiversity that is relatively understudied, especially for insects. Studies of West African arthropod diversity can therefore help address important questions regarding conservation, ecosystem services, and insecticide use and other species-control interventions in agriculture and disease management. We intensively sampled arthropods in Ghana using complementary trapping methods, generated DNA barcodes, and classified sequences by Barcode Index Numbers (BINs, a species proxy). Using this dataset, we investigate assemblage composition, temporal activity patterns, and the state of regional biodiversity sampling. ResultsSequencing DNA from 95,996 individuals captured using Malaise, yellow pan, pitfall, Heath and Centre for Disease Control (CDC) traps, we identified 10,120 unique BINs. The rate of species accumulation did not approach an asymptote for any taxonomic group or trap type, indicating high biodiversity. The different trap types sampled different subsets of the local community, with greatest similarity between yellow pan and pitfall traps. More insects and species (BINs) were trapped during the day than at night. Our dataset shared more BINs in the Barcode of Life Database with South Africa than with any other country, although this predominantly reflects the limited sampling and DNA sequencing campaigns in Africa. ConclusionsThis study more than doubles the published BINs for West Africa, offering insights into the biodiversity of an ecologically important but understudied taxon and region. Using multiple trap types allowed a more complete assessment of the local arthropod assemblage. The public release of these data will support and stimulate further taxonomic and ecological work in the region.

ecology↗

bioRxiv2025

SurfacOmics: an R shiny application integrating variable Feature Selection for gene biomarker discovery using Elastic-Net Regularization

Affordable sequencing technologies have resulted in a rapid rise in genomic and proteomic data. As a result, a massive amount of data is being analyzed, and the outcomes must be summarized as relevant clinical biomarkers. One of the major challenges is enabling wet-lab researchers to make meaningful inferences from the data, even in the absence of expertise in pipeline development and statistical training. We present a user-friendly R shiny application, SurfacOmics, which allows the user to perform biomarker identification via penalized regression algorithms. It also enables researchers to choose a crucial binary variable, such as treatment or group, from the study design metadata to anticipate potential biomarkers. We have introduced a novel concept of scoring scheme to characterize potential biomarkers for prediction, prioritization, and ranking. The tool integrates Gene Ontology information for sub-cellular localization together with a manually curated knowledgebase to provide valuable insights on biological processes, molecular functions and antibody resources, offering a comprehensive view in a single interface.

bioinformatics↗

bioRxiv2025

Mesenteric ischemia and bacterial translocation precipitate the intoxication phase of yellow fever

Yellow fever (YF) is classically conceptualized as a hepatotropic disease; indeed, the liver is the primary site of yellow fever virus (YFV) replication. However, circumstantial evidence suggests that extra-hepatic disease may be important for the [~]30% of YF cases that progress to the severe "intoxication" phase of the disease. Using a Syrian hamster-adapted (HA)-YFV, we worked backwards from observations in humans to examine early events that precipitate the intoxication phase of YF. HA-YFV caused severe disease in [~]80% of infected animals characterized by lethargy and weight loss that progressed to widespread petechiae and death by day 6. Clinical chemistry, coagulation testing, histology, immunohistochemistry, and in-situ hybridization were consistent with a cascade of hepatocyte-specific virus replication causing liver damage and a defect in clotting factor synthesis. Despite a lack of extra-hepatic HA-YFV replication, severe pathology was observed in the intestines and pancreas. Histopathological analysis over the time-course of HA-YFV infection revealed an ischemic pattern in these tissues, culminating in fibrinoid/coagulative necrosis of these organs. Further investigation showed that ischemia-induced erosion of the gut epithelial barrier serves as an entry point for luminal bacteria that spread systemically via the portal system. Thus, the intoxication phase of YF is a sepsis-like syndrome caused by translocation of bacteria from a damaged gastrointestinal tract. Evaluation of human YF cases for these previously overlooked disease features confirmed this overarching mechanism: bacteria were identified in the portal vein and liver parenchyma of fatal YF cases along with elevations in plasma markers of bacteremia and a bacteria-driven inflammatory response. Importantly, blood concentrations of the gastrointestinal damage marker intestinal fatty acid binding protein (I-FABP) were significantly elevated in fatal YF cases relative to non-fatal cases, suggesting that I-FABP measurements could be useful in prognosis and treatment decision making. Our findings tie together several recent and historically unexplained observations surrounding the highly-lethal intoxication phase of YF in humans: a high AST/ALT ratio, "black vomit," pancreatitis, and paradoxical neutrophilia. A better appreciation for the drivers of mesenteric ischemia, and preemption of bacterial sepsis, may improve outcomes in cases of severe YF.

microbiology↗

bioRxiv2024

Comparative analysis of protein expression between oesophageal adenocarcinoma and normal adjacent tissue

Oesophageal adenocarcinoma (OAC) is the 7th most common cancer in the United Kingdom and remains a significant health challenge. This study presents a proteomic analysis of seven OAC donors complementing our previous neoantigen identification study of their human leukocyte antigen (HLA) immunopeptidomes. Using label-free mass spectrometry proteomics, we compared OAC tumour tissue to matched normal adjacent tissue (NAT) to identify differentially expressed proteins. We identified differential expression of a number of proteins previously linked to OAC and other cancers. We observed enrichment of processes and pathways relating RNA processing and the immune system. Our findings also offer insight into the role of the protein stability in the generation of the neoantigen we previously identified. These results provide independent corroboration of existing oesophageal adenocarcinoma biomarker studies that may inform future diagnostic and therapeutic research.

cancer biology↗

bioRxiv2024

Identification of natural Zika virus peptides presented on the surface of paediatric brain tumour cells by HLA classI

Despite decades of research, survival from brain cancer has scarcely improved and is drastically lower than that of other cancers. Novel therapies, such as immunotherapy, hold great promise for treating brain tumours and are desperately needed. Zika virus (ZIKV) infects and kills aggressive cancer cells with stem-like properties (CSCs) from both paediatric and adult brain tumours. Whilst T cell recruitment into ZIKV-infected brain tumours is becoming well documented, the specific mechanisms through which they are activated are poorly understood. We address this by employing a combined LC-MS/MS global proteome and immunopeptidome approach to describe, for the first time, human leukocyte antigen (HLA) presentation of ZIKV peptides on the surface of infected brain tumour cells. We first show that HLA class I (HLA-I) antigen processing & presentation is the most highly enriched immune response pathway in the global proteome of aggressive paediatric USP7-ATRT brain tumour cells following ZIKV infection. We identify USP7-ATRT cells as a good immunopeptidome model due to their homozygous of the globally most common HLA-A allotype (A*02:01). We predict the majority of the 19 ZIKV peptides that we identify here to strongly bind and be presented by HLA-A*02:01. We show that immunopeptide presentation corresponds with cellular ZIKV protein abundance, with ten peptides arising from the most abundant viral protein; non-structural protein 3 (NS3). Specifically, we show the ZIKV NS3 helicase domain to be a rich source of peptides. Finally, we verify that the identified ZIKV peptides do not mimic predicted peptides of the human proteome. The ZIKV peptides we identify here are potential candidates for developing novel epitope-specific brain tumour immunotherapies, and our findings provide potential insight into the efficacious cytotoxic T cell response that oncolytic ZIKV virotherapy can induce against brain tumours. Author SummaryViruses can attack cancer through two mechanisms: 1) infecting and killing the cancer cell and 2) activating the immune system against the tumour. Zika virus (ZIKV) uses both mechanisms to fight brain cancer. Here, we employ a powerful proteomic technique to identify fragments of viral proteins (peptides) presented by cell surface receptors on brain cancer cells infected with ZIKV. In the human body, immune system cells such as T cells recognise and become activated in response to these viral peptides and subsequently attack the infected patient tumour. We identify 19 ZIKV peptides, three of which have been shown previously to elicit T cell responses, four identified elsewhere, and twelve are novel. Our work helps delineate a component of how ZIKV acts as an immunotherapy, the T cell-specific immune response that the virus raises to promote clearance of brain tumours. The significance of our study is that the ZIKV peptides we identify may lead to the development of a novel brain tumour immunotherapy.

cancer biology↗

bioRxiv2024

Comparative analysis of transcriptomic and proteomic expression between two non-small cell lung cancer subtypes

Non-small cell lung cancer (NSCLC) is frequently diagnosed at an advanced stage and has poor survival. NSCLC subtypes require different treatment regimes, hence there are extensive efforts to find more precise and non-invasive differential diagnostics tools. Complementing these efforts, we examined two NSCLC subtypes for differences that may inform treatment options and identify potential novel therapeutic pathways. Here we present a comparative analysis of transcriptomic and proteomic expression in tumours from a cohort of 22 NSCLC patients: 8 squamous cell carcinoma (LUSC), 14 adenocarcinoma (LUAD). We examined differential gene and differential protein expression between LUSC and LUAD, and between NSCLC subtypes and either PBMCs or normal adjacent lung tissue (NAT). We found that both NSCLC subtypes shared common differences in gene expression to PBMC relating to developmental and structural changes, and common protein expression differences to NAT relating to protein translation and RNA related processing and splicing. Between NSCLC subtypes we found differential gene expression relating to cell differentiation for LUSC and cellular structure and immune response regulation for LUAD. Differential protein expression between NSCLC subtypes related to extracellular structure for LUSC and metabolic processes, including glucose metabolism for LUAD. Many of our observations of differentially expressed genes and proteins between NSCLC subtypes support and inform existing observations, aiding both basic and clinical research seeking to identify subtype biomarkers or druggable targets.

cancer biology↗

bioRxiv2024

Proteogenomics guided identification of functional neoantigens in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) has poor survival even with modern checkpoint inhibitor therapies. Personalised vaccines based on short peptide neoantigens containing tumour mutations are an attractive precision medicine strategy, but identifying therapeutically relevant neoantigens remains challenging, with existing methods yielding positive responses in only 6% of candidates tested. We developed an immunopeptidomics approach to improve neoantigen identification in 24 NSCLC patients (15 adenocarcinoma, 9 squamous cell carcinoma). We directly identified one neoantigen and using whole exome sequencing, transcriptomics and mass spectrometry-based immunopeptidomics, we filtered predicted neoantigens based on observed cohort HLA peptide presentation. This approach achieved positive functional responses in 5 of 6 patients tested (83% success rate) with 13% of putative neoantigens (9 out of 70) eliciting strong responses. Bayesian modelling of our initial rules-based neoantigen selection further revealed patient specific peptide presentation patterns and propensities. Our findings demonstrate that incorporating donor specific HLA peptide presentation data substantially improves neoantigen identification success rates and immune response specificity, advancing personalised cancer vaccine development.

immunology↗

bioRxiv2024

Acute, chronic and conditioned effects of intranasal oxytocin in the mu opioid receptor knockout mouse model of autism: social context matters

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behaviours. Multiple studies have highlighted the potential of oxytocin (OT) to ameliorate behavioural abnormalities in animal models and subjects with ASD. Clinical trials, however, yielded disappointing results. Our study aimed at challenging hypotheses accounting for such negative results by assessing the behavioural effects of different regimens of OT administration in the Oprm1 null mouse model of ASD. We assessed the effects of intranasal OT injected once at different doses and time points following administration, or chronically, on ASD-related behaviours in Oprm1+/+and Oprm1-/- mice. We then tested whether pairing intranasal OT injection with social experience would influence its outcome on ASD-like core symptoms, and measured gene expression in several regions of the reward/social circuit. Acute intranasal OT improved social behaviour in Oprm1-/- mice at a moderate dose (0.3 IU) shortly after administration (5 min). Effects on non-social behaviours were limited. Chronic OT at this dose maintained beneficial effects in Oprm1 null mice but was deleterious in wild-type mice. Finally, improvements in the social behaviour of Oprm1-/- mice were greater and longer lasting when OT was administered in a social context, while the expression of OT and vasopressin receptor genes, as well as marker genes of striatal projection neurons, was suppressed. Our results highlight the importance of considering dosage and social context when evaluating the effects of OT treatment in ASD. HighlightsO_LIAcute intranasal oxytocin improved social behaviour shortly after administration C_LIO_LIEffects of oxytocin on non-social behaviours were limited C_LIO_LIChronic oxytocin maintained beneficial effects in mutant mice but was deleterious in wild-type mice C_LIO_LIOxytocin triggers greater and longer-lasting improvements in social behaviour when administered within a social context C_LIO_LIChronic oxytocin suppresses the expression of its own receptor gene and key striatal neuron gene markers C_LI

animal behavior and cognition↗

bioRxiv2024

Toward Sustainable Biocultural Tourism: An Integrated Spatial Analysis of Cultural and Biodiversity Richness in Colombia

O_LITourism plays a vital role in both economic development and depending on the scale, it can also aid environmental conservation. Tourism planning often considers culture-based and nature-based tourism separately, failing to recognize the synergies between them, with the potential to market locations as biocultural destinations. C_LIO_LIUsing Colombia as a case study, we created metrics of taxonomic biological diversity as measured by vertebrate species richness (including birds, mammals, freshwater fishes, reptiles, and amphibians) and institutionalized cultural richness (by counting the number of UNESCO world heritage sites, intangible cultural heritage sites, museums, endemic music festivals, Afro-Colombian territories, and Indigenous reserves), and evaluated the spatial correlations between them. C_LIO_LITo determine biocultural tourism potential, we evaluated whether biocultural richness was accessible, and mapped potential biocultural tourism supply. By mapping areas of sports fisheries, birdwatching destinations, and airport arrivals we also estimated spatial demand. We also analyzed the difference between demand and supply to assess the realized and untapped potential for biocultural destinations. C_LIO_LIWhile biocultural richness is high in the Amazon, Pacific, and Caribbean regions, we found that there are no win-win-win locations where culture, species richness, and accessibility are all high. Areas with great potential for biocultural tourism development largely coincide with designated Indigenous reserves and Afro-Colombian territories. C_LIO_LIThis study underscores the power of integrating cultural and biological variables to reshape the tourism sector. Our paper offers practical recommendations for policymakers, conservation organizations, and local communities seeking to create transformative and inclusive tourism experiences. C_LI

ecology↗

bioRxiv2022

Identification of neoantigens in esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) has a relatively poor long-term survival and limited treatment options. Promising targets for immunotherapy are short peptide neoantigens containing tumor mutations, presented to cytotoxic T-cells by human leukocyte antigen molecules (HLA). Despite an association between putative neoantigen abundance and therapeutic response across cancers, immunogenic neoantigens are challenging to identify. Here we characterized the mutational and immunopeptidomic landscapes of tumors from a cohort of seven patients with EAC. We directly identified one HLA-I presented neoantigen from one patient, and report functional T-cell responses from a predicted HLA-II neoantigen in a second patient. The predicted class II neoantigen contains both HLA I and II binding motifs. Our exploratory observations are consistent with previous neoantigen studies in finding that neoantigens are rarely directly observed, and an identification success rate following prediction in the order of 10%. However, our identified putative neoantigen is capable of eliciting strong T-cell responses, emphasizing the need for improved strategies for neoantigen identification.

cancer biology↗

bioRxiv2022

Diet suppresses tumour initiation by maintaining quiescence of mutation-bearing neural stem cells

Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a pre-requisite for tumour initiation. Although inactivation of the tumour suppressor p53 is a frequent event in gliomagenesis, whether, or how, it affects quiescent NSCs (qNSCs) remains unclear. Here we show that p53 maintains quiescence by inducing fatty acid oxidation (FAO) and that acute p53 deletion in qNSCs results in their premature activation to a proliferative state. Mechanistically, this occurs through direct transcriptional induction of PPARGC1a, which in turn activates PPAR to upregulate FAO genes. Strikingly, dietary supplementation with fish oil containing omega-3 fatty acids, natural PPAR ligands, fully restores quiescence of p53-deficient NSCs and delays tumour initiation in a glioblastoma mouse model. Thus, diet can silence glioblastoma driver mutations, with important implications for cancer prevention.

cancer biology↗

bioRxiv2022

Isolation of a potently neutralizing and protective human monoclonal antibody targeting yellow fever virus

Yellow fever virus (YFV) causes sporadic outbreaks of infection in South America and sub-Saharan Africa. While live-attenuated yellow fever virus vaccines based on three substrains of 17D are considered some of the most effective vaccines in use, problems with production and distribution have created large populations of unvaccinated, vulnerable individuals in endemic areas. To date, specific antiviral therapeutics have not been licensed for human use against YFV or any other related flavivirus. Recent advances in monoclonal antibody (mAb) technology have allowed for identification of numerous candidate therapeutics targeting highly pathogenic viruses, including many flaviviruses. Here, we sought to identify a highly neutralizing antibody targeting YFV envelope (E) protein as a therapeutic candidate. We used human B cell hybridoma technology to isolate mAbs from the circulating memory B cells from human YFV vaccine recipients. These antibodies bound to recombinant YFV E protein and recognized at least five major antigenic sites on E. Two mAbs (designated YFV-136 and YFV-121) recognized a shared antigenic site and neutralized the YFV 17D vaccine strain in vitro. YFV-136 also potently inhibited infection by multiple wild-type YFV strains, in part, at a post-attachment step in the virus replication cycle. YFV-136 showed therapeutic protection in two animal models of YFV challenge including hamsters and immunocompromised mice engrafted with human hepatocytes. These studies define features of the antigenic landscape on YFV E protein recognized by the human B cell response and identify a therapeutic antibody candidate that inhibits infection and disease caused by highly virulent strains of YFV.

immunology↗