Biology subjects

Levey, D.

Publications and source records attributed to Levey, D..

3 recordsLinked to original sources

bioRxiv2024

MAPK/ERK signaling in gliomas modulates interferon responses, T cell recruitment, enhances tumor-microglia crosstalk, and drives immune checkpoint blockade efficacy.

BackgroundGlioblastoma (GB) remains a formidable challenge in neuro-oncology, with immune checkpoint blockade (ICB) showing limited efficacy in unselected patients. We previously recently established that MAPK/ERK signaling is associated with overall survival following anti-PD-1 and anti-CTLA-4 treatment in recurrent GB. However, the causal relationship between MAPK/ERK signaling and susceptibility to ICB, as well as the mechanisms underlying this association, remain poorly understood. MethodWe conducted in vivo kinome-wide CRISPR/Cas9 screenings in murine gliomas to identify key regulators of susceptibility to anti-PD-1 and CD8+ T cell responses and performed survival studies to validate the most relevant genes. Additionally, paired single cell RNA- sequencing (scRNA-seq) with p-ERK staining, spatial transcriptomics on GB samples, and ex-vivo slice culture of a BRAFV600E mutant GB tumor treated with BRAFi/MEKi were used to determine the causal relationship between MAPK signaling, tumor cell immunogenicity, and modulation of microglia phenotype. ResultsCRISPR/Cas9 screens identified the MAPK pathway, particularly the RAF-MEK-ERK pathway, as the most critical modulator of glioma susceptibility to CD8+ T cells, and anti-PD-1 across all kinases. Experimentally-induced ERK phosphorylation in gliomas enhanced survival with ICB treatment, led to durable anti-tumoral immunity upon re-challenge and memory T cell infiltration in long-term survivors. Elevated p-ERK in glioma cells correlated with increased interferon responses, antigen presentation and T cell infiltration in GB. Moreover, spatial transcriptomics and scRNA-seq analysis revealed the modulation of interferon responses by the MAPK/ERK pathway in BRAFV600E human GB cells with ERK1/2 knockout and in slice cultures of human BRAFV600E GB tissue. Notably, BRAFi/MEKi treatment disrupted the interaction between tumor cells and tumor-associated macrophages/microglia in slice cultures from BRAFV600E mutant GB. ConclusionOur data indicate that the MAPK/ERK pathway is a critical regulator of GB cell susceptibility to anti-tumoral immunity, modulating interferon responses, and antigen-presentation in glioma cells, as well as tumor cell interaction with microglia. These findings not only elucidate the mechanistic underpinnings of immunotherapy resistance in GB but also highlight the MAPK/ERK pathway as a promising target for enhancing immunotherapeutic efficacy in this challenging malignancy.

cancer biology↗

bioRxiv2024

Can't carve air, can't weave names: Plant species used in Colombian artisan crafts are not equally assessed for vulnerability at the international and national level

Humanity has maintained cultural connections with our environments for time immemorial. Plants and artisan crafts are a prime example, as craft purpose, skill, design, and species used can vary greatly between communities and the loss of a critical plant species can result in a loss of access to cultural craft practices. To mitigate global biodiversity loss, conservationists are faced with the challenge of assessing species vulnerability to extinction and prioritizing species for conservation funding using information instruments, like the IUCN red list. This process does not necessarily consider a species cultural importance. In this paper we sought to address this gap for plant species used in artisan crafts in Colombia. We aim to answer the following: (1) how represented are endemic species in artisan crafts; (2) how threatened are artisan craft species according to (a) international and (b) national vulnerability status? We used the number of species-associated common names as a proxy for cultural awareness. We found that continentally regional species were far more represented in Colombian artisan crafts than national endemics. We also found a strong positive relationship between number of common names and national vulnerability assessment status, but no statistically significant relationship for international vulnerability status. Based on our results, well-known plants used in Colombian artisan crafts are more likely to be assessed nationally than internationally. While the IUCN is thorough in their recommendations, more can be done to prioritize the inclusion of conservation assessments for species based on their contributions to cultural diversity. Positionality statementWe are 14 scientists and practitioners who are deeply committed to the conservation of nature and culture in a changing world. We are trained in diverse fields including ecology, evolutionary biology, botany, music, anthropology, law, and public health. We all have postgraduate academic education (Masters or PhDs underway) but most of us are early career scholars. Six of us grew up in Colombia and we represent many places including Mexico, the United States, Ireland, Chile, Brazil, Germany, and Viet Nam. None of us self-identify as Indigenous.

ecology↗

bioRxiv2019

Meta-analysis of problematic alcohol use in 435,563 individuals identifies 29 risk variants and yields insights into biology, pleiotropy and causality

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies (GWASs) have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU combining alcohol use disorder and problematic drinking in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n=67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in genomic conserved and regulatory regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior, and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other outcomes.

genetics↗