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Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra- and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote 'off-the-shelf' precision immunotherapies, alleviating limitations of personalized treatments., Introduction Immunotherapy sparked new hope for oncology in recent years, due to its remarkable ability to induce long-term tumor regression of metastatic cancer. This feature is shared across immunotherapeutic modalities, [...]

Since the emergence of the original SARS-CoV-2, several variants were described, raising questions as to the ability of recently developed vaccine platforms to induce immunity and provide protection against these variants. Here, we utilized the K18-hACE2 mouse model to show that VSV-ΔG-spike vaccination provides protection against several SARS-CoV-2 variants: alpha, beta, gamma, and delta. We show an overall robust immune response, regardless of variant identity, leading to reduction in viral load in target organs, prevention of morbidity and mortality, as well as prevention of severe brain immune response, which follows infection with various variants. Additionally, we provide a comprehensive comparison of the brain transcriptomic profile in response to infection with different variants of SARS-CoV-2 and show how vaccination prevents these disease manifestations. Taken together, these results highlight the robust VSV-ΔG-spike protective response against diverse SARS-CoV-2 variants, as well as its promising potential against newly arising variants. [ABSTRACT FROM AUTHOR]

Prolonged metabolic stress can lead to severe pathologies. In metabolically challenged primary fibroblasts, we assigned a novel role for the poorly characterized miR‐4734 in restricting ATF4 and IRE1‐mediated upregulation of a set of proinflammatory cytokines and endoplasmic reticulum stress‐associated genes. Conversely, inhibition of this miRNA augmented the expression of those genes. Mechanistically, miR‐4734 was found to restrict the expression of the transcriptional activator NF‐kappa‐B inhibitor zeta (NFKBIZ), which is required for optimal expression of the proinflammatory genes and whose mRNA is targeted directly by miR‐4734. Concordantly, overexpression of NFKBIZ compromised the effects of miR‐4734, underscoring the importance of this direct targeting. As the effects of miR‐4734 were evident under stress but not under basal conditions, it may possess therapeutic utility towards alleviating stress‐induced pathologies. [ABSTRACT FROM AUTHOR]

The whitefly Bemisia tabaci is a closely related group of >35 cryptic species that feed on the phloem sap of a broad range of host plants. Species in the complex differ in their host‐range breadth, but the mechanisms involved remain poorly understood. We investigated, therefore, how six different B. tabaci species cope with the environmental unpredictability presented by a set of four common and novel host plants. Behavioral studies indicated large differences in performances on the four hosts and putative specialization of one of the species to cassava plants. Transcriptomic analyses revealed two main insights. First, a large set of genes involved in metabolism (>85%) showed differences in expression between the six species, and each species could be characterized by its own unique expression pattern of metabolic genes. However, within species, these genes were constitutively expressed, with a low level of environmental responsiveness (i.e., to host change). Second, within each species, sets of genes mainly associated with the super‐pathways "environmental information processing" and "organismal systems" responded to the host switching events. These included genes encoding for proteins involved in sugar homeostasis, signal transduction, membrane transport, and immune, endocrine, sensory and digestive responses. Our findings suggested that the six B. tabaci species can be divided into four performance/transcriptomic "Types" and that polyphagy can be achieved in multiple ways. However, polyphagy level is determined by the specific identity of the metabolic genes/pathways that are enriched and overexpressed in each species (the species' individual metabolic "tool kit"). [ABSTRACT FROM AUTHOR]

Abstract Background Olfactory receptors (ORs) are the largest gene family in the human genome. Although they are expected to be expressed specifically in olfactory tissues, some ectopic expression has been reported, with special emphasis on sperm and testis. The present study systematically explores the expression patterns of OR genes in a large number of tissues and assesses the potential functional implication of such ectopic expression. Results We analyzed the expression of hundreds of human and mouse OR transcripts, via EST and microarray data, in several dozens of human and mouse tissues. Different tissues had specific, relatively small OR gene subsets which had particularly high expression levels. In testis, average expression was not particularly high, and very few highly expressed genes were found, none corresponding to ORs previously implicated in sperm chemotaxis. Higher expression levels were more common for genes with a non-OR genomic neighbor. Importantly, no correlation in expression levels was detected for human-mouse orthologous pairs. Also, no significant difference in expression levels was seen between intact and pseudogenized ORs, except for the pseudogenes of subfamily 7E which has undergone a human-specific expansion. Conclusion The OR superfamily as a whole, show widespread, locus-dependent and heterogeneous expression, in agreement with a neutral or near neutral evolutionary model for transcription control. These results cannot reject the possibility that small OR subsets might play functional roles in different tissues, however considerable care should be exerted when offering a functional interpretation for ectopic OR expression based only on transcription information.

Summary: Carbon reserve use is a major drought response in trees, enabling tree survival in conditions prohibiting photosynthesis. However, regulation of starch metabolism under drought at the whole‐tree scale is still poorly understood.To this end, we combined measurements of nonstructural carbohydrates (NSCs), tree physiology and gene expression. The experiment was conducted outside on olive trees in pots under 90 d of seasonal spring to summer warming. Half of the trees were also subjected to limited water conditions for 28 d.Photosynthesis decreased in dehydrating trees from 19 to 0.5 µmol m−2 s−1 during the drought period. Starch degradation and mannitol production were a major drought response, with mannitol increasing to 71% and 41% out of total NSCs in shoots and roots, respectively. We identified the gene family members potentially relevant either to long‐term or stress‐induced carbon storage. Partitioning of expression patterns among β amylase and starch synthase family members was observed, with three β amylases possibly facilitating the rapid starch degradation under heat and drought.Our results suggest a group of stress‐related, starch metabolism genes, correlated with NSC fluctuations during drought and recovery. The daily starch metabolism gene expression was different from the stress‐mode starch metabolism pattern, where some genes are uniquely expressed during the stress‐mode response. [ABSTRACT FROM AUTHOR]