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This letter discusses a study that used single-cell RNA sequencing to analyze the gene expression profiles of peripheral blood mononuclear cells (PBMCs) in people with cystic fibrosis (pwCFs) who have different stages of Mycobacterium abscessus lung disease. The study identified 10 distinct cell populations within the PBMCs and found that there was no significant cellular variation among pwCFs with different risks of M. abscessus lung disease. However, the CD14+ monocyte cluster in the MABSC-PD group displayed the highest number of upregulated genes compared to other cellular clusters. The study suggests that single-cell transcriptomic profiling of PBMCs could be used to identify diagnostic signatures or therapeutic targets for pwCFs with NTM infection. [Extracted from the article]

Neuroinflammation plays a key role in exacerbating dopaminergic neuron (DAN) loss in Parkinson's disease (PD). However, it remains unresolved how to effectively normalize this immune response given the complex interplay between the innate and adaptive immune responses occurring within a scarcely accessible organ like the brain. In this study, we uncovered a consistent correlation between neuroinflammation, brain parenchymal lymphocytes, and DAN loss among several commonly used mouse models of PD generated by a variety of pathological triggers. We validated a viral therapeutic approach for the microglia-specific expression of interleukin 10 (IL-10) to selectively mitigate the excessive inflammatory response. We found that this approach induced a local nigral IL-10 release that alleviated DAN loss in mice overexpressing the human SNCA gene in the substantia nigra. Single-cell transcriptomics revealed that IL-10 induced the emergence of a molecularly distinct microglial cell state, enriched in markers of cell activation with enhanced expression of prophagocytic pathways. IL-10 promoted microglial phagocytotic and clearance activities in vitro and reduced αSYN aggregate burden in the nigral area in mice overexpressing SNCA. Furthermore, IL-10 stimulated the differentiation of CD4+ T lymphocytes into active T regulatory cells and promoted inhibitory characteristics in CD8+ T cells. In summary, our results show that local and microglia-specific IL-10 transduction elicited strong immunomodulation in the nigral tissue with enhanced suppression of lymphocyte toxicity that was associated with DAN survival. These results offer insights into the therapeutic benefits of IL-10 and showcase a promising gene delivery approach that could minimize undesired side effects. Editor's summary: Reactive microglia contribute to Parkinson's disease (PD) pathogenesis. Certain cytokines such as interleukin-10 (IL-10) can restore microglia homeostasis, but targeting maladaptive immune responses without inducing systemic side effects remains a challenge. Bido et al. adopted a microRNA-detargeting system that inhibits the expression of a transgene in all but the cell type of choice. Using this system for lentiviral-mediated, local, and microglia-specific expression of IL-10 in PD mice led to reduced neuropathology and the emergence of microglial subtypes with enhanced clearance signatures. These results suggest the therapeutic potential of cell type–specific gene delivery for PD. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

Motivation Single-cell profiling has become a common practice to investigate the complexity of tissues, organs, and organisms. Recent technological advances are expanding our capabilities to profile various molecular layers beyond the transcriptome such as, but not limited to, the genome, the epigenome, and the proteome. Depending on the experimental procedure, these data can be obtained from separate assays or the very same cells. Yet, integration of more than two assays is currently not supported by the majority of the computational frameworks avaiable. Results We here propose a Multi-Omic data integration framework based on Wasserstein Generative Adversarial Networks suitable for the analysis of paired or unpaired data with a high number of modalities (>2). At the core of our strategy is a single network trained on all modalities together, limiting the computational burden when many molecular layers are evaluated. Availability and implementation Source code of our framework is available at https://github.com/vgiansanti/MOWGAN [ABSTRACT FROM AUTHOR]

Cryotrapping and X-ray crystallography were used to characterize the binding interactions between the slowly hydrolyzed substrate inosine and the Escherichia coli pyrimidine-specific nucloeside hydrolase (NH) YeiK. The results provided direct evidence for the distinct subsets of amino acid residues which are involved in the hydrolysis of purine or pyrimidine nucleosides in group I NHs.

Sleeping sickness is a deadly disease that primarily affects sub-Saharan Africa and is caused by protozoan parasites of the Trypanosoma genus. Trypanosomes are purine auxotrophs and their uptake pathway has long been appreciated as an attractive target for drug design. Recently, one tight-binding competitive inhibitor of the trypanosomal purine-specific nucleoside hydrolase (IAGNH) showed remarkable trypanocidal activity in a murine model of infection. Here, the enzymatic characterization of T. brucei brucei IAGNH is presented, together with its high-resolution structures in the unliganded form and in complexes with different inhibitors, including the trypanocidal compound UAMC-00363. A description of the crucial contacts that account for the high-affinity inhibition of IAGNH by iminoribitol-based compounds is provided and the molecular mechanism underlying the conformational change necessary for enzymatic catalysis is identified. It is demonstrated for the first time that metalorganic complexes can compete for binding at the active site of nucleoside hydrolase enzymes, mimicking the positively charged transition state of the enzymatic reaction. Moreover, we show that divalent metal ions can act as noncompetitive IAGNH inhibitors, stabilizing a nonproductive conformation of the catalytic loop. These results open a path for rational improvement of the potency and the selectivity of existing compounds and suggest new scaffolds that may be used as blueprints for the design of novel antitrypanosomal compounds. [ABSTRACT FROM AUTHOR]

Respiratory and emotional responses to blood-acidifying inhalation of CO 2 are markers of some human anxiety disorders, and can be enhanced by repeatedly cross-fostering (RCF) mouse pups from their biological mother to unrelated lactating females. Yet, these dynamics remain poorly understood. We show RCF-associated intergenerational transmission of CO 2 sensitivity in normally-reared mice descending from RCF-exposed females, and describe the accompanying alterations in brain DNA methylation patterns. These epigenetic signatures were compared to DNA methylation profiles of monozygotic twins discordant for emotional reactivity to a CO 2 challenge. Altered methylation was consistently associated with repeated elements and transcriptional regulatory regions among RCF-exposed animals, their normally-reared offspring, and humans with CO 2 hypersensitivity. In both species, regions bearing differential methylation were associated with neurodevelopment, circulation, and response to pH acidification processes, and notably included the ASIC2 gene. Our data show that CO 2 hypersensitivity is associated with specific methylation clusters and genes that subserve chemoreception and anxiety. The methylation status of genes implicated in acid-sensing functions can inform etiological and therapeutic research in this field.