The emergence of multidrug-resistant bacteria and biofilms requires discovering new antimicrobial agents from unexplored environments. This study aims to isolate and characterize a new actinobacterial strain from the Hoggar Mountains in southern Algeria and evaluate its ability to produce bioactive molecules with potential antibacterial and antibiofilm activities. A novel halotolerant actinobacterial strain, designated HG-17, was isolated from the Hoggar Mountains, and identified based on phenotypic characterizations, 16S rDNA sequence analysis, and phylogenetic analysis. The antibacterial and antibiofilm activities of the strain were assessed, and the presence of biosynthetic genes (PKS-I and NRPS) was confirmed. Two active compounds, HG-7 and HG-9, were extracted butanol solvent, purified by HPLC, and their chemical structures were elucidated using ESI mass spectrometry and NMR spectroscopy. The strain HG-17 was identified as Streptomyces purpureus NBRC with 98.8

Abstract Cytidine deaminase (CDA) functions in the pyrimidine salvage pathway for DNA and RNA syntheses and has been shown to protect cancer cells from deoxycytidine-based chemotherapies. In this study, we observed that CDA was overexpressed in pancreatic adenocarcinoma from patients at baseline and was essential for experimental tumor growth. Mechanistic investigations revealed that CDA localized to replication forks where it increased replication speed, improved replication fork restart efficiency, reduced endogenous replication stress, minimized DNA breaks, and regulated genetic stability during DNA replication. In cellular pancreatic cancer models, high CDA expression correlated with resistance to DNA-damaging agents. Silencing CDA in patient-derived primary cultures in vitro and in orthotopic xenografts in vivo increased replication stress and sensitized pancreatic adenocarcinoma cells to oxaliplatin. This study sheds light on the role of CDA in pancreatic adenocarcinoma, offering insights into how this tumor type modulates replication stress. These findings suggest that CDA expression could potentially predict therapeutic efficacy and that targeting CDA induces intolerable levels of replication stress in cancer cells, particularly when combined with DNA-targeted therapies. Significance: Cytidine deaminase reduces replication stress and regulates DNA replication to confer resistance to DNA-damaging drugs in pancreatic cancer, unveiling a molecular vulnerability that could enhance treatment response.

Supplementary Table 3 contains the location of isoform selective phosphorylations in the protein.

Stress granules (SGs) and processing bodies (PBs) are membraneless cytoplasmic assemblies regulating mRNAs under environmental stress such as viral infections, neurological disorders, or cancer. Upon antigen stimulation, T lymphocytes mediate their immune functions under regulatory mechanisms involving SGs and PBs. However, the impact of T cell activation on such complexes in terms of formation, constitution, and relationship remains unknown. Here, by combining proteomic, transcriptomic, and immunofluorescence approaches, we simultaneously characterized the SGs and PBs from primary human T lymphocytes pre and post stimulation. The identification of the proteomes and transcriptomes of SGs and PBs indicate an unanticipated molecular and functional complementarity. Notwithstanding, these granules keep distinct spatial organizations and abilities to interact with mRNAs. This comprehensive characterization of the RNP granule proteomic and transcriptomic landscapes provides a unique resource for future investigations on SGs and PBs in T lymphocytes.

This file contains the additional information for Material and method, including method for cell transduction, cell treatment and WB, RT-qPCR analysis, viablity assays, proliferation assays, DEVD cleavage assay, flow cytometry, soft agar assay, organoid and soft agar assay quantification and ImageJ plugin, scriot for analaysis of unpaired heavy/light phosphopeptides, method for SILAC labelling, SILAC sample preparation, data-dependent acquisition LC-MS/MS, phosphoproteomic data analysis, mice housing, details on statistics, as well as Legends of supplementary figures and tables, table with sequences of shRNAs, used antibodies, RT-qPCR primers.

Summary Objective Increased consumption of meat is an epidemiologically validated risk condition for pancreatic cancer development, but the underlying mechanisms and whether it is related to induction of epithelial cell plasticity are unknown. Design Experimental protocol to test the influence of high consumption of meat was compared to pancreatic inflammation experimental models. To determine the molecular drivers promoting pancreatic cell plasticity, we compared transcriptomics data sets from human samples of pancreatic inflammation and pancreatic cancer (PDAC) prone to plasticity and validated in vivo, ex vivo and in vitro the main identified target. Results Meat-enriched diet promoted plasticity of pancreatic acinar cells, that transdifferentiated in duct-like cells, and presented PI3K activation. We identified a selective PI3K activation gene signature enriched with plasticity. In this signature, PHGDH , which encodes an enzyme responsible for amino acid serine synthesis, was differentially expressed. High level of PHGDH in acinar cells was necessary for the proliferative action of PI3Kα sustained by an increased maximal mitochondrial capacity and decreased cyclin-dependent inhibitor p27 level. PHGDH level was decreased in transdifferentiated acinar cells. In this context, active PI3Kα promoted cell plasticity but decreased the number of cycling cells. Both epithelial-restricted genetic inactivation of PI3Kα and full PI3Kα inhibition by pharmacological dosage reduced inflammation-induced tissue damage, while a pharmacological PI3Kα activator promoted PanIN precancer lesion development. Conclusion Meat-enriched diet promoted plasticity. Blockage of plasticity by PI3Kα inhibition provoked an increased rate of acinar cell proliferation that had a beneficial impact on the tissue microenvironment less prone to precancer lesion development. What is already known on this topic It is now well accepted that inflammatory conditions predispose to pancreatic tumour development; increased consumption of red and processed meat is an epidemiologically validated risk condition, but the underlying mechanisms are unknown. What this study adds We identify PI3K activation as a common molecular pathway activated by increased consumption of red and processed meat and by inflammatory condition to promote pancreatic plasticity and precancer lesion development. How this study might affect research, practice or policy As we show that treatments with the clinically available PI3Kα inhibitor block pancreatic plasticity under inflammatory stress while maintaining pancreas mass and limiting inflammatory reaction damage, they may represent an efficient and safe preventive interception drug in patients at risk of developing pancreatic cancer. PI3K pro-cancer action is exacerbated by the loss of serine synthesis enzyme; hence, diets that alter amino acid synthesis should be tightly controlled in those patients.

Supplementary Figures file contains merged Figure S1 to S8 including description of cell lines, Human samples, PI3K inhibitor stability, SILAC setup and controls, STRING analysis, quantifications of WB and cellular assays, prediction of kinase motifs found regulated, effects of combination of treatment in vitro, correlation between cell survival and phosphopeptide intensity, effects of combination treatment in Human samples and in vivo.

Supplementary Table 2 contains the list of isoform selective peptides in each condition, with quantification and global pathway analysis.

BACKGROUND:The development of single-cell technologies yields large datasets of information as diverse and multimodal as transcriptomes, immunophenotypes, and spatial position from tissue sections in the so-called 'spatial transcriptomics'. Currently however, user-friendly, powerful, and free algorithmic tools for straightforward analysis of spatial transcriptomic datasets are scarce.RESULTS:Here, we introduce Single-Cell Spatial Explorer, an open-source software for multimodal exploration of spatial transcriptomics, examplified with 9 human and murine tissues datasets from 4 different technologies.CONCLUSIONS:Single-Cell Spatial Explorer is a very powerful, versatile, and interoperable tool for spatial transcriptomics analysis.

Supplementary Figures S1-S10 and Tables S1-S3

Supplementary Table 1 contains the list of files deposited on PRIDE Proteome X Change under the number PXD008410.

Tyrosine kinase inhibitors pazopanib and sunitinib are both used to treat advanced renal cell carcinoma but expose patients to an increased risk of hepatotoxicity. We have previously identified two aldehyde derivatives for pazopanib and sunitinib (P-CHO and S-CHO, respectively) in liver microsomes. In this study, we aimed to decipher their role in hepatotoxicity by treating HepG2 and HepaRG hepatic cell lines with these derivatives and evaluating cell viability, mitochondrial dysfunction, and oxidative stress accumulation. Additionally, plasma concentrations of P-CHO were assessed in a cohort of patients treated with pazopanib. Results showed that S-CHO slightly decreased the viability of HepG2, but to a lesser extent than sunitinib, and affected the maximal respiratory capacity of the mitochondrial chain. P-CHO decreased viability and ATP production in HepG2. Traces of P-CHO were detected in the plasma of patients treated with pazopanib. Overall, these results showed that P-CHO and S-CHO affect hepatocyte integrity and could be involved in the pazopanib and sunitinib hepatotoxicity.

Multi-resistant bacterial pathogens are a major public health problem for treating nosocomial infections owing to their high resistance to antibiotics. The objective of this research was to characterize the bioactive molecules secreted by a novel moderately halophilic actinobacterium strain, designated GSB-11, exhibiting a strong antagonistic activity against several multidrug-resistant pathogenic bacteria. This potential strain was identified by phenotypic, genotypic (16S rRNA), and phylogenetic analyses. GSB-11 was related to "Streptomyces acrimycini" NBRC 12736 T with 99.59% similarity. Molecular screening by PCR assay demonstrated that the strain possesses two biosynthetic genes coding for NRPS and PKS-II. Two active compounds GSB11-6 and GSB11-7 were extracted from the cell-free culture supernatant of Bennett medium and purified using reversed-phase HPLC. According to spectrometric (mass spectrum) and spectroscopic (1H NMR, 13C NMR, 1H-1H COSY, and 1H-13C HMBC) spectra analyses, the compounds GSB11-6 and GSB11-7 were identified to be maculosin and N-acetyltyramine, respectively. Their minimum inhibitory concentrations (MIC) revealed interesting values against certain multidrug-resistant pathogenic bacteria. They were between 5 and 15 mg/mL for GSB11-6, 10 and 30 mg/mL for GSB11-7. To our best knowledge, this is the first study of these active substances isolated from "Streptomyces acrimycini" showing an interesting antibacterial activity. Therefore, these essential compounds could be candidates for future research against multidrug-resistant bacteria.

Aim: The aim of this article is to characterize in detail the γδ T lymphocytes from an adult patient with primary cutaneous T-cell lymphoma of γδ subtype (γδ CTCL). Methods: Here this article reports trajectory mapping on high-resolution differentiation trajectories of γδ T lymphocytes digitally extracted from a scRNAseq dataset. Results: In the patch-to-plaque progression of CTCL, the TCRVγnon9 subset of γδ T cells differentiated from naive T cells (Tn) and central memory T cells (Tcm) to abundant effector memory T cells (Tem) while other cutaneous γδ T and CD8 T cells remained unchanged. Conclusions: This transcriptomic switch underlies the emergence of a CTCL-like progression of the TCRVγnon9 γδ T subtype and suggests new routes for treating these diseases.