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Frontiers in Immunology 2024Resection of colorectal liver metastasis is the standard of care for patients with Stage IV CRC. Despite undoubtedly improving the overall survival of patients, pHx for...
BACKGROUND
Resection of colorectal liver metastasis is the standard of care for patients with Stage IV CRC. Despite undoubtedly improving the overall survival of patients, pHx for colorectal liver metastasis frequently leads to disease recurrence. The contribution of this procedure to metastatic colorectal cancer at a molecular level is poorly understood. We designed a mouse model of orthograde metastatic colorectal cancer (CRC) to investigate the effect of partial hepatectomy (pHx) on tumor progression.
METHODS
CRC organoids were implanted into the cecal walls of wild type mice, and animals were screened for liver metastasis. At the time of metastasis, 1/3 partial hepatectomy was performed and the tumor burden was assessed longitudinally using MRI. After euthanasia, different tissues were analyzed for immunological and transcriptional changes using FACS, qPCR, RNA sequencing, and immunohistochemistry.
RESULTS
Mice that underwent pHx presented significant liver hypertrophy and an increased overall metastatic load compared with SHAM operated mice in MRI. Elevation in the metastatic volume was defined by an increase in liver metastasis without any effect on the growth of each metastasis. Concordantly, the livers of pHx mice were characterized by neutrophil and bacterial infiltration, inflammatory response, extracellular remodeling, and an increased abundance of tight junctions, resulting in the formation of a premetastatic niche, thus facilitating metastatic seeding.
CONCLUSIONS
Regenerative pathways following pHx accelerate colorectal metastasis to the liver by priming a premetastatic niche.
Topics: Animals; Colorectal Neoplasms; Hepatectomy; Mice; Liver Neoplasms; Liver; Tumor Microenvironment; Disease Models, Animal; Humans; Mice, Inbred C57BL; Inflammation; Male
PubMed: 38919609
DOI: 10.3389/fimmu.2024.1388272 -
Horticulture Research Jun 2024To date, there has been no high-quality sequence for genomes of the East Asian grape species, hindering biological and breeding efforts to improve grape cultivars. This...
To date, there has been no high-quality sequence for genomes of the East Asian grape species, hindering biological and breeding efforts to improve grape cultivars. This study presents ~522 Mb of the () genome sequence containing 27 635 coding genes. Phylogenetic analysis indicated that () may have first split from the other two species, and (). Divergent numbers of duplicated genes reserved among grapes suggests that the core eudicot-common hexaploidy (ECH) and the subsequent genome instability still play a non-negligible role in species divergence and biological innovation. Prominent accumulation of sequence variants might have improved cold resistance in , resulting in a more robust network of regulatory cold resistance genes, explaining why it is extremely cold-tolerant compared with and . In contrast, has preserved many fewer nucleotide binding site (NBS) disease resistance genes than the other grapes. Notably, multi-omics analysis identified one -cinnamate 4-monooxygenase gene positively correlated to the resveratrol accumulated during berry development. A selective sweep analysis revealed a hypothetical sex-determination region (SDR). Besides, a PPR-containing protein-coding gene in the hypothetical SDR may be related to sex determination in . The content and arrangement order of genes in the putative SDR of female were similar to those of female . However, the putative SDR of female has lost one flavin-containing monooxygenase (FMO) gene and contains one extra protein-coding gene uncharacterized so far. These findings will improve the understanding of biology and contribute to the improvement of grape breeding.
PubMed: 38919553
DOI: 10.1093/hr/uhae117 -
Biotechnology For Biofuels and... Jun 2024β-Arbutin, a hydroquinone glucoside found in pears, bearberry leaves, and various plants, exhibits antioxidant, anti-inflammatory, antimicrobial, and anticancer...
BACKGROUND
β-Arbutin, a hydroquinone glucoside found in pears, bearberry leaves, and various plants, exhibits antioxidant, anti-inflammatory, antimicrobial, and anticancer effects. β-Arbutin has wide applications in the pharmaceutical and cosmetic industries. However, the limited availability of high-performance strains limits the biobased production of β-arbutin.
RESULTS
This study established the β-arbutin biosynthetic pathway in C. glutamicum ATCC13032 by introducing codon-optimized ubiC, MNX1, and AS. Additionally, the production titer of β-arbutin was increased by further inactivation of csm and trpE to impede the competitive metabolic pathway. Further modification of the upstream metabolic pathway and supplementation of UDP-glucose resulted in the final engineered strain, C. glutamicum AR11, which achieved a β-arbutin production titer of 7.94 g/L in the optimized fermentation medium.
CONCLUSIONS
This study represents the first successful instance of de novo β-arbutin production in C. glutamicum, offering a chassis cell for β-arbutin biosynthesis.
PubMed: 38918796
DOI: 10.1186/s13068-024-02540-2 -
BMC Cancer Jun 2024High-grade B-cell lymphoma (HGBCL), the subtype of non-Hodgkin lymphoma, to be relapsed or refractory in patients after initial therapy or salvage chemotherapy. Dual...
High-grade B-cell lymphoma (HGBCL), the subtype of non-Hodgkin lymphoma, to be relapsed or refractory in patients after initial therapy or salvage chemotherapy. Dual dysregulation of MYC and BCL2 is one of the important pathogenic mechanisms. Thus, combined targeting of MYC and BCL2 appears to be a promising strategy. Dihydroorotate dehydrogenase (DHODH) is the fourth rate-limiting enzyme for the de novo biosynthesis of pyrimidine. It has been shown to be a potential therapeutic target for multiple diseases. In this study, the DHODH inhibitor brequinar exhibited growth inhibition, cell cycle blockade, and apoptosis promotion in HGBCL cell lines with MYC and BCL2 rearrangements. The combination of brequinar and BCL2 inhibitors venetoclax had a synergistic inhibitory effect on the survival of DHL cells through different pathways. Venetoclax could upregulate MCL-1 and MYC expression, which has been reported as a resistance mechanism of BCL2 inhibitors. Brequinar downregulated MCL-1 and MYC, which could potentially overcome drug resistance to venetoclax in HGBCL cells. Furthermore, brequinar could downregulate a broad range of genes, including ribosome biosynthesis genes, which might contribute to its anti-tumor effects. In vivo studies demonstrated synergetic tumor growth inhibition in xenograft models with brequinar and venetoclax combination treatment. These results provide preliminary evidence for the rational combination of DHODH and BCL2 blockade in HGBCL with abnormal MYC and BCL2.
Topics: Humans; Animals; Proto-Oncogene Proteins c-bcl-2; Dihydroorotate Dehydrogenase; Mice; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic; Proto-Oncogene Proteins c-myc; Xenograft Model Antitumor Assays; Drug Synergism; Cell Line, Tumor; Oxidoreductases Acting on CH-CH Group Donors; Apoptosis; Lymphoma, B-Cell; Gene Rearrangement; Cell Proliferation; Biphenyl Compounds; Quinaldines
PubMed: 38918775
DOI: 10.1186/s12885-024-12534-w -
BMC Genomics Jun 2024The nervous system is central to coordinating behavioural responses to environmental change, likely including ocean acidification (OA). However, a clear understanding of...
BACKGROUND
The nervous system is central to coordinating behavioural responses to environmental change, likely including ocean acidification (OA). However, a clear understanding of neurobiological responses to OA is lacking, especially for marine invertebrates.
RESULTS
We evaluated the transcriptomic response of the central nervous system (CNS) and eyes of the two-toned pygmy squid (Idiosepius pygmaeus) to OA conditions, using a de novo transcriptome assembly created with long read PacBio ISO-sequencing data. We then correlated patterns of gene expression with CO treatment levels and OA-affected behaviours in the same individuals. OA induced transcriptomic responses within the nervous system related to various different types of neurotransmission, neuroplasticity, immune function and oxidative stress. These molecular changes may contribute to OA-induced behavioural changes, as suggested by correlations among gene expression profiles, CO treatment and OA-affected behaviours.
CONCLUSIONS
This study provides the first molecular insights into the neurobiological effects of OA on a cephalopod and correlates molecular changes with whole animal behavioural responses, helping to bridge the gaps in our knowledge between environmental change and animal responses.
Topics: Animals; Transcriptome; Behavior, Animal; Carbon Dioxide; Seawater; Hydrogen-Ion Concentration; Decapodiformes; Gene Expression Profiling; Cephalopoda; Oceans and Seas; Ocean Acidification
PubMed: 38918719
DOI: 10.1186/s12864-024-10542-5 -
Scientific Data Jun 2024
PubMed: 38918444
DOI: 10.1038/s41597-024-03545-0 -
NPJ Parkinson's Disease Jun 2024Striosomes and matrix are two compartments that comprise the striatum, each having its own distinct immunohistochemical properties, function, and connectivity. It is...
Striosomes and matrix are two compartments that comprise the striatum, each having its own distinct immunohistochemical properties, function, and connectivity. It is currently not clear whether prodromal or early manifest Parkinson's disease (PD) is associated with any striatal matrix or striosomal abnormality. Recently, a method of striatal parcellation using probabilistic tractography has been described and validated, using the distinct connectivity of these two compartments to identify voxels with striosome- and matrix-like connectivity. The goal of this study was to use this approach in tandem with DAT-SPECT, a method used to quantify the level of nigrostriatal denervation, to analyze the striatum in populations of de novo diagnosed, treatment-naïve patients with PD, isolated REM behavioral disorder (iRBD) patients, and healthy controls. We discovered a shift in striatal connectivity, which showed correlation with nigrostriatal denervation. Patients with PD exhibited a significantly higher matrix-like volume and associated connectivity than healthy controls and higher matrix-associated connectivity than iRBD patients. In contrast, the side with less pronounced nigrostriatal denervation in PD and iRBD patients showed a decrease in striosome-like volume and associated connectivity indices. These findings could point to a compensatory neuroplastic mechanism in the context of nigrostriatal denervation and open a new avenue in the investigation of the pathophysiology of Parkinson's disease.
PubMed: 38918417
DOI: 10.1038/s41531-024-00736-9 -
NPJ Parkinson's Disease Jun 2024
PubMed: 38918412
DOI: 10.1038/s41531-024-00726-x -
Microbiology Spectrum Jun 2024Riboflavin (vitamin B) is the precursor of the flavin coenzymes, FAD and FMN, which play a central role in cellular redox metabolism. While humans must obtain riboflavin...
UNLABELLED
Riboflavin (vitamin B) is the precursor of the flavin coenzymes, FAD and FMN, which play a central role in cellular redox metabolism. While humans must obtain riboflavin from dietary sources, certain microbes, including (Mtb), can biosynthesize riboflavin . Riboflavin precursors have also been implicated in the activation of mucosal-associated invariant T (MAIT) cells which recognize metabolites derived from the riboflavin biosynthesis pathway complexed to the MHC-I-like molecule, MR1. To investigate the biosynthesis and function of riboflavin and its pathway intermediates in mycobacterial metabolism and physiology, we constructed conditional knockdowns (hypomorphs) in riboflavin biosynthesis and utilization genes in (Msm) and Mtb by inducible CRISPR interference. Using this comprehensive panel of hypomorphs, we analyzed the impact of gene silencing on viability, on the transcription of (other) riboflavin pathway genes, on the levels of the pathway proteins, and on riboflavin itself. Our results revealed that (i) despite lacking a canonical transporter, both Msm and Mtb assimilate exogenous riboflavin when supplied at high concentration; (ii) there is functional redundancy in lumazine synthase activity in Msm; (iii) silencing of or is profoundly bactericidal in Mtb; and (iv) in Msm, silencing results in concomitant knockdown of other pathway genes coupled with RibA2 and riboflavin depletion and is also bactericidal. In addition to their use in genetic validation of potential drug targets for tuberculosis, this collection of hypomorphs provides a useful resource for future studies investigating the role of pathway intermediates in MAIT cell recognition of mycobacteria.
IMPORTANCE
The pathway for biosynthesis and utilization of riboflavin, precursor of the essential coenzymes, FMN and FAD, is of particular interest in the flavin-rich pathogen, (Mtb), for two important reasons: (i) the pathway includes potential tuberculosis (TB) drug targets and (ii) intermediates from the riboflavin biosynthesis pathway provide ligands for mucosal-associated invariant T (MAIT) cells, which have been implicated in TB pathogenesis. However, the riboflavin pathway is poorly understood in mycobacteria, which lack canonical mechanisms to transport this vitamin and to regulate flavin coenzyme homeostasis. By conditionally disrupting each step of the pathway and assessing the impact on mycobacterial viability and on the levels of the pathway proteins as well as riboflavin, our work provides genetic validation of the riboflavin pathway as a target for TB drug discovery and offers a resource for further exploring the association between riboflavin biosynthesis, MAIT cell activation, and TB infection and disease.
PubMed: 38916330
DOI: 10.1128/spectrum.03207-23 -
Microbiology Spectrum Jun 2024The presence of intermittently dispersed insertion sequences and transposases in the (Mtb) genome makes intra-genome recombination events inevitable. Understanding...
The presence of intermittently dispersed insertion sequences and transposases in the (Mtb) genome makes intra-genome recombination events inevitable. Understanding their effect on the gene repertoires (GR), which may contribute to the development of drug-resistant Mtb, is critical. In this study, publicly available WGS data of clinical Mtb isolates (endemic region = 2,601; non-endemic region = 1,130) were assembled, filtered, scaffolded into assemblies, and functionally annotated. Out of 2,601 Mtb WGS data sets from endemic regions, 2,184 (drug resistant/sensitive: 1,386/798) qualified as high quality. We identified 3,784 core genes, 123 softcore genes, 224 shell genes, and 762 cloud genes in the pangenome of Mtb clinical isolates from endemic regions. Sets of 33 and 39 genes showed positive and negative associations ( < 0.01) with drug resistance status, respectively. Gene ontology clustering showed compromised immunity to phages and impaired DNA repair in drug-resistant Mtb clinical isolates compared to the sensitive ones. Multidrug efflux pump repressor genes (Rv3830c and Rv3855c) and CRISPR genes (Rv2816c-19c) were absent in the drug-resistant Mtb. A separate WGS data analysis of drug-resistant Mtb clinical isolates from the Netherlands ( = 1130) also showed the absence of CRISPR genes (Rv2816c-17c). This study highlights the role of CRISPR genes in drug resistance development in Mtb clinical isolates and helps in understanding its evolutionary trajectory and as useful targets for diagnostics development.IMPORTANCEThe results from the present Pan-GWAS study comparing gene sets in drug-resistant and drug-sensitive Mtb clinical isolates revealed intricate presence-absence patterns of genes encoding DNA-binding proteins having gene regulatory as well as DNA modification and DNA repair roles. Apart from the genes with known functions, some uncharacterized and hypothetical genes that seem to have a potential role in drug resistance development in Mtb were identified. We have been able to extrapolate many findings of the present study with the existing literature on the molecular aspects of drug-resistant Mtb, further strengthening the relevance of the results presented in this study.
PubMed: 38916315
DOI: 10.1128/spectrum.00527-24