Degrading aurora kinase A in neuroblastoma
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Integrated proteogenomic characterization of ampullary adenocarcinoma
Ampullary adenocarcinoma (AMPAC) is a rare and heterogeneous malignancy. Here we performed a comprehensive proteogenomic analysis of 198 samples from Chinese AMPAC patients and duodenum patients. Genomic data illustrate that 4q loss causes fatty acid accumulation and cell proliferation. Proteomic analysis has revealed three distinct clusters (C-FAM, C-AD, C-CC), among which the most aggressive cluster, C-AD, is associated with the poorest prognosis and is characterized by focal adhesion. Immune clustering identifies three immune clusters and reveals that immune cluster M1 (macrophage infiltration cluster) and M3 (DC cell infiltration cluster), which exhibit a higher immune score compared to cluster M2 (CD4+ T-cell infiltration cluster), are associated with a poor prognosis due to the potential secretion of IL-6 by tumor cells and its consequential influence. This study provides a comprehensive proteogenomic analysis for seeking for better understanding and potential treatment of AMPAC.
Different types of cell death and their interactions in myocardial ischemia–reperfusion injury
Myocardial ischemia–reperfusion (I/R) injury is a multifaceted process observed in patients with coronary artery disease when blood flow is restored to the heart tissue following ischemia-induced damage. Cardiomyocyte cell death, particularly through apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, is pivotal in myocardial I/R injury. Preventing cell death during the process of I/R is vital for improving ischemic cardiomyopathy. These multiple forms of cell death can occur simultaneously, interact with each other, and contribute to the complexity of myocardial I/R injury. In this review, we aim to provide a comprehensive summary of the key molecular mechanisms and regulatory patterns involved in these five types of cell death in myocardial I/R injury. We will also discuss the crosstalk and intricate interactions among these mechanisms, highlighting the interplay between different types of cell death. Furthermore, we will explore specific molecules or targets that participate in different cell death pathways and elucidate their mechanisms of action. It is important to note that manipulating the molecules or targets involved in distinct cell death processes may have a significant impact on reducing myocardial I/R injury. By enhancing researchers’ understanding of the mechanisms and interactions among different types of cell death in myocardial I/R injury, this review aims to pave the way for the development of novel interventions for cardio-protection in patients affected by myocardial I/R injury.
Proteome selectivity profiling of photoaffinity probes derived from imidazopyrazine-kinase inhibitors
Kinases are attractive drug targets, but the design of highly selective kinase inhibitors remains challenging. Selectivity may be evaluated against a panel of kinases, or – preferred – in a complex proteome. Probes that allow photoaffinity-labeling of their targets can facilitate this process. Here, we report photoaffinity probes based on the imidazopyrazine scaffold, which is found in several kinase inhibitors and drugs or drug candidates. By chemical proteomics experiments, we find a range of off-targets, which vary between the different probes. In silico analysis suggests that differences between probes may be related to the size, spatial arrangement and rigidity of the imidazopyrazine and its substituent at the 1-position.
Horizontal metaproteomics and CAZymes analysis of lignocellulolytic microbial consortia selectively enriched from cow rumen and termite gut
Selectively enriched microbial consortia are potentially useful for the
conversion of lignocellulose (LC) into biofuels and commodity chemicals. Consortia
are also of interest to elucidate the roles of individual microorganisms and the
dynamics of enzymes involved in LC deconstruction. Using metaproteomics, 16 S rRNA
gene amplicon sequencing and multivariate discriminant analysis, we revealed the
temporal dynamics of microbial species and their proteins during anaerobic
conversion of LC by microbial consortia derived from cow rumen (RWS) and termite gut
(TWS) microbiomes. Bacteroidetes (Bacteroidota), Firmicutes (Bacillota) and
Proteobacteria (Pseudomonadota) phyla were dominant, irrespective the inoculum
origin, displaying functional complementarities. We identified a large variety of
carbohydrate-active enzymes, distributed in 94 CAZy families, involved in biomass
deconstruction. Additionally, proteins involved in short chain fatty acids
biosynthesis were detected. Multivariate analysis clearly differentiates RWS and TWS
metaproteomes, with differences originating in the initial inoculates. Further
supervised discriminant analysis of the temporal succession of CAZymes revealed that
both consortia consume easily accessible oligosaccharides during the early stage of
incubation, degrading more complex hemicellulose and cellulose fractions at later
stages, an action that pursues throughout the incubation period. Our results provide
new insights regarding the functional roles and complementarities existing in
lignocellulolytic consortia and highlight their potential for biorefinery
applications.
Identification and cultivation of anaerobic bacterial scavengers of dead cells
The cycle of life and death and Earth’s carbon cycle(s) are intimately linked, yet how bacterial cells, one of the largest pools of biomass on Earth, are recycled back into the carbon cycle remains enigmatic. In particular, no bacteria capable of scavenging dead cells in oxygen-depleted environments have been reported thus far. In this study, we discover the first anaerobes that scavenge dead cells and the two isolated strains use distinct strategies. Based on live-cell imaging, transmission electron microscopy, and hydrolytic enzyme assays, one strain (designated CYCD) relied on cell-to-cell contact and cell invagination for degrading dead food bacteria where as the other strain (MGCD) degraded dead food bacteria via excretion of lytic extracellular enzymes. Both strains could degrade dead cells of differing taxonomy (bacteria and archaea) and differing extents of cell damage, including those without artificially inflicted physical damage. In addition, both depended on symbiotic metabolic interactions for maximizing cell degradation, representing the first cultured syntrophic Bacteroidota. We collectively revealed multiple symbiotic bacterial decomposition routes of dead prokaryotic cells, providing novel insight into the last step of the carbon cycle.
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