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Civil war
This edition of the Civil War replaces the earlier Loeb Classical Library edition by A.G. Peskett (1914) with new text, translation, introduction, and bibliography.
Book
Single-atom catalysts-based catalytic ROS clearance for efficient psoriasis treatment and relapse prevention via restoring ESR1
Psoriasis is a common inflammatory disease of especially high recurrence rate (90%) which is suffered by approximately 3% of the world population. The overexpression of reactive oxygen species (ROS) plays a critical role in psoriasis progress. Here we show that biomimetic iron single-atom catalysts (FeN
4
O
2
-SACs) with broad-spectrum ROS scavenging capability can be used for psoriasis treatment and relapse prevention via related gene restoration. FeN
4
O
2
-SACs demonstrate attractive multiple enzyme-mimicking activities based on atomically dispersed Fe active structures, which are analogous to those of natural antioxidant enzymes, iron superoxide dismutase, human erythrocyte catalase, and ascorbate peroxidase. Further, in vitro and in vivo experiments show that FeN
4
O
2
-SACs can effectively ameliorate psoriasis-like symptoms and prevent the relapse with augmented efficacy compared with the clinical drug calcipotriol. Mechanistically, estrogen receptor 1 (ESR1) is identified as the core protein upregulated in psoriasis treatment through RNA sequencing and bioinformatic analysis. Together, this study provides a proof of concept of psoriasis catalytic therapy (PCT) and multienzyme-inspired bionics (MIB).
Psoriasis is a common inflammatory disease, and the overproduction of reactive oxygen species (ROS) in skin lesions plays a critical role in the progress of psoriasis. Here, the authors report the use of multienzyme-inspired biomimetic iron single-atom catalysts (FeN
4
O
2
-SACs) with broad-spectrum ROS-scavenging capability for psoriasis treatment and relapse prevention via related gene restoration.
Journal Article
Crossing the Rubicon : Caesar's decision and the fate of Rome
A dramatic account of the fateful year leading to the ultimate crisis of the Roman Republic and the rise of Caesar's autocracy. When the Senate ordered Julius Caesar, conqueror of Gaul, to disband his troops, he instead marched his soldiers across the Rubicon River, in violation of Roman law. The Senate turned to its proconsul, Pompey the Great, for help. But Pompey's response was unexpected: he commanded magistrates and senators to abandon Rome-a city that, until then, had always been defended. The consequences were the ultimate crisis of the Roman Republic and the rise of Caesar's autocracy. In this new history, Luca Fezzi argues that Pompey's actions sealed the Republic's fate. Drawing on a wide range of primary sources, including Cicero's extensive letters, Fezzi shows how Pompey's decision shocked the Roman people, severely weakened the city, and set in motion a chain of events that allowed Caesar to take power. Seamlessly translated by Richard Dixon, this book casts fresh light on the dramatic events of this crucial moment in ancient Roman history.
Book
Global fungal-host interactome mapping identifies host targets of candidalysin
Candidalysin, a cytolytic peptide toxin secreted by the human fungal pathogen
Candida albicans
, is critical for fungal pathogenesis. Yet, its intracellular targets have not been extensively mapped. Here, we performed a high-throughput enhanced yeast two-hybrid (HT-eY2H) screen to map the interactome of all eight Ece1 peptides with their direct human protein targets and identified a list of potential interacting proteins, some of which were shared between the peptides. CCNH, a regulatory subunit of the CDK-activating kinase (CAK) complex involved in DNA damage repair, was identified as one of the host targets of candidalysin. Mechanistic studies revealed that candidalysin triggers a significantly increased double-strand DNA breaks (DSBs), as evidenced by the formation of γ-H2AX foci and colocalization of CCNH and γ-H2AX. Importantly, candidalysin binds directly to CCNH to activate CAK to inhibit DNA damage repair pathway. Loss of CCNH alleviates DSBs formation under candidalysin treatment. Depletion of candidalysin-encoding gene fails to induce DSBs and stimulates CCNH upregulation in a murine model of oropharyngeal candidiasis. Collectively, our study reveals that a secreted fungal toxin acts to hijack the canonical DNA damage repair pathway by targeting CCNH and to promote fungal infection.
Candidalysin is a toxin secreted by
Candida albicans
. Although critical for pathogenesis, its intracellular targets are not well mapped. Here, Zhang et al screen for interacting proteins and identify that candidalysin can modulate the DNA damage repair pathway to promote fungal infection.
Journal Article
H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions
The mechanisms underlying gene repression and silencers are poorly understood. Here we investigate the hypothesis that H3K27me3-rich regions of the genome, defined from clusters of H3K27me3 peaks, may be used to identify silencers that can regulate gene expression via proximity or looping. We find that H3K27me3-rich regions are associated with chromatin interactions and interact preferentially with each other. H3K27me3-rich regions component removal at interaction anchors by CRISPR leads to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. Cells with H3K27me3-rich regions knockout also show changes in phenotype associated with cell identity, and altered xenograft tumor growth. Finally, we observe that H3K27me3-rich regions-associated genes and long-range chromatin interactions are susceptible to H3K27me3 depletion. Our results characterize H3K27me3-rich regions and their mechanisms of functioning via looping.
Mechanisms underlying gene repression and silencers remain poorly understood. Here the authors investigate the role of H3K27me3-rich regions in the genome, as defined from clusters of H3K27me3 peaks, in regulating gene expression via looping.
Journal Article
Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing
The cyclin-dependent kinase inhibitor p21
WAF1/CIP1
(p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4–CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery—an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs.
Galanos and colleagues observe p21 accumulation in proliferating cancer cells, and show that in cultured p53-null cells, p21 can cause genomic instability by perturbing replication licensing through inhibition of the CRL4-CDT ubiquitin ligase.
Journal Article
The lantern bearers
Instead of leaving with the last of the Roman legions, Aquila, a young officer, decides that his loyalties lie with Britain, and he eventually joins the forces of the Roman-British leader Ambrosius to fight against the Saxon hordes.
Book
Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention
Composition of gut bacteria and serum metabolites in young, obese individuals is partially restored following weight loss surgery, including
Bacteroides thetaiotaomicron
, which decreases serum glutamate levels and fat mass gain in mice.
Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of
Bacteroides thetaiotaomicron
, a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with
B. thetaiotaomicron
reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of
B. thetaiotaomicron
and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota.
Journal Article