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WDR5 remodels NANOG condensates to drive transcriptional programs and sustain stem cell identity
Boosting carbon nanotube transistors through γ-ray irradiation
A fully degradable triboelectric vagus nerve stimulator for attenuating cardiac remodeling and heart failure at different stages
Atmospheric deposition enhances marine methane production and emissions from global oceans
ZNF683+ NK cells govern chemotherapy sensitivity in advanced HPSCC via reshaping immune microenvironment
Endothelial cell responses in sepsis are attenuated by targeting truncated procalcitonin
Abstract Sepsis is associated with hypotension, vascular leakage, vasoplegia and microvascular dysfunction. Therefore, the endothelium is a target for sepsis therapies. Since truncated procalcitonin exerts vascular activity, we here evaluated the efficacy of targeting procalcitonin for vascular integrity and sepsis outcomes. Sepsis up-regulated >2000 genes involved in pro-inflammatory responses while similar numbers of genes involving cell growth and maintenance were down-regulated. Transcriptomic changes in endothelial cells diminished by >50% by anti-procalcitonin antibodies and this was functionally associated with preserved vascular barrier integrity in lungs and intestines, reduced sepsis-induced vasoplegia, preserved endothelial nitric oxide bioavailability, improved organ integrity and reduced sepsis severity in mice. Mechanistically, procalcitonin neutralization was associated with reduced signaling of the interleukin-17 pathway. We here show sepsis induces substantial changes to the endothelial transcriptome and vascular integrity and neutralizing procalcitonin is a suitable means to preserve endothelial homeostasis at a transcriptomic and functional level that could translate into organ protection during sepsis.
Spatiotemporal regulation of energetic charge dictates T cell function
Divergent aging of nulliparous and parous mammary glands reveals IL33+ hybrid epithelial cells
Abstract Aging increases breast cancer risk while an early first pregnancy reduces a woman’s life-long risk. Several studies have explored the effect of either aging or pregnancy on mammary stem/progenitor cells, however, the combined effect of both remains unclear. Here, we interrogate the functional and transcriptomic changes at single-cell resolution in the mammary gland of aged nulliparous and parous mice to discover that pregnancy normalizes age-related imbalances in lineage composition, while also inducing a differentiated cell state. Importantly, we uncover a minority population of Il33 -expressing epithelial cells that express both luminal and basal markers (i.e. hybrid), which accumulate in aged nulliparous mice but are significantly reduced in aged parous mice. Functionally, IL33 treatment of mammary epithelial cells from young mice phenocopies aged nulliparous epithelial cells, induces proliferation and promotes formation of organoids with Trp53 knockdown. Collectively, our study demonstrates that pregnancy blocks the age-associated imbalances in lineage integrity in the basal layer, including a decrease in Il33+ hybrid cells, that could potentially contribute to pregnancy-induced breast cancer protection.
Sugar rationing during the first 1000 days of life and lifelong risk of heart failure
An alternative EGFR activation by patient-derived R252C mutation promotes cancer progression
Abstract Mutations in the extracellular or intracellular domains of epidermal growth factor receptor (EGFR) are implicated in the development of various cancers. While the intracellular mutations of EGFR have been extensively studied, the function of extracellular mutations remains poorly understood. In this study, we identify an EGFR mutant (EGFR R252C) in a patient with multifocal lung cancer and glioma, in which arginine (R) 252 is mutated to cysteine (C) in the EGFR extracellular domain. This mutation promotes C252-C252 disulfide-mediated EGFR dimerization and induces a conformational change of EGFR, leading to absent autophosphorylation and enhanced direct interaction between EGFR and extracellular signal-regulated protein kinase 1/2 (ERK1/2). Importantly, EGFR directly phosphorylates ERK1/2 at threonine (T) 202 / tyrosine (Y) 204 and activates ERK1/2, thereby promoting tumor cell proliferation and tumor growth in vivo. Afatinib, a second-generation EGFR tyrosine kinase inhibitor, effectively suppresses primary tumor growth and extends progression-free survival in the patient with multifocal lung cancer and glioma driven by EGFR R252C. Our finding elucidates the activation mechanism of this extracellular EGFR mutation and demonstrates the efficacy of afatinib in treating lung cancer or glioma patients with this variant.
Neoadjuvant chemoradiotherapy plus sintilimab in proficient mismatch repair locally advanced rectal cancer with intermediate/high-immunoscore (SILAR): a single-arm phase II trial
A stochastic mechanism drives fast substrate translocation in the AAA+ machine ClpB
Abstract How biological machines harness ATP to drive mechanical work remains a crucial question. Structural studies of protein-translocating AAA+ machines proposed a coupled and sequential translocation process, whereby ATP hydrolysis events lead to short threading steps. Yet, direct real-time observation of these events remains elusive. Here, we employ single-molecule FRET spectroscopy to track substrate translocation through ClpB, a quality control AAA+ machine. We isolate ClpB and its substrate within lipid vesicles and find that translocation events, while dependent on ATP, take milliseconds, much faster than ATP hydrolysis times. Surprisingly, the translocation rate depends weakly on temperature and ATP concentration. Using three-color FRET experiments, we find that translocation events can occur bidirectionally but are not always complete. Replacing ATP with the slowly hydrolysable analog ATPγS abolishes both rapid translocation and directionality. These results indicate a fast, stochastic Brownian-motor-like mechanism, redefining how ATP is coupled with mechanical action in AAA+ machines.