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Measurement of phospholipid lateral diffusion at high pressure by in situ magic-angle spinning NMR spectroscopy
The development of experimental methodologies that enable investigations of biochemistry at high pressure promises to yield significant advances in our understanding of life on Earth and its origins. Here, we introduce a method for studying lipid membranes at thermodynamic conditions relevant for life at deep sea hydrothermal vents. Using in situ high pressure magic-angle spinning solid state nuclear magnetic resonance spectroscopy (NMR), we measure changes in the fluidity of model microbial membranes at pressures up to 28 MPa. We find that the fluid-phase lateral diffusion of phospholipids at high pressure is significantly affected by the stoichiometric ratio of lipids in the membrane. Our results were facilitated by an accessible pressurization strategy that we have developed to enable routine preparation of solid state NMR rotors to pressures of 30 MPa or greater.
Blood pressure elevations post-lenvatinib treatment in hepatocellular carcinoma: a potential marker for better prognosis
Lenvatinib is a tyrosine kinase inhibitor that effectively inhibits vascular endothelial growth factor signaling and is used for treating hepatocellular carcinoma. However, angiogenesis inhibitors often cause hypertension. Although lenvatinib-induced hypertension has been proposed as a potential surrogate marker for better prognosis, studies on blood pressure elevations and outcomes following lenvatinib initiation are limited. This study included 67 patients who underwent lenvatinib therapy at the Department of Gastroenterology, Kagoshima University Hospital, between May 2018 and December 2023. The median age of the cohort was 71 years, and 82.1% of the patients were male. The median blood pressure at admission was 128/73 mmHg, which significantly increased to 136/76 mmHg the day after lenvatinib administration. Grade 3 hypertension (≥160/100 mmHg) occurred in 37.3% of patients during hospitalization. The median increase in systolic blood pressure from admission to its peak during hospitalization was 26 mmHg. Patients who experienced an increase in blood pressure of ≥26 mmHg were classified into the blood pressure elevation group, which showed a significantly lower mortality rate than that of the blood pressure non-elevation group (35.3% vs. 81.8%, log-rank p = 0.007), even after adjusting for age, sex, disease stage, performance status, and liver reserve function. This study demonstrated that patients who experienced earlier blood pressure elevation after lenvatinib administration had lower overall mortality rates. These findings suggest that blood pressure elevations after lenvatinib initiation may serve as valuable prognostic indicators in patients with cancer undergoing lenvatinib therapy.
The YTHDC1 reader protein recognizes and regulates the lncRNA MEG3 following its METTL3-mediated m6A methylation: a novel mechanism early during radiation-induced liver injury
While apoptotic cell death is known to be central to the pathogenesis of radiation-induced liver injury (RILI), the mechanistic basis for this apoptotic activity remains poorly understood. N6-methyladenosine (m6A) modifications are the most common form of reversible methylation observed on lncRNAs in eukaryotic cells, with their presence leading to pronounced changes in the activity of a range of biological processes. The degree to which m6A modification plays a role in the induction of apoptotic cell death in response to ionizing radiation (IR) in the context of RILI remains to be established. Here, IR-induced apoptosis was found to significantly decrease the levels of m6A present, with a pronounced decrease in the expression of methyltransferase-like 3 (METTL3) at 2 d post radiation in vitro. From a mechanistic perspective, a methylated RNA immunoprecipitation assay found that lncRNA MEG3 was a major METTL3 target. The expression of MEG3 was upregulated via METTL3-mediated m6A in a process that was dependent on YTHDC1, ultimately reversing the miR-20b-mediated inhibition of BNIP2 expression. Together, these findings demonstrate that the responsivity of METTL3 activity to IR plays a role in IR-induced apoptotic cell death, leading to the reverse of miR-20b-mediated BNIP2 inhibition through the YTHDC1-dependent m6A modification of MEG3, suggesting that this process may play a central role in RILI incidence.
STING directly interacts with PAR to promote apoptosis upon acute ionizing radiation-mediated DNA damage
Acute ionizing radiation (IR) causes severe DNA damage, leading to cell cycle arrest, cell death, and activation of the innate immune system. The role and signaling pathway of stimulator of interferon genes (STING) in IR-induced tissue damage and cell death are not well understood. This study revealed that STING is crucial for promoting apoptosis in response to DNA damage caused by acute IR both in vitro and in vivo. STING binds to poly (ADP‒ribose) (PAR) produced by activated poly (ADP‒ribose) polymerase-1 (PARP1) upon IR. Compared with that in WT cells, apoptosis was suppressed in Stinggt-/gt- cells. Excessive PAR production by PARP1 due to DNA damage enhances STING phosphorylation, and inhibiting PARP1 reduces cell apoptosis after IR. In vivo, IR-induced crypt cell death was significantly lower in Stinggt-/gt- mice or with low-dose PARP1 inhibitor, PJ34, resulting in substantial resistance to abdominal irradiation. STING deficiency or inhibition of PARP1 function can reduce the expression of the proapoptotic gene PUMA, decrease the localization of Bax on the mitochondrial membrane, and thus reduce cell apoptosis. Our findings highlight crucial roles for STING and PAR in the IR-mediated induction of apoptosis, which may have therapeutic implications for controlling radiation-induced apoptosis or acute radiation symptoms.
Tuning a magnetic energy scale with pressure and field in UTe2
When a fragile ordered state is suppressed to zero temperature, a quantum phase transition occurs, which is often marked by the appearance of unconventional superconductivity. While the quantum critical point can be hidden, the influence of the quantum criticality extends to fairly high temperatures, manifesting non-Fermi liquid behavior in a wide range of the field-temperature-pressure phase space. Here, we report the tuning of a magnetic energy scale in the heavy-fermion superconductor UTe2, previously identified with a peak in the c-axis electrical transport temperature dependence, using applied hydrostatic pressures and a-axis-oriented magnetic fields as complementary (and opposing) tuning parameters: the characteristic peak in c-axis resistivity decreases in temperature with applied pressure before vanishing near the critical pressure of 15 kbar (1.5 GPa), while the application of field shifts the peak to a higher temperature and broadens it under all studied pressures. At the critical pressure, the transport behavior deviates from Fermi liquid behavior, exhibiting a nearly linear temperature dependence of resistivity with an enhanced pre-factor. Our results shed light on the microscopic origin of the c-axis resistivity peak and provide a clear picture of magnetic energy scale evolution relevant to quantum criticality in UTe2.
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