SUMMARYIron excess is closely associated with tumorigenesis in multiple types of human cancers, with underlying mechanisms yet unclear. Recently, iron deprivation has emerged as a major strategy for chemotherapy, but it exerts tumor suppression only on select human malignancies. Here, we report that the tumor suppressor protein p53 is downregulated during iron excess. Strikingly, the iron polyporphyrin heme binds to p53 protein, interferes with p53-DNA interactions, and triggers both nuclear export and cytosolic degradation of p53. Moreover, in a tumorigenicity assay, iron deprivation suppressed wild-type p53-dependent tumor growth, suggesting that upregulation of wild-type p53 signaling underlies the selective efficacy of iron deprivation. Our findings thus identify a direct link between iron/heme homeostasis and the regulation of p53 signaling, which not only provides mechanistic insights into iron-excess-associated tumorigenesis but may also help predict and improve outcomes in iron-deprivation-based chemotherapy.

Two-dimensional (2D) membranes exhibit exceptional properties in molecular separation and transport, which reveals their potential use in various applications. However, ion sieving with 2D membranes is severely restrained due to intercalation-induced swelling.Here, we describe how to efficiently stabilize the lamellar architecture using Keggin Al 13 polycations as pillars in a Ti 3 C 2 T x membrane. More importantly, interlayer spacing can be easily adjusted with angstrom precision over a wide range (2.7−11.2 Å) to achieve selective and tunable ion sieving. A membrane with narrow d-spacing demonstrated enhanced selectivity for monovalent ions. When applied in a forward osmosis desalination process, this membrane exhibited high NaCl exclusion (99%) with a fast water flux (0.30 L m −2 h −1 bar −1 ). A membrane with wide d-spacing showed notable selectivity, which was dependent on the cation valence. When it was applied to acid recovery from iron-based industrial wastewater, the membrane showed good H + /Fe 2+ selectivity, which makes it a promising substitute for traditional polymeric membranes. Thus, we introduce a possible route to construct 2D membranes with appropriate structures to satisfy different ion-sieving requirements in diverse environment-, resource-, and energy-related applications. KEYWORDS: Ti 3 C 2 T x membrane, interlayer spacing, Al 13 Keggin ions, tunable ion sieving, desalination

The intestinal invasion of pathogenic microorganisms can have serious health consequences. Recent evidence has shown that the N6-methyladenosine (m6A) mRNA modification is closely associated with innate immunity; however, the underlying mechanism is poorly understood. Here, we examined the function and mechanism of m6A mRNA modification and the YTH domain-containing protein YTHDF1 (YTH N6-methyladenosine RNA-binding protein 1) in the innate immune response against bacterial pathogens in the intestine. Ribo-seq and m6A-seq analyses revealed that YTHDF1 directs the translation of Traf6 mRNA, which encodes tumor necrosis factor receptor-associated factor 6, thereby regulating the immune response via the m6A modification near the transcript's stop codon. Furthermore, we identified a unique mechanism by which the P/Q/N-rich domain in YTHDF1 interacts with the DEAD domain in the host factor DDX60, thereby regulating the intestinal immune response to bacterial infection by recognizing the target Traf6 transcript. These results provide novel insights into the mechanism by which YTHDF1 recognizes its target and reveal YTHDF1 as an important driver of the intestinal immune response, opening new avenues for developing therapeutic strategies designed to modulate the intestinal immune response to bacterial infection.

A high-resolution imaging x-ray crystal spectrometer is described for implementation on the EAST tokamak to provide spatially and temporally resolved data on the ion temperature, electron temperature and poloidal plasma rotation. These data are derived from observations of the satellite spectra of helium-like argon, Ar XVII, which is the dominant charge state for electron temperatures in the range from 0.4 to 3.0 keV and which is accessible to EAST. Employing a novel design, which is based on the imaging properties of spherically bent crystals, the spectrometers will provide spectrally and spatially resolved images of the plasma for all experimental conditions, which include ohmically heated discharges as well as plasmas with rf and neutral-beam heating. The experimental setup and initial experimental results are presented.

Recent studies found that mutations in the human SLC30A10 gene, which encodes a manganese (Mn) efflux transporter, are associated with hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC). However, the relationship between Mn metabolism and HMDPC is poorly understood, and no specific treatments are available for this disorder. Here, we generated two zebrafish slc30a10 mutant lines using the CRISPR/Cas9 system. Compared to wild-type animals, mutant adult animals developed significantly higher systemic Mn levels, and Mn accumulated in the brain and liver of mutant embryos in response to exogenous Mn. Interestingly, slc30a10 mutants developed neurological deficits in adulthood, as well as environmental Mn-induced manganism in the embryonic stage; moreover, mutant animals had impaired dopaminergic and GABAergic signaling. Finally, mutant animals developed steatosis, liver fibrosis, and polycythemia accompanied by increased epo expression. This phenotype was rescued partially by EDTA- CaNa2 chelation therapy and iron supplementation. Interestingly, prior to the onset of slc30a10 expression, expressing ATP2C1 (ATPase secretory pathway Ca2+ transporting 1) protected mutant embryos from Mn exposure, suggesting a compensatory role for Atp2c1 in the absence of Slc30a10. Notably, expressing either wild-type or mutant forms of SLC30A10 was sufficient to inhibit the effect of ATP2C1 in response to Mn challenge in both zebrafish embryos and HeLa cells. These findings suggest that either activating ATP2C1 or restoring the Mn-induced trafficking of ATP2C1 can reduce Mn accumulation, providing a possible target for treating HMDPC.

Aims De-differentiation and activation of pro-inflammatory pathways are key transitions vascular smooth muscle cells (SMCs) make during atherogenesis. Here, we explored the upstream regulators of this ‘atherogenic transition’. Methods and results Genome-wide sequencing studies, including ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) and RNA-seq, were performed on cells isolated from both murine SMC-lineage tracing models of atherosclerosis and human atherosclerotic lesions. At the bulk level, alterations in chromatin accessibility were associated with the atherogenic transitioning of lesional SMCs, especially in relation to genes that govern differentiation status and complement-dependent inflammation. Using computational biology, we observed that a transcription factor previously related to coronary artery disease, ATF3 (Activating transcription factor 3), was predicted to be an upstream regulator of genes altered during the transition. At the single-cell level, our results indicated that ATF3 is a key repressor of SMC transitioning towards the subset of cells that promote vascular inflammation by activating the complement cascade. The expression of ATF3 and complement component C3 were negatively correlated in SMCs from human atherosclerotic lesions, suggesting translational relevance. Phenome-wide association studies indicated that genetic variation that results in reduced expression of ATF3 is correlated with an increased risk for atherosclerosis, and the expression of ATF3 was significantly downregulated in humans with advanced vascular disease. Conclusion Our study indicates that the plasticity of atherosclerotic SMCs may in part be explained by dynamic changes in their chromatin architecture, which in turn may contribute to their maladaptive response to inflammation-induced stress. Translational perspective The recent CANTOS and COLCOT trials have shown that targeting inflammatory pathways lowers the risk of major adverse cardiovascular events. However, more specific targets are needed to avoid immunosuppressive side effects. Our data identify an upstream regulator of pro-inflammatory SMCs, ATF3, which is involved in the initial atherogenic transitioning of lesional SMCs. Restoring ATF3 activity may prevent the de-differentiation of SMCs and offer a novel translational approach for the suppression of complement-dependent inflammation in atherosclerotic lesions.

To explore the relationship between the zinc distribution and zinc transporter 3 (ZnT3) mRNA expression in the mouse brain, zinc contents and its distribution were determined by synchrotron radiation x-ray fluorescence (SRXRF), and ZnT3 mRNA expression was examined by reverse-transcription polymerase chain reaction and in situ hybridization. The results showed that the zinc contents were not distributed evenly in various brain tissues. The zinc contents in cerebral cortex and hippocampus were nearly 5-10 times higher than that in other neural locations. Correspondingly, ZnT3 mRNA expression was observed in high abundance in the cerebral cortex, hippocampus, and testis, but was not detected in other organs and tissues. In the nervous system, ZnT3 mRNA was detected mainly in hippocampus, cerebral cortex, and spinal ganglion. The present results show the coincident distribution of zinc and ZnT3 mRNA in mouse brain. The high zinc contents might be determined by the high expression of ZnT3. More meaningfully, the results showed the feasibility of applying of SRXRF in examining the distribution of minerals in different organs and tissues. In addition, it was observed for the first time that ZnT3 mRNA was expressed in the facial nucleus. The function of ZnT3 in facial nucleus awaits further study.

A lamellar membrane assembled by parallel restacking of two-dimensional nanosheets provides a novel platform for studying the electrostatic manipulation of ion mobility under angstrom-scale confinement. The membrane nanostructure in aqueous solution is unstable due to intercalation. However, because accurate measurements of structural changes under different charged conditions are difficult, their effect on the ion modulation was seldom fully addressed, and the electrostatic modulation mechanism was not good. Here, we report the efficient manipulation of ion diffusion in the confined channels through a Ti 3 C 2 T x membrane and gain insight into the mechanism by an in situ measurement of the lamellar nanostructure using an electrochemical quartz crystal microbalance with dissipation (EQCM-D). By precisely tuning the external potential directly applied to the membrane, the ion permeation rate can be effectively and reversibly increased by 6 times or decreased by 15 times. The EQCM-D measurement provides empirical evidence to demonstrate that the anomalous ionflow modulation is determined by both the channel diameter and an ion rearrangement in the electrical double layers (EDLs), particularly, in the Stern layers. Although the channel expanded at low negative voltage, the ion permeation rate decelerated due to the counterion distribution in the Stern layers.