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It is well established that ferroptosis is primarily controlled by glutathione peroxidase 4 (GPX4). Surprisingly, we observed that p53 activation modulates ferroptotic responses without apparent effects on GPX4 function. Instead, ALOX12 inactivation diminishes p53-mediated ferroptosis induced by reactive oxygen species stress and abrogates p53-dependent inhibition of tumour growth in xenograft models, suggesting that ALOX12 is critical for p53-mediated ferroptosis. The ALOX12 gene resides on human chromosome 17p13.1, a hotspot of monoallelic deletion in human cancers. Loss of one Alox12 allele is sufficient to accelerate tumorigenesis in Eμ-Myc lymphoma models. Moreover, ALOX12 missense mutations from human cancers abrogate its ability to oxygenate polyunsaturated fatty acids and to induce p53-mediated ferroptosis. Notably, ALOX12 is dispensable for ferroptosis induced by erastin or GPX4 inhibitors; conversely, ACSL4 is required for ferroptosis upon GPX4 inhibition but dispensable for p53-mediated ferroptosis. Thus, our study identifies an ALOX12-mediated, ACSL4-independent ferroptosis pathway that is critical for p53-dependent tumour suppression. Chu et al. identify the lipoxygenase ALOX12 as essential for p53-dependent ferroptosis in a pathway independent of GPX4. Monoallelic deletion of Alox12 abrogates p53-mediated suppression in a model of Eµ-Myc -driven lymphoma.

In order to develop high power lithium ion batteries (LIBs), urgent requirements including adequate safety, higher current density and superior cyclic stability are proposed for separator. Tissue paper, composed of packed cellulose fibers, possesses lower production cost, easier accessibility, superior wettability together with outstanding thermostability, and is thus a candidate to be the substrate for high performance separator. To address the issue of structural failure usually encountered by single polymer as binder during long term cycling, crosslinked binder was constructed on tissue paper to adhere nano-SiO 2 through chemical reactions between poly (vinylidene fluoride- co -hexafluoropropylene) (PVDF-HFP) and hyperbranched polyethyleneimine (PEI) in this work. The effects of crosslinking degree on physical properties and electrochemical performance were studied thoroughly. When the feed ratio of PVDF-HFP and PEI is fixed at 10:1, the crosslinked composite separator displays excellent electrolyte uptake and wettability, superior ionic conductivity, better interfacial compatibility as well as higher Li + transference number (0.56), thus offering battery with prominent rate capabilities. Besides, this crosslinked composite separator exhibits satisfying dimensional stability even treated at 250 °C, better flame retardancy, enhanced mechanical behavior, wider electrochemical window and outstanding cycle stability. Accordingly, tissue paper-based crosslinked composite separators can meet higher requirements put forward by high power LIBs. Graphical abstract

We aimed to evaluate the role of cone-beam computed tomography (CT) performed as an adjunct to angiography for the determination of feeding vessels responsible for bleeding during arterial embolization for massive hemoptysis. In this retrospective study, 23 patients with massive hemoptysis who underwent cone-beam CT evaluation prior to arterial embolization from December 2014 to December 2017 were included. During the angiographic session, two interventional radiologists selected the possible feeding vessels that were likely to supply the bleeding target lesions. Contrast-enhanced cone-beam CT was performed at the indefinite feeding arteries as an adjunct to angiography to determine whether the artery was a real feeding vessel, based on whether the target lesion was detected in the perfused territory of the study artery on images. Selective cone-beam CT was successfully performed in 21 patients, at 26 possible feeding vessels that were detected by selective angiography. Cone-beam CT determined the feeding vessel in 24 arteries (92.3%) in 19 patients (90.5%). As a result of cone-beam CT findings, 16 of 24 study arteries were judged as definitively not feeding vessels (66.7%) and the remaining 8 study arteries were judged as definitively feeding vessels (33.3%). In 2 of 26 study arteries cone-beam CT could not determine the feeding vessel (7.7%). Cone-beam CT performed as an adjunctive technique to angiography is sufficient to provide adequate information for confident determination of the feeding vessel, which is essential for the operators to perform accurate embolization during arterial embolization for massive hemoptysis.

Although p53-mediated cell-cycle arrest, senescence and apoptosis serve as critical barriers to cancer development, emerging evidence suggests that the metabolic activities of p53 are also important. Here we show that p53 inhibits cystine uptake and sensitizes cells to ferroptosis, a non-apoptotic form of cell death, by repressing expression of SLC7A11 , a key component of the cystine/glutamate antiporter. Notably, p53 3KR , an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, fully retains the ability to regulate SLC7A11 expression and induce ferroptosis upon reactive oxygen species (ROS)-induced stress. Analysis of mutant mice shows that these non-canonical p53 activities contribute to embryonic development and the lethality associated with loss of Mdm2 . Moreover, SLC7A11 is highly expressed in human tumours, and its overexpression inhibits ROS-induced ferroptosis and abrogates p53 3KR -mediated tumour growth suppression in xenograft models. Our findings uncover a new mode of tumour suppression based on p53 regulation of cystine metabolism, ROS responses and ferroptosis. p53 suppresses expression of SLC7A11, a key component of the cystine/glutamate amino acid transport machinery, leading to inhibition of cystine uptake and promoting ferroptosis, an iron-dependent form of cell death. Novel mechanism for p53 tumour suppression The tumour suppressor activity of the transcription factor p53 is typically thought to reflect its ability to induce cell cycle arrest, apoptosis or senescence in response to cellular stress, but there is emerging evidence for other activities of p53. Here Wei Gu and colleagues show that a metabolic target of p53 can also contribute to its tumour suppressor activity. In particular, they find that p53 suppresses expression of SLC7A11 , a key component of the cystine/glutamate amino acid transport machinery. This leads to inhibition of cystine uptake and promotes ferroptosis, an iron-dependent form of cell death. This previously unrecognized function of p53 seems to be important in tumour suppression, particularly when other pathways are inoperative.

CDK11 gene encodes two proteins, p110 and p58. CDK11 p110 proteins are part of large-molecular-weight complexes containing RNA polymerase II, transcriptional elongation and general pre-mRNA splicing factors, suggesting they couple transcription and pre-mRNA splicing. CDK11 p58 is expressed only during G2/M from an internal ribosome entry site (IRES) present in the mRNA encoding CDK11p110 and appears to regulate mitosis. To examine the in vivo role of CDK11p110/p58 kinases, we generated CDK11p110/p58-null mice and found CDK11 p110/p58 deficiency results in early embryonic lethality and apoptosis between E3.5 and E4.0. Cells within CDK11p110/p58-/- embryos exhibit both proliferative defects and a mitotic arrest. These results indicated that the CDK11p110/p58 kinases are essential for cellular viability and normal early embryonic development. CDK11p110/p58 T cell-specific knockout mice generated by using Cre/loxP system show defects in T cell development. Deletion of CDK11p110/p58 in thymocytes results in a block at the double negative (DN) stage due to the defective pre-TCR signaling, impaired proliferation and apoptosis. CDK11p110/p58 deficiency in thymocytes also affects alternative splicing of CD45. Taken together, these results indicate that CDK11 protein kinases play important roles in transcription, splicing and mitotic regulation.

Situated at a geographic crossroads, the eastern Tianshan Mountain region in northwest China is crucial to understanding various economic, social, and cultural developments on the Eurasian Steppes. One promising way to gain a better knowledge of ancient subsistence economy, craft production, and social change in the eastern Tianshan Mountain region is to study the artifact assemblages from archaeological contexts. Here, we present an analysis of 488 worked animal bones from the large site of Shirenzigou (ca. 1300–1 BCE), to date the largest assemblage of this kind uncovered in the eastern Tianshan Mountain region. We classified these worked bones into six categories, including “ritual objects”, “ornaments”, “tools”, “worked astragali”, “warfare and mobility”, and “indeterminate”. The identification of animal species and skeletal elements indicates that worked bones from Shirenzigou are characterized by a predominance of caprine products, particularly worked astragali, which is consistent with the large proportion of caprine fragments found in animal remains associated with food consumption. This demonstrates the contribution of caprine pastoralism to bone working activities at Shirenzigou. The making of most worked bones does not appear to have required advanced or specialized skills. Considering the absence of dedicated bone working space, alongside the variability in raw material selection and in dimensions of certain types of artifacts, we infer that worked bone production at Shirenzigou was not standardized. In terms of raw material selection and mode of production, Shirenzigou differed from their settled, farming counterparts in the Yellow River valley of northern China. In addition, along with the evidence for violence and horseback riding, the increasing use of bone artifacts associated with warfare and mobility during the late occupation phase of Shirenzigou reflects growing social instability and implies the likely emergence of single mounted horsemen, equipped with light armors, in the region during the late first millennium BCE. Our results provide new insights into animal resource exploitation and changing lifeways of early pastoral societies in the eastern Tianshan Mountain region, expanding our knowledge of the economic, social, and political milieu of late Bronze Age and early Iron Age eastern Eurasia.

To investigate the role of Sigma1 receptor (Sigma1R) in mitochondrial energy metabolism remodeling in atrial myocytes, elucidate the associated molecular mechanisms, and evaluate its therapeutic potential in atrial fibrillation (AF). HL-1 atrial myocytes were subjected to tachypacing at 5 Hz for 24 h to establish an AF model. Lentiviral vectors were used to modulate Sigma1R and IRE1α expression. Cell viability was assessed by CCK-8 assay, apoptosis by Annexin V-FITC/PI staining and flow cytometry, mitochondrial function by TMRE staining for membrane potential, MitoSOX Red for reactive oxygen species (ROS) detection, and ATP assays. Calcium dynamics were measured using Fura-2/AM and Fluo-3/AM imaging. Protein expression was analyzed by Western blot, and subcellular localization was confirmed by fluorescence in situ hybridization (FISH). Tachypacing induced significant damage in atrial myocytes, including a 32.16% apoptosis rate, decreased Sigma1R expression, mitochondrial swelling, a 38% reduction in ATP levels, a 37% increase in mitochondrial ROS, and a 122% increase in cytosolic calcium compared to control cells. Overexpression of Sigma1R significantly mitigated these effects: cell viability increased by 55% ( P  < 0.001), apoptosis was reduced by 55% ( P  < 0.01), ATP levels were restored to 84% of control values ( P  < 0.01), and mitochondrial ROS decreased by 55% ( P  < 0.05). Mechanistically, Sigma1R overexpression normalized calcium homeostasis, reducing cytosolic calcium to 134 ± 11 nM from 218 ± 16 nM in the AF group ( P  < 0.01) and suppressed pathological expansion of endoplasmic reticulum-mitochondria contact sites. The activation of the IRE1α/XBP1 pathway was inhibited by Sigma1R, as evidenced by reductions in IRE1α, phosphorylated IRE1α, and XBP1s protein levels by 39–47% ( P  < 0.05). Conversely, IRE1α overexpression abrogated the protective effects of Sigma1R, leading to a 22% increase in apoptosis ( P  < 0.01) and exacerbating mitochondrial and calcium dysfunction. Sigma1R protects atrial myocytes from tachypacing-induced injury by enhancing mitochondrial function, reducing oxidative stress, and regulating calcium homeostasis at mitochondria-associated membranes, primarily through inhibition of the IRE1α/XBP1 pathway. These findings highlight Sigma1R as a promising therapeutic target for mitigating mitochondrial remodeling in AF.

To examine the clinicopathologic and immunohistochemical features of a group of newly defined low-grade oncocytic renal tumors (LOT) that have the “CD117 negative/cytokeratin (CK)7 positive” immunoprofile. We have queried our hospital database and found 4456 consecutive renal tumors between 2016 and 2019. Among these renal tumors, eight (8) cases meet the morphologic and immunohistochemical characterization for low-grade oncocytic renal tumor (LOT). The eight (8) patients’ mean age is 56.6 years (range 39–70 years old), and the male to female ratio is 1:1. Macroscopically, these LOTs generally present with tan-brown and solid cut surfaces and demonstrate similar solid, compact nested growth pattern microscopically. Tumor cells exhibit oncocytic cytoplasm and uniformly rounded to oval nuclei. There are areas of edematous stroma containing dispersed single or small clustered tumor cells. All tumors are negative for CD117 and positive for CK7. Uniform reactivity is also found for BerEP4, cyclin D1, and SDHB. Besides, CD10, vimentin, and AMACR are either negative or only focally positive. All of the tumors are negative for CA9 and TFE. The Ki-67 index is less than 5% in the seven (7) internal cases. Seven (7) of the eight (8) patients who are available for follow-up are alive and without disease recurrence (mean follow-up period of 21.6 months, ranging from 6 to 43 months). We described a group of low-grade oncocytic renal tumors identified retrospectively in a large tertiary cancer center, which was probably the first report originated from China or even Asia in the English literature so far. These tumors demonstrated eosinophilic cytoplasm and low-grade appearing nuclei with a “CD117 negative/CK7 positive” immunoprofile. The incidence rate was about 3.7% of the oncocytic renal tumors and 0.18% of all the renal tumors that were received in our lab during the four-year period. It is necessary to separate this group of tumors by its characteristic morphologic and immunophenotypic features.

Horseback riding was a transformative force in the ancient world, prompting radical shifts in human mobility, warfare, trade, and interaction. In China, domestic horses laid the foundation for trade, communication, and state infrastructure along the ancient Silk Road, while also stimulating key military, social, and political changes in Chinese society. Nonetheless, the emergence and adoption of mounted horseback riding in China is still poorly understood, particularly due to a lack of direct archaeological data. Here we present a detailed osteological study of eight horse skeletons dated to ca. 350 BCE from the sites of Shirenzigou and Xigou in Xinjiang, northwest China, prior to the formalization of Silk Road trade across this key region. Our analyses reveal characteristic osteological changes associated with equestrian practices on all specimens. Alongside other relevant archaeological evidence, these data provide direct evidence for mounted horseback riding, horse equipment, and mounted archery in northwest China by the late first millennium BCE. Most importantly, our results suggest that this region may have played a crucial role in the spread of equestrian technologies from the Eurasian interior to the settled civilizations of early China, where horses facilitated the rise of the first united Chinese empires and the emergence of transcontinental trade networks.

Quantum photonic integrated circuits are reshaping quantum networks and sensing by providing compact, efficient platforms for practical quantum applications. Despite continuous breakthroughs, integrating entangled registers into photonic devices on a CMOS-compatible platform presents significant challenges. Herein, we present single electron-nuclear spin entanglement and its integration into a silicon-carbide-on-insulator (SiCOI) waveguide. We demonstrate the successful generation of single divacancy electron spins and near-unity spin initialization of single 13 C nuclear spins. Both single nuclear and electron spin can be coherently controlled and a maximally entangled state with a fidelity of 0.89 has been prepared under ambient conditions. Based on the nanoscale positioning techniques, the entangled quantum register has been further integrated into SiC photonic waveguides for the first time. We find that the intrinsic optical and spin characteristics of the register are well preserved and the fidelity of the entangled state remains as high as 0.88. Our findings highlight the promising prospects of the SiCOI platform as a compelling candidate for future scalable quantum photonic applications. Silicon-carbide-on-insulator is a promising platform for scalable quantum photonic circuits. Here the authors demonstrate the integration of a single electron-nuclear spin register into silicon-carbide-on-insulator waveguides, which is an important step toward CMOS-compatible quantum photonic devices.