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The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain obscure. Here we identify PKCβII as a critical contributor of ferroptosis through independent genome-wide CRISPR–Cas9 and kinase inhibitor library screening. Our results show that PKCβII senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKCβII–ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKCβII as a sensor of lipid peroxidation, and the lipid peroxidation–PKCβII–ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment. Through CRISPR–Cas9 and kinase inhibitor screening, Zhang et al. show that PKCβII phosphorylates and activates ACSL4 to enhance polyunsaturated fatty acid-containing lipid biosynthesis, thereby promoting accumulation of lipid peroxidation and ferroptosis.

Background: Poor habits can worsen gastroesophageal reflux disease (GERD) and reduce treatment efficacy. Few large-scale studies have examined lifestyle influences, particularly eating habits, on GERD in China, and research related to eating quickly, hyperphagia, and eating hot foods is quite limited. The aim of this study was to evaluate the relationship between GERD pathogenesis and lifestyle factors to produce useful information for the development of a clinical reference guide through a national multicenter survey in China. Methods: Symptom and lifestyle/habit questionnaires included 19 items were designed. The questionnaire results were subjected to correlation analysis relative to GERD symptom onset. A standard proton pump inhibitor (PPI) was advised to correct patients with unhealthful lifestyle habits. Results: A total of 1518 subjects (832 GERD, 686 non-GERD) enrolled from six Chinese hospitals completed symptom and lifestyle/habit questionnaires. The top lifestyle factors related to GERD were fast eating, eating beyond fullness, and preference for spicy food. Univariate analysis showed that 21 factors, including male gender, a supra-normal body mass index (BMI), smoking, drinking alcohol, fast eating, eating beyond fullness, eating very hot foods, and drinking soup, among others, were associated with GERD (p < 0.05). Logistic multivariate regression analysis revealed the following risk factors for GERD [with odds ratios (ORs)]: fast eating (4.058), eating beyond fullness (2.849), wearing girdles or corsets (2.187), eating very hot foods (1.811), high BMI (1.805), lying down soon after eating (1.544), and smoking (1.521). Adjuvant lifestyle interventions improved outcomes over medication alone (z = –8.578, p < 0.001 Mann–Whitney rank sum test). Conclusions: Lifestyle interventions can improve medication efficacy in GERD patients. Numerous habits, including fast eating, eating beyond fullness, and eating very hot foods, were associated with GERD pathogenesis. The present results may be useful as a reference for preventive education and treatment.

Improving the absorption of electromagnetic waves at low-frequency bands (2-8 GHz) is crucial for the increasing electromagnetic (EM) pollution brought about by the innovation of the fifth generation (5G) communication technology. However, the poor impedance matching and intrinsic attenuation of material in low-frequency bands hinders the development of low-frequency electromagnetic wave absorbing (EMWA) materials. Here we propose an interface-induced dual-pinning mechanism and establish a magnetoelectric bias interface by constructing bilayer core-shell structures of NiFe 2 O 4 (NFO)@BiFeO 3 (BFO)@polypyrrole (PPy). Such heterogeneous interface could induce distinct magnetic pinning of the magnetic moment in the ferromagnetic NFO and dielectric pinning of the dipole rotation in PPy. The establishment of the dual-pinning effect resulted in optimized impedance and enhanced attenuation at low-frequency bands, leading to better EMWA performance. The minimum reflection loss (RL min ) at thickness of 4.43 mm reaches -65.30 dB (the optimal absorption efficiency of 99.99997%), and the effective absorption bandwidth (EAB) can almost cover C-band (4.72 ~ 7.04 GHz) with low filling of 15.0 wt.%. This work proposes a mechanism to optimize low-frequency impedance matching with electromagnetic wave (EMW) loss and pave an avenue for the research of high-performance low-frequency absorbers. This paper proposes a dual-pinning mechanism induced by a magneto-electric bias interface and uses it to designs a double-layer core-shell structure, demonstrating that the mechanism improves electromagnetic wave absorption in the low-frequency bands.

Background GC pairs are generally more stable than AT pairs; GC-rich genomes were proposed to be more adapted to high temperatures than AT-rich genomes. Previous studies consistently showed positive correlations between growth temperature and the GC contents of structural RNA genes. However, for the whole genome sequences and the silent sites of the codons in protein-coding genes, the relationship between GC content and growth temperature is in a long-lasting debate. Results With a dataset much larger than previous studies (681 bacteria and 155 archaea with completely assembled genomes), our phylogenetic comparative analyses showed positive correlations between optimal growth temperature (Topt) and GC content both in bacterial and archaeal structural RNA genes and in bacterial whole genome sequences, chromosomal sequences, plasmid sequences, core genes, and accessory genes. However, in the 155 archaea, we did not observe a significant positive correlation of Topt with whole-genome GC content (GC w ) or GC content at four-fold degenerate sites. We randomly drew 155 samples from the 681 bacteria for 1000 rounds. In most cases (> 95%), the positive correlations between Topt and genomic GC contents became statistically nonsignificant ( P  > 0.05). This result suggested that the small sample sizes might account for the lack of positive correlations between growth temperature and genomic GC content in the 155 archaea and the bacterial samples of previous studies. Comparing the GC content among four categories (psychrophiles/psychrotrophiles, mesophiles, thermophiles, and hyperthermophiles) also revealed a positive correlation between GC w and growth temperature in bacteria. By including the GC w of incompletely assembled genomes, we expanded the sample size of archaea to 303. Positive correlations between GC w and Topt appear especially after excluding the halophilic archaea whose GC contents might be strongly shaped by intense UV radiation. Conclusions This study explains the previous contradictory observations and ends a long debate. Prokaryotes growing in high temperatures have higher GC contents. Thermal adaptation is one possible explanation for the positive association. Meanwhile, we propose that the elevated efficiency of DNA repair in response to heat mutagenesis might have the by-product of increasing GC content like that happens in intracellular symbionts and marine bacterioplankton.

Brassicales plants produce glucosinolates and myrosinases that generate toxic isothiocyanates conferring broad resistance against pathogens and herbivorous insects. Nevertheless, some cosmopolitan fungal pathogens, such as the necrotrophic white mold Sclerotinia sclerotiorum, are able to infect many plant hosts including glucosinolate producers. Here, we show that S. sclerotiorum infection activates the glucosinolate-myrosinase system, and isothiocyanates contribute to resistance against this fungus. S. sclerotiorum metabolizes isothiocyanates via two independent pathways: conjugation to glutathione and, more effectively, hydrolysis to amines. The latter pathway features an isothiocyanate hydrolase that is homologous to a previously characterized bacterial enzyme, and converts isothiocyanate into products that are not toxic to the fungus. The isothiocyanate hydrolase promotes fungal growth in the presence of the toxins, and contributes to the virulence of S. sclerotiorum on glucosinolate-producing plants.

Virtual reality (VR) is the use of computer technology to create an interactive three-dimensional (3D) world, which gives users a sense of spatial presence. In nursing education, VR has been used to help optimize teaching and learning processes. The purpose of this study was to evaluate the effectiveness of VR in nursing education in the areas of knowledge, skills, satisfaction, confidence, and performance time. We conducted a meta-analysis of the effectiveness of VR in nursing education based on the Cochrane methodology. An electronic literature search using the Cochrane Library, Web of Science, PubMed, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature), up to December 2019 was conducted to identify studies that reported the effectiveness of VR on knowledge, skills, satisfaction, confidence, and performance time. The study selection and data extraction were carried out by two independent reviewers. The methodological quality of the selected studies was determined using the Cochrane criteria for risk-of-bias assessment. A total of 12 studies, including 821 participants, were selected for the final analysis. We found that VR was more effective than the control conditions in improving knowledge (standard mean difference [SMD]=0.58, 95% CI 0.41-0.75, P<.001, I =47%). However, there was no difference between VR and the control conditions in skills (SMD=0.01, 95% CI -0.24 to 0.26, P=.93, I =37%), satisfaction (SMD=0.01, 95% CI -0.79 to 0.80, P=.99, I =86%), confidence (SMD=0.00, 95% CI -0.28 to 0.27, P=.99, I =0%), and performance time (SMD=-0.55, 95% CI -2.04 to 0.94, P=.47, I =97%). The results of this study suggest that VR can effectively improve knowledge in nursing education, but it was not more effective than other education methods in areas of skills, satisfaction, confidence, and performance time. Further rigorous studies with a larger sample size are warranted to confirm these results.

Most patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC. B7H3 is a transmembrane B7 family checkpoint molecule present on many cancer cells. Here the authors show that FUT8 mediates fucosylation of B7H3 to limit the immune response to triple-negative breast cancer as a potentially targeted mechanism of non-responsiveness to current checkpoint therapies.

The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Philadelphia chromosome (Ph) and is a hallmark of chronic myeloid leukemia (CML). In leukemia cells, Ph not only impairs the physiological signaling pathways but also disrupts genomic stability. This aberrant fusion gene encodes the breakpoint cluster region‐proto‐oncogene tyrosine‐protein kinase (BCR‐ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity. The kinase activity is responsible for maintaining proliferation, inhibiting differentiation, and conferring resistance to cell death. During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase, the expression patterns of different BCR‐ABL1 transcripts vary. Each BCR‐ABL1 transcript is present in a distinct leukemia phenotype, which predicts both response to therapy and clinical outcome. Besides CML, the Ph is found in acute lymphoblastic leukemia, acute myeloid leukemia, and mixed‐phenotype acute leukemia. Here, we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph‐positive leukemia and highlight key findings regarding leukemogenesis.

Mitochondria are highly dynamic organelles undergoing cycles of fusion and fission to modulate their morphology, distribution, and function, which are referred as ‘mitochondrial dynamics’. Dynamin-related protein 1 (Drp1) is known as the major pro-fission protein whose activity is tightly regulated to clear the damaged mitochondria via mitophagy, ensuring a strict control over the intricate process of cellular and organ dynamics in heart. Various posttranslational modifications (PTMs) of Drp1 have been identified including phosphorylation, SUMOylation, palmitoylation, ubiquitination, S-nitrosylation, and O-GlcNAcylation, which implicate a role in the regulation of mitochondrial dynamics. An intact mitochondrial homeostasis is critical for heart to fuel contractile function and cardiomyocyte metabolism, while defects in mitochondrial dynamics constitute an essential part of the pathophysiology underlying various cardiovascular diseases (CVDs). In this review, we summarize current knowledge on the critical role of Drp1 in the pathogenesis of CVDs including endothelial dysfunction, smooth muscle remodeling, cardiac hypertrophy, pulmonary arterial hypertension, myocardial ischemia–reperfusion, and myocardial infarction. We also highlight how the targeting of Drp1 could potentially contribute to CVDs treatments.

Cell membrane (CM) is a phospholipid bilayer that maintains integrity of a whole cell and relates to many physiological and pathological processes. Developing CM imaging tools is a feasible method for visualizing membrane-related events. In recent decades, small-molecular fluorescent probes in the near-infrared (NIR) region have been pursued extensively for CM staining to investigate its functions and related events. In this review, we summarize development of such probes from the aspect of design principles, CM-targeting mechanisms and biological applications. Moreover, at the end of this review, the challenges and future research directions in designing NIR CM-targeting probes are discussed. This review indicates that more efforts are required to design activatable NIR CM-targeting probes, easily prepared and biocompatible probes with long retention time regarding CM, super-resolution imaging probes for monitoring CM nanoscale organization and multifunctional probes with imaging and phototherapy effects.