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Aims: Red blood cell distribution width‐to‐albumin ratio (RAR), an innovate biomarker of inflammation, can independently predict adverse cardiovascular outcomes. However, the association between RAR and prognosis in patients with non‐ischaemic heart failure (NIHF) remains unclear. Methods and results: A total of 2077 NIHF patients admitted to the Heart Failure Care Unit, Fuwai Hospital, were consecutively enrolled from December 2006 to October 2017 in this retrospective study. The primary endpoint was a composite outcome of all‐cause mortality and heart transplantation. The correlation between RAR and the composite outcome was assessed by the Kaplan–Meier survival analysis and the Cox regression analysis. Incremental predictive values and the clinical performance of RAR for all‐cause mortality or heart transplantation were also assessed based on a 12‐variable traditional risk model. The median follow‐up time in this study was 1433 (1341, 1525) days. As the gender no longer satisfied the Cox proportional risk assumption after 1150 days, we set 1095 days as the follow‐up time for analysis. A total of 500 patients reached the composite outcome. Multivariable Cox regression showed that per log2 increase of RAR was significantly associated with a 132.9% [hazard ratio 2.329, 95% confidence interval (CI) 1.677–3.237, P < 0.001] increased risk of all‐cause mortality or heart transplantation. Better model discrimination [concordance index: 0.766 (95% CI 0.754–0.778) vs. 0.758 (95% CI 0.746–0.770), P < 0.001], calibration (Akaike information criterion: 1487.3 vs. 1495.74; Bayesian information criterion: 1566.25 vs. 1569.43; Brier score: 1569.43 vs. 1569.43; likelihood ratio test P < 0.001), and reclassification (integrated discrimination improvement: 1.35%, 95% CI 0.63–2.07%, P < 0.001; net reclassification improvement: 13.73%, 95% CI 2.05–27.18%, P = 0.034) were improved after adding RAR to the traditional model (P < 0.001 for all). A higher overall net benefit was also obtained in the threshold risk probability of 20–55%. Conclusions: High level of RAR was an independent risk factor of poor outcome in NIHF. [ABSTRACT FROM AUTHOR]

PIWI‐interacting RNAs (piRNAs) are highly expressed in various cardiovascular diseases. However, their role in cardiomyocyte death caused by ischemia/reperfusion (I/R) injury, especially necroptosis, remains elusive. In this study, a heart necroptosis‐associated piRNA (HNEAP) is found that regulates cardiomyocyte necroptosis by targeting DNA methyltransferase 1 (DNMT1)‐mediated 5‐methylcytosine (m5C) methylation of the activating transcription factor 7 (Atf7) mRNA transcript. HNEAP expression level is significantly elevated in hypoxia/reoxygenation (H/R)‐exposed cardiomyocytes and I/R‐injured mouse hearts. Loss of HNEAP inhibited cardiomyocyte necroptosis and ameliorated cardiac function in mice. Mechanistically, HNEAP directly interacts with DNMT1 and attenuates m5C methylation of the Atf7 mRNA transcript, which increases Atf7 expression level. ATF7 can further downregulate the transcription of Chmp2a, an inhibitor of necroptosis, resulting in the reduction of Chmp2a level and the progression of cardiomyocyte necroptosis. The findings reveal that piRNA‐mediated m5C methylation is involved in the regulation of cardiomyocyte necroptosis. Thus, the HNEAP‐DNMT1‐ATF7‐CHMP2A axis may be a potential target for attenuating cardiac injury caused by necroptosis in ischemic heart disease. [ABSTRACT FROM AUTHOR]

Despite the prevalence of superresolution (SR) microscopy, quantitative live-cell SR imaging that maintains the completeness of delicate structures and the linearity of fluorescence signals remains an uncharted territory. Structured illumination microscopy (SIM) is the ideal tool for live-cell SR imaging. However, it suffers from an out-of-focus background that leads to reconstruction artifacts. Previous post hoc background suppression methods are prone to human bias, fail at densely labeled structures, and are nonlinear. Here, we propose a physical model-based Background Filtering method for living cell SR imaging combined with the 2D-SIM reconstruction procedure (BF-SIM). BF-SIM helps preserve intricate and weak structures down to sub-70 nm resolution while maintaining signal linearity, which allows for the discovery of dynamic actin structures that, to the best of our knowledge, have not been previously monitored. Quantitative live-cell superresolution imaging that maintains the linearity of fluorescence signals remains difficult. Here, the authors propose a physical model-based background filtering method for 2D-SIM, which allows for quantitative imaging and high signal completeness. [ABSTRACT FROM AUTHOR]

Golgi-derived PI4P-containing vesicles play important roles in mitochondrial division, which is essential for maintaining cellular homeostasis. However, the mechanism of the PI4P-containing vesicle effect on mitochondrial division is unclear. Here, we found that actin appeared to polymerize at the contact site between PI4P-containing vesicles and mitochondria, causing mitochondrial division. Increasing the content of PI4P derived from the Golgi apparatus increased actin polymerization and reduced the length of the mitochondria, suggesting that actin polymerization through PI4P-containing vesicles is involved in PI4P vesicle-related mitochondrial division. Collectively, our results support a model in which PI4P-containing vesicles derived from the Golgi apparatus cooperate with actin filaments to participate in mitochondrial division by contributing to actin polymerization, which regulates mitochondrial dynamics. This study enriches the understanding of the pathways that regulate mitochondrial division and provides new insight into mitochondrial dynamics. [ABSTRACT FROM AUTHOR]

PIWI‐interacting RNAs (piRNAs) are abundantly expressed in heart. However, their functions and molecular mechanisms during myocardial infarction remain unknown. Here, a heart‐apoptosis‐associated piRNA (HAAPIR), which regulates cardiomyocyte apoptosis by targeting N‐acetyltransferase 10 (NAT10)‐mediated N4‐acetylcytidine (ac4C) acetylation of transcription factor EC (Tfec) mRNA transcript, is identified. HAAPIR deletion attenuates ischemia/reperfusion induced myocardial infarction and ameliorate cardiac function compared to WT mice. Mechanistically, HAAPIR directly interacts with NAT10 and enhances ac4C acetylation of Tfec mRNA transcript, which increases Tfec expression. TFEC can further upregulate the transcription of BCL2‐interacting killer (Bik), a pro‐apoptotic factor, which results in the accumulation of Bik and progression of cardiomyocyte apoptosis. The findings reveal that piRNA‐mediated ac4C acetylation mechanism is involved in the regulation of cardiomyocyte apoptosis. HAAPIR‐NAT10‐TFEC‐BIK signaling axis can be potential target for the reduction of myocardial injury caused by cardiomyocyte apoptosis in ischemia heart diseases. [ABSTRACT FROM AUTHOR]

Ferroptosis is a new form of programmed cell death (PCD) characterized by an excess iron accumulation and subsequent unbalanced redox states. Ferroptosis is different from the already reported PCD and has unique morphological features and biochemical processes. Ferroptosis was first elaborated by Brent R. Stockwell's lab in 2012, in which small molecules erastin and RSL-3 induce PCD in Ras mutant cell lines. Ferroptosis involves various physiological processes and occurrence of disease and especially shows strong potential in cancer treatment. Development of small molecule compounds based on Stockwell's research was found to kill cancer cells, and some FDA-approved drugs were discovered to result in ferroptosis of cancer cells. Radiotherapy and checkpoint therapy have been widely used as a treatment for many types of cancer. Recently, some papers have reported that chemotherapy, radiotherapy, and checkpoint therapy induce ferroptosis of cancer cells, which provides new strategies for cancer treatment. Nevertheless, the limitless proliferation of tumor cells and the lack of cell death mechanisms are important reasons for drug resistance for tumor therapy. Therefore, we reviewed the molecular mechanism of ferroptosis and sensitivity to ferroptosis of different cancer cells and tumor treatment strategy. [ABSTRACT FROM AUTHOR]

Blood cells are the most integral part of the body, which are made up of erythrocytes, platelets and white blood cells. The examination of subcellular structures and proteins within blood cells at the nanoscale can provide valuable insights into the health status of an individual, accurate diagnosis, and efficient treatment strategies for diseases. Super-resolution microscopy (SRM) has recently emerged as a cutting-edge tool for the study of blood cells, providing numerous advantages over traditional methods for examining subcellular structures and proteins. In this paper, we focus on outlining the fundamental principles of various SRM techniques and their applications in both normal and diseased states of blood cells. Furthermore, future prospects of SRM techniques in the analysis of blood cells are also discussed. [ABSTRACT FROM AUTHOR]

Pyroptosis is a form of programmed cell death, in which gasdermin E (GSDME) plays an important role in cancer cells, which can be induced by activated caspase-3 on apoptotic stimulation. Triclabendazole is a new type of imidazole in fluke resistance and has been approved by the FDA for the treatment of fascioliasis and its functions partially acting through apoptosis-related mechanisms. However, it remains unclear whether triclabendazole has obvious anti-cancer effects on breast cancer cells. In this study, to test the function of triclabendazole on breast cancer, we treated breast cancer cells with triclabendazole and found that triclabendazole induced lytic cell death in MCF-7 and MDA-MB-231, and the dying cells became swollen with evident large bubbles, a typical sign of pyroptosis. Triclabendazole activates apoptosis by regulating the apoptoic protein levels including Bax, Bcl-2, and enhanced cleavage of caspase-8/9/3/7 and PARP. In addition, enhanced cleavage of GSDME was also observed, which indicates the secondary necrosis/pyroptosis is further induced by active caspase-3. Consistent with this, triclabendazole-induced GSDME–N-terminal fragment cleavage and pyroptosis were reduced by caspase-3–specific inhibitor (Ac-DEVD-CHO) treatment. Moreover, triclabendazole induced reactive oxygen species (ROS) elevation and increased JNK phosphorylation and lytic cell death, which could be rescued by the ROS scavenger (NAC), suggesting that triclabendazole-induced GSDME-dependent pyroptosis is related to the ROS/JNK/Bax-mitochondrial apoptotic pathway. Besides, we showed that triclabendazole significantly reduced the tumor volume by promoting the cleavage of caspase-3, PARP, and GSDME in the xenograft model. Altogether, our results revealed that triclabendazole induces GSDME-dependent pyroptosis by caspase-3 activation at least partly through augmenting the ROS/JNK/Bax-mitochondrial apoptotic pathway, providing insights into this on-the-market drug in its potential new application in cancer treatment. [ABSTRACT FROM AUTHOR]

As the most important organ in our bodies, the brain plays a critical role in deciding sex-related differential features; however, the underlying neural circuitry basis remains unclear. Here, we used a cell-type-specific rabies virus-mediated monosynaptic tracing system to generate a sex differences-related whole-brain input atlas of locus coeruleus noradrenaline (LC-NE) neurons. We developed custom pipelines for brain-wide comparisons of input sources in both sexes with the registration of the whole-brain data set to the Allen Mouse Brain Reference Atlas. Among 257 distinct anatomical regions, we demonstrated the differential proportions of inputs to LC-NE neurons in male and female mice at different levels. Locus coeruleus noradrenaline neurons of two sexes showed general similarity in the input patterns, but with differentiated input proportions quantitatively from major brain regions and diverse sub-regions. For instance, inputs to male LC-NE neurons were found mainly in the cerebrum, interbrain, and cerebellum, whereas inputs to female LC-NE neurons were found in the midbrain and hindbrain. We further found that specific subsets of nuclei nested within sub-regions contributed to overall sex-related differences in the input circuitry. Furthermore, among the totaled 123 anatomical regions with proportion of inputs >0.1%, we also identified 11 sub-regions with significant statistical differences of total inputs between male and female mice, and seven of them also showed such differences in ipsilateral hemispheres. Our study not only provides a structural basis to facilitate our understanding of sex differences at a circuitry level but also provides clues for future sexually differentiated functional studies related to LC-NE neurons. [ABSTRACT FROM AUTHOR]