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Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8+ CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.

Chinese immigrants are underrepresented in research on intimate partner violence (IPV). There is a lack of quantitative research on help-seeking behaviors and patterns among Chinese immigrant women experiencing IPV. In this study, using a cross-sectional design, we examine patterns of help-seeking behaviors among Chinese immigrant survivors of IPV, as well as associated factors. Participants were recruited through the WeChat and Prolific platforms to complete an online survey. A total of 139 women who reported IPV while residing in the U.S. participated. The survey's questions addressed five forms of informal help and eight forms of formal help, as well as reasons for not seeking help. The survey also included measures of social isolation, loneliness, preferences for the ethnicity of people at social gatherings, depression, anxiety, sociodemographic characteristics, and immigration-related factors. Latent class analysis revealed two distinct help-seeking patterns. The majority either refrained from seeking help or solely relied on family and friends, while a smaller group sought support from a wider range of sources, but still primarily relied on family and friends. Factors associated with Chinese immigrant women's use of broad sources for support included older age; being single, separated, divorced, or widowed; U.S. citizenship or permanent residency; attending social gatherings primarily with Americans; depression symptoms; and lower loneliness levels. The study's findings underscore the importance of interventions to promote help-seeking behaviors among Chinese immigrant survivors by expanding social networks, fostering collaborations between mainstream IPV services and Chinese community organizations to implement community outreach, offering interventions that are empowerment-based, and training bilingual and bicultural service providers. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a leading cause of disability and mortality worldwide. Recently, increasing evidence implicates microRNAs (miRs) in the pathophysiology of ischemic stroke. Studies have shown that miR-15a/16-1 is abnormally expressed in brains after ischemic stroke, and its upregulation may increase ischemic damage. Given that sex and age are significant modifiers of stroke outcomes, here we investigated whether inhibiting miR-15a/16-1 with antagomirs mitigates cerebral ischemia/reperfusion (I/R) injury in a sex- and age-dependent manner. Young (3 months) and aged (18 months) male and female C57/BL mice underwent 1-h middle cerebral artery occlusion and 3–7 days reperfusion (tMCAO). We administered miR-15a/16-1 antagomir (30 pmol/g) or control antagomir (NC, 30 pmol/g) via tail vein 2 h post-MCAO. Neurobehavioral testing and infarct volume assessment were performed on days 3 and 7. Compared to controls, antagomir treatment significantly improved neurobehavioral outcomes and reduced infarct volume in tMCAO mice at day 7, with the effects being more pronounced in young mice. Notably, young female mice exhibited superior survival and sensorimotor function compared to young male mice. These results were also replicated in a permanent MCAO (pMCAO) mice model. This suggests miR-15a/16-1 antagomir and estradiol may synergistically regulate genes involved in neurovascular cell death, inflammation, and oxidative stress, with sex and age-dependent expression of miR-15a/16-1 and its targets likely underlying the observed variations. Overall, our findings identify miR-15a/16-1 antagomir as a promising therapeutic for ischemic stroke and suggest that sex and age should be considered when developing miR-based therapeutic strategies. [ABSTRACT FROM AUTHOR]

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Aims: To retrospectively compare the long‐term outcomes following atrial fibrillation (AF) ablation between heart failure (HF) with preserved ejection fraction (EF) (HFpEF) and reduced/mildly reduced EF (HFr‐mrEF) patients, and to identify novel predictors of adverse clinical events. Methods: In total, 1402 AF patients with HF who underwent successful ablation were consecutively enrolled. Adverse clinical events including all‐cause death, HF hospitalization, and stroke were followed up. Cox proportional hazards models were used to assess the associations between clinical factors and events. Kaplan–Meier analysis was performed to estimate the cumulative incidences of these events. A receiver operating characteristic curve was used to test the ability of these predictors. Results: During a follow‐up period of 42 ± 15 months, 265 (18.9%) patients experienced adverse clinical events after ablation. The cumulative incidence of adverse clinical events was significantly higher in HFr‐mrEF than in HFpEF (25.4% vs. 15.7%, P < 0.001), the similar tendency was observed on all‐cause death (10.5% vs. 6.5%, P = 0.011) and HF hospitalization (17.2% vs. 10.1%, P < 0.001). After multivariate adjustment, non‐paroxysmal AF [hazard ratio (HR) 1.922, 95% confidence interval (CI) 1.130–3.268, P = 0.016], LAD ≥ 45 mm (HR 2.197, 95% CI 1.206–4.003, P < 0.001), LVEF (HR 0.959, 95% CI 0.946–0.981, P < 0.001), and RAD ≥ 45 mm (HR 2.044, 95% CI 1.362–3.238, P < 0.001) remained the independent predictors for developing adverse clinical events. A predictive model performed with non‐paroxysmal AF, LAD ≥ 45 mm and RAD ≥ 45 mm yielded an area under curve of 0.728 (95% CI 0.696–0.760, P < 0.001). Conclusions: AF patients with HFpEF had better long‐term outcomes than those with HFr‐mrEF, and moderate/severe biatrial dilation could predict adverse clinical events following catheter ablation in AF and HF patients. [ABSTRACT FROM AUTHOR]

Vase life directly affects the ornamental value of cut flowers, and extending vase life has been a research focus in the floriculture industry. The antioxidant and antimicrobial properties of Nano-Se provide a new direction to extend the life of cut-flower vase life. In order to explore the postharvest quality of Nano-Se on cut-flower roses, this study treated cut-flower roses with different concentrations of Nano-Se (200, 400, and 600 mM) using a commercially available preservative solution as a base solution. The results showed that appropriate concentrations of Nano-Se significantly increased the vase life of cut-flower roses and helped to maintain high petal moisture content. Nano-Se at concentrations of 200, 400, and 600 mM extended the vase life of cut roses by 4.3, 5.7, and 3.7 d, respectively. As the vase period extended, the Nano-Se treatment group effectively delayed the decline in antioxidant enzyme activities such as peroxidase (POD) and catalase (CAT), maintained the soluble sugar (SS) and soluble protein (SP) contents in the cut roses, and inhibited the production of malondialdehyde (MDA) and hydrogen peroxide (H2O2), reducing their accumulation. A correlation analysis of the physiological indexes of cut roses showed that vase life was positively correlated with POD and CAT activities, SS and SP contents, and total phenolic acid content and negatively correlated with MDA and H2O2 contents. This study provides a solid theoretical basis for the diversification of preservatives and the development of new preservatives for fresh-cut roses, which is expected to provide significant economic benefits. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease, and mild cognitive impairment (MCI) is considered a transitional stage between healthy aging and dementia. Early detection of MCI can help slow down the progression of AD. At present, there are few studies exploring the characteristics of abnormal dynamic brain activity in AD. This article uses a method called leading eigenvector dynamics analysis (LEiDA) to study resting-state functional magnetic resonance imaging (rs-fMRI) data of AD, MCI, and cognitively normal (CN) participants. By identifying repetitive states of phase coherence, intergroup differences in brain dynamic activity indicators are examined, and the neurobehavioral scales were used to assess the relationship between abnormal dynamic activities and cognitive function. The results showed that in the indicators of occurrence probability and lifetime, the globally synchronized state of the patient group decreased. The activity state of the limbic regions significantly detected the difference between AD and the other two groups. Compared to CN, AD and MCI have varying degrees of increase in default and visual region activity states. In addition, in the analysis related to the cognitive scales, it was found that individuals with poorer cognitive abilities were less active in the globally synchronized state and more active in limbic region activity state and visual region activity state. Taken together, these findings reveal abnormal dynamic activity of resting-state networks in patients with AD and MCI, provide new insights into the dynamic analysis of brain networks, and contribute to a deeper understanding of abnormal spatial dynamic patterns in AD patients. NEW & NOTEWORTHY: Alzheimer's disease (AD) is a neurodegenerative disease, but few studies have explored the characteristics of abnormal dynamic brain activity in AD patients. Here, our report reveals the abnormal dynamic activity of the patients' resting-state network, providing new insights into the dynamic analysis of brain networks and helping to gain a deeper understanding of the abnormal spatial dynamic patterns in AD patients. [ABSTRACT FROM AUTHOR]

In this Article, the sentence: "After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50-100 per tumour) non-recurrent coding mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).", should have read: "After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50-100 per tumour) non-recurrent mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).". This has been corrected online. In Extended Data Fig. 6a and b, which show the number of point mutations identified per sample and the mutational signatures, all sequence variants (including non-coding mutations) are shown. Fig. 2d also presents all variants compared to human mutations. In the Supplementary Information to this Amendment, we now provide the comparisons of all variants and coding variants to human mutations.

Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases. Although mitochondrial damage is needed for the assembly and activation of the NLRP3 inflammasome, it is unclear how macrophages are able to respond to structurally diverse inflammasome-activating stimuli. Here we show that the synthesis of mitochondrial DNA (mtDNA), induced after the engagement of Toll-like receptors, is crucial for NLRP3 signalling. Toll-like receptors signal via the MyD88 and TRIF adaptors to trigger IRF1-dependent transcription of CMPK2, a rate-limiting enzyme that supplies deoxyribonucleotides for mtDNA synthesis. CMPK2-dependent mtDNA synthesis is necessary for the production of oxidized mtDNA fragments after exposure to NLRP3 activators. Cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation. The dependence on CMPK2 catalytic activity provides opportunities for more effective control of NLRP3 inflammasome-associated diseases.

This corrects the article DOI: 10.1038/nature24302.