A transcription-independent mechanism determines rapid periodic fluctuations of BRCA1 expression.

BRCA1 expression is highly regulated to prevent genomic instability and tumorigenesis. Dysregulation of BRCA1 expression correlates closely with sporadic basal-like breast cancer and ovarian cancer. The most significant characteristic of BRCA1 regulation is periodic expression fluctuation throughout the cell cycle, which is important for the orderly progression of different DNA repair pathways throughout the various cell cycle phases and for further genomic stability. However, the underlying mechanism driving this phenomenon is poorly understood. Here, we demonstrate that RBM10-mediated RNA alternative splicing coupled to nonsense-mediated mRNA decay (AS-NMD), rather than transcription, determines the periodic fluctuations in G1/S-phase BRCA1 expression. Furthermore, AS-NMD broadly regulates the expression of period genes, such as DNA replication-related genes, in an uneconomical but more rapid manner. In summary, we identified an unexpected posttranscriptional mechanism distinct from canonical processes that mediates the rapid regulation of BRCA1 as well as other period gene expression during the G1/S-phase transition and provided insights into potential targets for cancer therapy.

C1QBP Promotes Homologous Recombination by Stabilizing MRE11 and Controlling the Assembly and Activation of MRE11/RAD50/NBS1 Complex.

MRE11 nuclease forms a trimeric complex (MRN) with RAD50 and NBS1 and plays a central role in preventing genomic instability. When DNA double-strand breaks (DSBs) occur, MRN is quickly recruited to the damage site and initiates DNA end resection; accordingly, MRE11 must be tightly regulated to avoid inefficient repair or nonspecific resection. Here, we show that MRE11 and RAD50 form a complex (MRC) with C1QBP, which stabilizes MRE11/RAD50, while inhibiting MRE11 nuclease activity by preventing its binding to DNA or chromatin. Upon DNA damage, ATM phosphorylates MRE11-S676/S678 to quickly dissociate the MRC complex. Either excess or insufficient C1QBP impedes the recruitment of MRE11 to DSBs and impairs the DNA damage response. C1QBP is highly expressed in breast cancer and positively correlates with MRE11 expression, and the inhibition of C1QBP enhances tumor regression with chemotherapy. By influencing MRE11 at multiple levels, C1QBP is, thus, an important player in the DNA damage response.

Running exercise alleviates hippocampal neuroinflammation and shifts the balance of microglial M1/M2 polarization through adiponectin/AdipoR1 pathway activation in mice exposed to chronic unpredictable stress.

Running exercise has been shown to alleviate depressive symptoms. However, the mechanism underlying the antidepressant effects of running exercise is not fully understood. The imbalance of M1/M2 microglia phenotype/polarization and concomitant dysregulation of neuroinflammation play crucial roles in the pathogenesis of depression. Running exercise increases circulating levels of adiponectin which is known to cross the blood‒brain barrier and suppress inflammatory responses. AdipoR1 is an adiponectin receptor that is involved in regulating microglial phenotypes and activation states. However, whether running exercise regulates hippocampal microglial phenotypes and neuroinflammation through adiponectin/AdipoR1 to exert its antidepressant effects remains unclear. In the current study, 4 weeks of running exercise significantly alleviated the depressive-like behaviors of chronic unpredictable stress (CUS)-exposed mice. Moreover, running exercise decreased the microglial numbers and altered microglial morphology in three subregions of the hippocampus to restore the M1/M2 balance; these effects were accompanied by regulation of pro-/anti-inflammatory cytokine production and secretion in CUS-exposed mice. These effects may involve elevation of peripheral tissue (adipose tissue and muscle) and plasma adiponectin levels, and hippocampal AdipoR1 levels as well as activation of the AMPK-NF-κB/STAT3 signaling pathway by running exercise. When an adeno-associated virus was used to knock down hippocampal AdipoR1, mice showed depressive-like behaviors and alterations in microglia and inflammatory factor expression in the hippocampus that were similar to those observed in CUS-exposed mice. Together, these results suggest that running exercise maintains the M1/M2 balance and inhibits neuroinflammation in the hippocampus of CUS-exposed mice. These effects might occur via adiponectin/AdipoR1-mediated activation of the AMPK-NF-κB/STAT3 signaling pathway.

Photoactivated Formation of an Extravascular Dynamic Hydrogel as an Intelligent Blood Flow Regulator to Reprogram the Immunogenic Landscape.

Long-term tumor starvation may be a potential strategy to elevate the antitumor immune response by depriving nutrients. However, combining long-term starvation therapy with immunotherapy often yields limited efficacy due to the blockage of immune cell migration pathways. Herein, an intelligent blood flow regulator (BFR) is first established through photoactivated in situ formation of the extravascular dynamic hydrogel to compress blood vessels, which can induce long-term tumor starvation to elicit metabolic stress in tumor cells without affecting immune cell migration pathways. By leveraging methacrylate-modified nanophotosensitizers (HMMAN) and biodegradable gelatin methacrylate (GelMA), the developed extravascular hydrogel dynamically regulates blood flow via enzymatic degradation. Additionally, aPD-L1 loaded into HMMAN continuously blocks immune checkpoints. Systematic in vivo experiments demonstrate that the combination of immune checkpoint blockade (ICB) and BFR-induced metabolic stress (BIMS) significantly delays the progression of Lewis lung and breast cancers by reshaping the tumor immunogenic landscape and enhancing antitumor immune responses.

Activation of the alternative complement pathway modulates inflammation in thoracic aortic aneurysm/dissection.

Thoracic aortic aneurysm/dissection (TAAD) is a lethal vascular disease, and several pathological factors participate in aortic medial degeneration. We previously discovered that the complement C3a-C3aR axis in smooth muscle cells promotes the development of thoracic aortic dissection (TAD) through regulation of matrix metalloproteinase 2. However, discerning the specific complement pathway that is activated and elucidating how inflammation of the aortic wall is initiated remain unknown. We ascertained that the plasma levels of C3a and C5a were significantly elevated in patients with TAD and that the levels of C3a, C4a, and C5a were higher in acute TAD than in chronic TAD. We also confirmed the activation of the complement in a TAD mouse model. Subsequently, knocking out Cfb (Cfb) or C4 in mice with TAD revealed that the alternative pathway and Cfb played a significant role in the TAD process. Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, and knocking out their receptors reduced the recruitment of inflammatory cells to the aortic wall. Moreover, we used serum from wild-type mice or recombinant mice Cfb as an exogenous source of Cfb to treat Cfb KO mice and observed that it exacerbated the onset and rupture of TAD. Finally, we knocked out Cfb in the FBN1C1041G/+ Marfan-syndrome mice and showed that the occurrence of TAA was reduced. In summary, the alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.NEW & NOTEWORTHY The alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.

The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy.

BACKGROUND: Malignant tumours seriously threaten human life and health, and effective treatments for cancer are still being explored. The ability of SHC SH2 domain-binding protein 1 (SHCBP1) to induce cell cycle disturbance and inhibit tumour growth has been increasingly studied, but its dynamic role in the tumour cell cycle and corresponding effects leading to mitotic catastrophe and DNA damage have rarely been studied. RESULTS: In this paper, we found that the nucleoprotein SHCBP1 exhibits dynamic spatiotemporal expression during the tumour cell cycle, and SHCBP1 knockdown slowed cell cycle progression by inducing spindle disorder, as reflected by premature mitotic entry and multipolar spindle formation. This dysfunction was caused by G2/M checkpoint impairment mediated by downregulated WEE1 kinase and NEK7 (a member of the mammalian NIMA-related kinase family) expression and upregulated centromere/kinetochore protein Zeste White 10 (ZW10) expression. Moreover, both in vivo and in vitro experiments confirmed the significant inhibitory effects of SHCBP1 knockdown on tumour growth. Based on these findings, SHCBP1 knockdown in combination with low-dose DNA-damaging agents had synergistic tumouricidal effects on tumour cells. In response to this treatment, tumour cells were forced into the mitotic phase with considerable unrepaired DNA lesions, inducing mitotic catastrophe. These synergistic effects were attributed not only to the abrogation of the G2/M checkpoint and disrupted spindle function but also to the impairment of the DNA damage repair system, as demonstrated by mass spectrometry-based proteomic and western blotting analyses. Consistently, patients with low SHCBP1 expression in tumour tissue were more sensitive to radiotherapy. However, SHCBP1 knockdown combined with tubulin-toxic drugs weakened the killing effect of the drugs on tumour cells, which may guide the choice of chemotherapeutic agents in clinical practice. CONCLUSION: In summary, we elucidated the role of the nucleoprotein SHCBP1 in tumour cell cycle progression and described a novel mechanism by which SHCBP1 regulates tumour progression and through which targeting SHCBP1 increases sensitivity to DNA-damaging agent therapy, indicating its potential as a cancer treatment.

Birth Prevalence of Sickle Cell Disease and County-Level Social Vulnerability - Sickle Cell Data Collection Program, 11 States, 2016-2020.

Sickle cell disease (SCD) remains a public health priority in the United States because of its association with complex health needs, reduced life expectancy, lifelong disabilities, and high cost of care. A cross-sectional analysis was conducted to calculate the crude and race-specific birth prevalence for SCD using state newborn screening program records during 2016-2020 from 11 Sickle Cell Data Collection program states. The percentage distribution of birth mother residence within Social Vulnerability Index quartiles was derived. Among 3,305 newborns with confirmed SCD (including 57% with homozygous hemoglobin S or sickle ß-null thalassemia across 11 states, 90% of whom were Black or African American [Black], and 4% of whom were Hispanic or Latino), the crude SCD birth prevalence was 4.83 per 10,000 (one in every 2,070) live births and 28.54 per 10,000 (one in every 350) non-Hispanic Black newborns. Approximately two thirds (67%) of mothers of newborns with SCD lived in counties with high or very high levels of social vulnerability; most mothers lived in counties with high or very high levels of vulnerability for racial and ethnic minority status (89%) and housing type and transportation (64%) themes. These findings can guide public health, health care systems, and community program planning and implementation that address social determinants of health for infants with SCD. Implementation of tailored interventions, including increasing access to transportation, improving housing, and advancing equity in high vulnerability areas, could facilitate care and improve health outcomes for children with SCD.

Immunization adherence among children with sickle cell disease and sickle cell trait: Results of a population-based study.

INTRODUCTION: Despite the importance of timely vaccine completion for protection from infectious disease, there is limited knowledge of the immunization adherence rates of children with sickle cell disease (SCD). METHODS: This is a retrospective cohort study comparing the immunization rates of children with SCD to those with sickle cell trait between 2008 and 2019 in Georgia. Completion rates for each vaccine and the proportion of children with up-to-date status at 24 and 35 months were calculated and compared between the cohorts. Chi-square tests with odds ratios (OR) for differences and 95% confidence intervals (CIs) were reported on the overall up-to-date rates and rates for individual vaccines at 24 and 35 months for the two cohorts. RESULTS: Children with SCD had higher up-to-date rates than children with sickle cell trait at 24 and 35 months. At 35 months, the overall up-to-date rates (OR = 1.17; 95% CI, 1.04-1.31; p = .004) and the four-dose pneumococcal conjugate vaccine series (OR = 1.36; 95% CI, 1.18-1.57; p < .001) were significantly different between the groups. Both cohorts had the highest completion rates for the hepatitis B series and the lowest rates for the varicella vaccine. Doses of diphtheria, tetanus, and acellular pertussis vaccine; varicella; and pneumococcal conjugate vaccines were most commonly missed by children in both cohorts. CONCLUSIONS: Children with SCD have better immunization coverage than children with sickle cell trait, but there is an opportunity for improvement. Policymakers and healthcare professionals should focus on increasing access to care coordination services among children with SCD to ensure on-time and preventive healthcare services.

Emergency department 30-Day emergency department revisits among people with sickle cell disease: Variations in characteristics.

People with sickle cell disease (SCD) often have emergency department (ED) revisits. The characteristics of people with SCD with ED revisits were assessed in this study using Medicaid administrative claims data from California and Georgia, representing 2794 and 3641 individuals with SCD, respectively. In both states, those with 6+ primary care provider (PCP) encounters had the highest percentage of ED revisits. In California, those with 6+ hematology encounters had the lowest percentage of individuals with an ED revisit; in Georgia, those with 1-2 hematology encounters. Increasing access to hematologic care may reduce ED revisits among people with SCD.

Unraveling Key Factors for Hypoxia Tolerance in Contrasting Varieties of Cotton Rose by Comparative Morpho-physiological and Transcriptome Analysis.

The cotton rose (Hibiscus mutabilis) is a plant species commonly found in tropical and subtropical regions. It is remarkably resilient to waterlogging stress; however, the underlying mechanism behind this trait is yet unknown. This study used hypoxia-tolerant "Danbanhong" (DBH) and more hypoxia-sensitive "Yurui" (YR) genotypes and compared their morpho-physiological and transcriptional responses to hypoxic conditions. Notably, DBH had a higher number of adventitious roots (20.3) compared to YR (10.0), with longer adventitious roots in DBH (18.3 cm) than in YR (11.2 cm). Furthermore, the formation of aerenchyma was 3-fold greater in DBH compared to YR. Transcriptomic analysis revealed that DBH had more rapid transcriptional responses to hypoxia than YR. Identification of a greater number of differentially expressed genes (DEGs) for aerenchyma, adventitious root formation and development, and energy metabolism in DBH supported that DBH had better morphological and transcriptional adaptation than YR. DEG functional enrichment analysis indicated the involvement of variety-specific biological processes in adaption to hypoxia. Plant hormone signaling transduction, MAPK signaling pathway and carbon metabolism played more pronounced roles in DBH, whereas the ribosome genes were specifically induced in YR. These results show that effective multilevel coordination of adventitious root development and aerenchyma, in conjunction with plant hormone signaling and carbon metabolism, is required for increased hypoxia tolerance. This study provides new insights into the characterization of morpho-physiological and transcriptional responses to hypoxia in H. mutabilis, shedding light on the molecular mechanisms of its adaptation to hypoxic environments.

The effect of trans-provincial immediate reimbursement for healthcare expenses on inequity in the utilization of healthcare services for migrants.

BACKGROUND: Improving the accessibility of public services for migrants is an important endeavor to promote equity in economic and social development. As a response to the large-scale movement of migrants and the fragmentation of China's health insurance system, the Chinese Government has launched a policy of trans-provincial immediate reimbursement for healthcare expenses. The present study hopes to examine the effect of immediate reimbursement policy on the utilization of healthcare services for migrants in China. METHODS: This study used two waves of data from the China Migrants Dynamic Survey (CMDS) collected in 2013 and 2017, with the sample comprising 13,540 individuals. We constructed a difference-in-differences (DID) model to investigate the impact of the policy on the utilization of healthcare services for migrants. Meanwhile, we also analyzed the heterogeneity of the policy effect by grouping the samples by industry, gender, income, and education level. RESULTS: The results found that the trans-provincial immediate reimbursement significantly promoted the probability of migrants' utilization of quality healthcare services (average treatment effect on the treated = 0.072, p < 0.05). Heterogeneity analyses revealed that the policy effect was more pronounced among higher-income and better-educated migrants. In addition, the policy effect was more significant for female migrants, and the benefits were more marked for migrants in high-risk industries. CONCLUSIONS: The trans-provincial immediate reimbursement policy has improved the inequity of healthcare services utilization among migrants as a whole; however, within the migrants, inequity still exists. More attention should also be paid to low-income or low-education groups in future policy design.

BCL6 attenuates hyperoxia-induced lung injury by inhibiting NLRP3-mediated inflammation in fetal mouse.

BACKGROUND: The transcriptional repressor B-cell lymphoma 6 (BCL6) has been reported to inhibit inflammation. So far, experimental evidence for the role of BCL6 in bronchopulmonary dysplasia (BPD) is lacking. Our study investigated the roles of BCL6 in the progression of BPD and its downstream mechanisms. METHODS: Hyperoxia or lipopolysaccharide (LPS) was used to mimic the BPD mouse model. To investigate the effects of BCL6 on BPD, recombination adeno-associated virus serotype 9 expressing BCL6 (rAAV9-BCL6) and BCL6 inhibitor FX1 were administered in mice. The pulmonary pathological changes, inflammatory chemokines and NLRP3-related protein were observed. Meanwhile, BCL6 overexpression plasmid was used in human pulmonary microvascular endothelial cells (HPMECs). Cell proliferation, apoptosis, and NLRP3-related protein were detected. RESULTS: Either hyperoxia or LPS suppressed pulmonary BCL6 mRNA expression. rAAV9-BCL6 administration significantly inhibited hyperoxia-induced NLRP3 upregulation and inflammation, attenuated alveolar simplification and dysregulated angiogenesis in BPD mice, which were characterized by decreased mean linear intercept, increased radical alveolar count and alveoli numbers, and the upregulated CD31 expression. Meanwhile, BCL6 overexpression promoted proliferation and angiogenesis, inhibited apoptosis and inflammation in hyperoxia-stimulated HPMECs. Moreover, administration of BCL6 inhibitor FX1 arrested growth and development. FX1-treated BPD mice exhibited exacerbation of alveolar pathological changes and pulmonary vessel permeability, with upregulated mRNA levels of pro-inflammatory cytokines and pro-fibrogenic factors. Furthermore, both rAAV9-BCL6 and FX1 administration exerted a long-lasting effect on hyperoxia-induced lung injury (≥4 wk). CONCLUSIONS: BCL6 inhibits NLRP3-mediated inflammation, attenuates alveolar simplification and dysregulated pulmonary vessel development in hyperoxia-induced BPD mice. Hence, BCL6 may be a target in treating BPD and neonatal diseases.

Complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice.

Mutations in fibrillin 1 (FBN1) is the main cause of Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. Activation of the complement system plays a key role in the formation of thoracic and abdominal aortic aneurysms. However, the role of the complement system in MFS-associated aortic aneurysms remains unclear. In this study, we observed increased levels of complement C3a and C5a in the plasma of MFS patients and mouse, and the increased deposition of the activated complement system product C3b/iC3b was also observed in the elastic fiber rupture zone of 3-month-old MFS mice. The expression of C3a receptor (C3aR) was increased in MFS aortas, and recombinant C3a promoted the expression of cytokines in macrophages. The administration of a C3aR antagonist (C3aRA) attenuated the development of thoracic aortic aneurysms in MFS mice. The increased inflammation response and matrix metalloproteinases activities were also attenuated by C3aRA treatment in MFS mice. Therefore, these findings indicate that the complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice.

Risk Factors for Rebleeding After Endoscopic Injection of Cyanoacrylate Glue for Gastric Varices: A Systematic Review and Meta-Analysis.

BACKGROUND: Rebleeding is a significant complication of endoscopic injection of cyanoacrylate in gastric varices in cirrhotic patients. AIM: This systematic review and meta-analysis aimed to evaluate the efficiency of endoscopic cyanoacrylate injection and summarized the risk factors for rebleeding. METHODS: Databases were searched for articles published between January 2012 and December 2022. Studies evaluating the efficiency of endoscopic injection of cyanoacrylate glue for gastric varices and the risk factors for rebleeding were included. RESULTS: The final analysis included data from 24 studies. The hemostatic rates ranged from 65 to 100%. The pooled rate of gastric varices recurrence was 34% [95% CI 21-46, I2 = 61.4%], early rebleeding rate was 16% [95% CI 11-20, I2 = 37.4%], late rebleeding rate was 39% [95% CI 36-42, I2 = 90.9%], mild and moderate adverse events rate were 28% [95% CI 24-31, I2 = 91.6%], 3% [95% CI - 2 to 8, I2 = 15.3%], rebleeding-related mortality rate was 6% [95% CI 2-10, I2 = 0%], all-cause mortality rate was 17% [95% CI 12-22, I2 = 63.6%]. Independent risk factors for gastric variceal rebleeding included portal venous thrombosis, ascites, cyanoacrylate volume, fever/systemic inflammatory response syndrome, red Wale sign, previous history of variceal bleeding, active bleeding and paragastric veins. The use of proton pump inhibitors could be a protective factor. CONCLUSIONS: Endoscopic cyanoacrylate glue injection is an effective and safe treatment for gastric varices. Cirrhotic patients with the above risk factors may benefit from treatment aimed at reducing portal hypertension, antibiotic prophylaxis, and anticoagulation if they meet the indications.

Unraveling the complex interplay between statistical learning and working memory in Chinese children with and without dyslexia across different ages.

The relation between statistical learning and working memory in children with developmental dyslexia (DD) remains unclear. This study employed a distributional and a conditional statistical learning experiment and a working memory task to examine this relation in 651 Chinese 6- to 12-year-olds with and without DD (NDD = 199, 101 females; NwoDD = 452, 227 females; participated 2014-2019). Results showed working memory positively associated with recognizing high-predictable and familiar items in both groups, but negatively associated with recognizing unfamiliar items in the DD group only. These findings uncovered the complex interplay between statistical learning and working memory, demonstrating how different working memory abilities in children with and without DD relate to various statistical learning mechanisms at the item level.

Effect of blockage of Trem1 on the M1 polarization of macrophages in the regulation dental pulp inflammation.

Dental pulp inflammation is a common and significant factor related to poor dental prognosis. Current treatment strategies primarily concentrate on managing the inflammatory response, with specific targets for intervention still under investigation. Triggering receptors expressed on myeloid cells (TREMs) are a group of receptor molecules extensively present on myeloid cell surfaces, crucial in the regulation of inflammatory process. Our analysis of transcriptomic sequencing data from clinical pulp samples of dataset GSE77459 and animal models revealed up-regulation of Trem1 during pulpitis. Administration of the Trem1-blocking peptide LP17 led to lower (more than 1-fold) levels of several pro-inflammatory factors and inhibition of M1 macrophage polarization both in vivo and in vitro. This study of the expression patterns and functions of Trem1 in the development of dental pulp inflammation provides novel insights into the therapeutic strategies for clinical pulpitis.

Effectiveness of a home-based, post-discharge early intervention program for very preterm infants in reducing parental stress: a randomized controlled trial.

BACKGROUND: This study aims to evaluate the impact of a home-based, post-discharge early intervention (EI) program on reducing parental stress levels in families with preterm infants born between 28+ 0 and 31+ 6 weeks gestational age. METHODS: A randomized controlled trial was conducted, with families randomly allocated to either the EI or standard care (SC) group. A term reference group was also recruited for comparison. The Parental Stress Index-Short Form was used to assess parental stress levels, yielding a total stress score and three subdomain scores. Assessment was performed at baseline, at the 60-day mark of the study, and when the infants reached six corrected months of age. Parents in the reference group were assessed only at six months of corrected age for infants. The intervention comprised three sections: intellectual, physical, and social training, which was administered to the infants in the EI group immediately after discharge and to those in the SC group after 60 days of enrollment. RESULTS: Seventy-three families were enrolled in this study, with 37 allocated to the EI group, and 36 to the SC group. Prior to intervention, higher stress levels were reported by mothers in both groups than fathers, with no difference observed between the EI and SC groups. Re-assessment performed at 60 days of the study showed that mothers and fathers in the EI group had significantly lower total stress score than those in the SC group (82.00 ± 5.64 vs. 94.26 ± 7.99, p < 0.001; 80.74 ± 7.14 vs. 89.94 ± 9.17, p < 0.001, respectively), which was predominantly due to the lower scores in parental distress and parental-child dysfunction interaction subdomains in the EI group (both had p < 0.001). Mothers in the EI group exhibited a more pronounced reduction in total stress score after intervention when compared to fathers (13.15 ± 4.68 vs. 8.26 ± 4.03, p < 0.001). At six months of infant age, the total stress score and subdomain scores of parents in the EI and SC groups were similar, but significantly higher than those of the reference group. CONCLUSION: The home-based, post-discharge EI program demonstrated significant effectiveness in reducing parental stress levels among the parents of very preterm infants. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (registration number: CTR1900028330). Registration date: December 19, 2019.

Growth and thermal maturation of the Toba magma reservoir.

The Toba volcanic system in Indonesia has produced two of the largest eruptions (>2,000 km3 dense-rock equivalent [DRE] each) on Earth since the Quaternary. U-Pb crystallization ages of zircon span a period of ∼600 ky before each eruptive event, and in the run-up to each eruption, the mean and variance of the zircons' U content decrease. To quantify the process of accumulation of eruptible magma underneath the Toba caldera, we integrated these observations with thermal and geochemical modeling. We show that caldera-forming eruptions at Toba are the result of progressive thermal maturation of the upper crustal magma reservoir, which grows and chemically homogenizes, by sustained magma influx at average volumetric rates between 0.008 and 0.01 km3/y over the past 2.2 My. Protracted thermal pulses related to magma-recharge events prime the system for eruption without necessarily requiring an increased magma-recharge rate before the two supereruptions. If the rate of magma input was maintained since the last supereruption of Toba at 75 ka, eruptible magma is currently accumulating at a minimum rate of ∼4.2 km3 per millennium, and the current estimate of the total volume of potentially eruptible magma available today is a minimum of ∼315 km3 Our approach to evaluate magma flux and the rate of eruptible magma accumulation is applicable to other volcanic systems capable of producing supereruptions and thereby could help in assessing the potential of active volcanic systems to feed supereruptions.

N6-methyladenosine facilitates arsenic-induced neoplastic phenotypes of human bronchial epithelial cells by promoting miR-106b-5p maturation.

Arsenic is a widespread carcinogen and an important etiological factor for lung cancer. Dysregulated miRNAs have been implicated in arsenic carcinogenesis and the mechanisms of arsenic-induced dysregulated miRNAs have not been fully elucidated. N6-methyladenosine (m6A) modification is known to modulate pri-miRNA processing. However, whether m6A-mediated pri-miRNA processing is involved in arsenic carcinogenesis is poorly understood. Here, we found that m6A modification was significantly increased in arsenite-transformed human bronchial epithelial BEAS-2B cells (0.5 µM arsenite, 16 weeks). Meanwhile, METTL3 was significantly upregulated at week 12 and 16 during cell transformation. The proliferation, migration, invasion, and anchorage-independent growth of arsenite-transformed cells were inhibited by the reduction of m6A levels through METTL3 knockdown. Further experiments suggest that the oncogene miR-106b-5p is a potentially essential m6A target mediating arsenic-induced lung cancer. miR-106b-5p was observed to be upregulated after exposure to arsenite for 12 and 16 weeks, and the reduction of m6A levels caused by METTL3 knockdown inhibited miR-106b-5p maturation in arsenite-transformed cells. What's more, miR-106b-5p overexpression successfully rescued METTL3 knockdown-induced inhibition of the neoplastic phenotypes of transformed cells. Additionally, Basonuclin 2 (BNC2) was uncovered as a potential target of miR-106b-5p and downregulated by METTL3 via enhancing miR-106b-5p maturation. Additionally, the METTL3 inhibitor STM2457 suppressed neoplastic phenotypes of arsenite-transformed BEAS-2B cells by blocking pri-miR-106b methylation. These results demonstrate that m6A modification promotes the neoplastic phenotypes of arsenite-transformed BEAS-2B cells through METTL3/miR-106b-5p/BNC2 pathway, providing a new prospective for understanding arsenic carcinogenesis.

Emergency department utilization before and during the COVID-19 pandemic among individuals with sickle cell disease.

BACKGROUND: The emergency department (ED) is a vital source of healthcare for individuals living with sickle cell disease (SCD). Prior research indicates that during the COVID-19 pandemic some individuals with SCD avoided the ED for fear of acquiring COVID-19 or delayed visiting the ED by self-management of symptoms or pain crisis at home. The purpose of the current study was to understand ED utilization rates before and during the pandemic among individuals living with SCD. METHODS: We conducted a retrospective cohort study using population-based SCD surveillance systems in California, Georgia, Michigan, and Tennessee to assess the impact of the pandemic on ED utilization among people with SCD by (1) analyzing trends in monthly ED utilization from January 2019 - December 2020, with specific attention given to immediate changes at the onset of the pandemic; and (2) calculating changes in the volume of utilization by comparing the total ED visits made from March - December 2020 to the same period in 2019, both overall and by demographic characteristics. RESULTS: Across all states, a decline in ED utilization during the onset of the pandemic was seen, with the largest decline seen in those under age 10. By December 2020, utilization rates were higher than their lowest observed month of April 2020, but had not fully returned to pre-COVID levels. During the pandemic, ED visits in each state decreased by as much as 25%, and the number of people with any ED utilization decreased by as much as 26%. CONCLUSIONS: This study confirms and extends the existing literature related to the impact of the pandemic on healthcare utilization patterns in the US, in a unique population with increased healthcare needs.