Search

Purpose Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect the human placenta and has been shown to have an adverse effect on Doppler ultrasound parameters and placental features. However, the specific effects of the SAS-CoV-2 infection on the fetal-placental unit in pregnant women remain unclear. The aim of this systematic review and meta-analysis was to evaluate the impact of SARS-CoV-2 infection on Doppler ultrasound and placental findings in pregnant women. Methods A systematic search was conducted using four electronic databases (PubMed, Embase, Scopus, and Cochrane Library) to select publications published in peer-reviewed journals written in English. Odds ratios (ORs) were calculated, along with their 95% confidence intervals (CIs). Heterogeneity was assessed using Cochrane Q and I2 statistics and the appropriate P-value. The analysis used RevMan 5.3. Results This meta-analysis included 1,210 pregnant women from 10 case-control studies. SARS-CoV-2–infected pregnant women exhibited higher likelihoods of placental abnormalities (OR, 2.62; 95% CI, 1.66 to 4.13), aberrant Doppler values (OR, 1.95; 95% CI, 1.16 to 3.27), an abnormal cerebroplacental ratio (OR, 2.68; 95% CI, 1.52 to 4.75), altered fetoplacental circulation (OR, 1.56; 95% CI, 1.07 to 2.28), and increased placental thickness and placental venous lakes (OR, 1.85; 95% CI, 1.25 to 2.72). Conclusion According to this meta-analysis, pregnant women infected with SARS-CoV-2 are more likely to experience altered Doppler ultrasonography parameters and placental abnormalities, including increased placental thickness, placental venous lakes, altered fetoplacental circulation, and cerebroplacental ratio. However, the limited number of case-control studies requires larger sample sizes to validate and enhance the evidence.

Abstract Acute myeloid leukemia (AML) cell survival and chemoresistance are influenced by the existence of bone marrow mesenchymal stem cells (BMMSCs); however, the pathways by which BMMSCs contribute to these processes remain unclear. We earlier revealed that methyltransferase-like 3 (METTL3) expression is significantly reduced in AML BMMSCs and that METTL3 mediates BMMSC adipogenesis to promote chemoresistance in human AML cell lines in vitro. In this investigation, we evaluated the METTL3 function in vivo. Mice exhibiting a conditional removal of Mettl3 in BMMSCs were developed by mating Prrx1-Cre ERT2 ;Mettl3 fl/+ mice with Mettl3 fl/fl mice using the CRISPR-Cas9 system. The Mettl3 deletion increased bone marrow adiposity, enhanced disease progression in the transplantation-induced MLL-AF9 AML mouse model, and chemoresistance to cytarabine. The removal of Mettl3 in BMMSCs resulted in a significant increase in BMMSC adipogenesis. This effect was attributed to the downregulation of AKT1 expression, an AKT serine/threonine kinase 1, in an m6A-dependent manner. The development of chemoresistance in AML is linked to the promoted adipogenesis of BMMSCs. We conclude that METTL3 expression in BMMSCs has a critical function in limiting AML progression and chemoresistance, providing a basis for the progression of therapeutic approaches for AML.

Abstract Background Hypervirulent Klebsiella pneumoniae (hvKp) infection-induced sepsis-associated acute lung injury (ALI) has emerged as a significant clinical challenge. Increasing evidence suggests that activated inflammatory macrophages contribute to tissue damage in sepsis. However, the underlying causes of widespread macrophage activation remain unclear. Methods BALB/c mice were intravenously injected with inactivated hvKp (iHvKp) to observe lung tissue damage, inflammation, and M1 macrophage polarization. In vitro, activated RAW264.7 macrophage-derived exosomes (iHvKp-exo) were isolated and their role in ALI formation was investigated. RT-PCR was conducted to identify changes in exosomal miRNA. Bioinformatics analysis and dual-luciferase reporter assays were performed to validate MSK1 as a direct target of miR-155-5p. Further in vivo and in vitro experiments were conducted to explore the specific mechanisms involved. Results iHvKp successfully induced ALI in vivo and upregulated the expression of miR-155-5p. In vivo, injection of iHvKp-exo induced inflammatory tissue damage and macrophage M1 polarization. In vitro, iHvKp-exo was found to promote macrophage inflammatory response and M1 polarization through the activation of the p38-MAPK pathway. RT-PCR revealed exposure time-dependent increased levels of miR-155-5p in iHvKp-exo. Dual-luciferase reporter assays confirmed the functional role of miR-155-5p in mediating iHvKp-exo effects by targeting MSK1. Additionally, inhibition of miR-155-5p reduced M1 polarization of lung macrophages in vivo, resulting in decreased lung injury and inflammation induced by iHvKp-exo or iHvKp. Conclusions The aforementioned results indicate that exosomal miR-155-5p drives widespread macrophage inflammation and M1 polarization in hvKp-induced ALI through the MSK1/p38-MAPK Axis. Graphical Abstract

Summary: KRAS inhibitor AMG510 covalently modifies the G12C residue and inactivates the KRAS/G12C function. Because there are many reactive cysteines in the proteome, it is important to characterize AMG510 on-target modification and off-targets. Here, we presented a streamlined workflow to measure abundant AMG510 modified peptides including that of KRAS/G12C by direct profiling, and a pan-AMG510 antibody peptide IP workflow to profile less abundant AMG510 off-targets. We identified over 300 off-target sites with three distinct kinetic patterns, expanding the AMG510 modified proteome involved in the nucleocytoplasmic transport, response to oxidative stress, adaptive immune system, and glycolysis. We found that AMG510 covalently modified cys339 of ALDOA and inhibited its enzyme activity. Moreover, AMG510 modified KEAP1 cys288 and induced NRF2 accumulation in the nuclear of NSCLC cells independent of KRAS/G12C mutation. Our study provides a comprehensive resource of protein off-targets of AMG510 and elucidates potential toxicological sideeffects for this covalent KRASG12C inhibitor.

Despite much attention on the history of goat evolution, information on origin, demographic history, and expansion route remains controversial. To address these questions, we collected 4,189 published goat DNA sequences including 1,228 sequences from 57 breeds in China and 2,961 sequences including 193 goat breeds from 71 other countries and carried out an integrated analysis. We found goat breeds from South China had the highest genetic diversity of lineage B, and subclades B2 only were found in Southwest China, suggesting that lineage B (particularly, subclade B2) probably originated from Southwest China and its surrounding areas. In addition, in this study, we found that lineage A from South China also presented higher genetic diversity and earlier expansion time (10, 606 years ago), even earlier than breeds from the Middle East. Hence, we speculated that South China and surrounding areas were the origin of lineage B and also the transportation hub for lineage A spreading to North China and Southwest Asia. Furthermore, according to the analysis of correlation between genetic differentiation value λ1 and λ2 and geographical distance, we further confirmed two phases of migration in goat breeds of North China. These results will contribute to a better understanding of the origin and migration history of domestic goat.

Abstract It has been proposed that elementary arithmetic induces spatial shifts of attention. However, the timing of this arithmetic-space association remains unknown. Here we investigate this issue with a target detection paradigm. Detecting targets in the right visual field was faster than in the left visual field when preceded by an addition operation, while detecting targets in the left visual field was faster than in the right visual field when preceded by a subtraction operation. The arithmetic-space association was found both at the end of the arithmetic operation and during calculation. In contrast, the processing of operators themselves did not induce spatial biases. Our results suggest that the arithmetic-space association resides in the mental arithmetic operation rather than in the individual numbers or the operators. Moreover, the temporal course of this effect was different in addition and subtraction.