Science China Life Sciences最新文献

Cardiac immune-related adverse events (irAEs) associated with anti-programmed death-1 (anti-PD1) immune checkpoint inhibitors (ICIs) are of major concern, as they can be fatal; however, their underlying molecular mechanisms remain poorly understood. In this study, we retrospectively investigated the role of anti-PD1 ICIs in the early stages of cardiotoxicity and the underlying mechanisms. We conducted in vitro and vivo experiments to investigate the underlying mechanisms. The hearts of male mice and HL-1 cells showed downregulated myocardial apolipoprotein A (Apoa) 1 and Apoa2 expression following anti-PD1 therapy. BATF transcriptionally activated Apoa1 and Apoa2 expression, and recombinant Apoa1/Apoa2 markedly improved cardiac function in anti-PD1-treated and PD1-knockout mice. Additionally, anti-PD1 therapy induced the myocardial infiltration of macrophages in male mice. These findings showed that nicotinamide could potentially preserve the left ventricular ejection fraction (LVEF) without compromising the anticancer efficacy of anti-PD1 therapy. Mechanistically, nicotinamide altered myocardial lipid metabolism and reduced the inflammation induced by anti-PD1 therapy. Findings from the randomized controlled trial involving twelve patients with cancer treated with anti-PD1 therapy confirmed a slight decrease in the LVEF and a marked increase in myocardial enzyme levels. Nicotinamide treatment effectively mitigated these changes compared with those observed in the control group. Our findings contribute to a better understanding of cardiac anti-PD1 irAEs and show that nicotinamide might be a promising preventive strategy in the early stages of anti-PD1 ICI-associated cardiotoxicity.

Cereal endosperm, derived from the fertilized central cell in the process of double fertilization, is a primary source of human food and animal feed. Early endosperm development involves rapid nuclear division, followed by cellularization, and disruptions to this process affect seed size, viability, and yield. However, the regulatory mechanisms governing the early cereal endosperm development remain largely unclear. Here, we demonstrate that the OsMKK6-OsMPK4 cascade plays an important role in early endosperm development of rice. Knockout of either OsMKK6 or OsMPK4 causes maternally inherited endosperm abortion due to impaired cellularization. Mechanistically, the OsMKK6-OsMPK4 cascade directly interacts and phosphorylates OsFIE1 and OsFIE2, core components of the Polycomb Repressive Complex 2 (PRC2), thereby modulating H3K27me3 at imprinted gene loci. Consistently, the osfie1osfie2 mutant exhibits endosperm cellularization defects similar to those of osmkk6 and osmpk4. Our work links MAPK signaling to PRC2 function in endosperm cellularization, providing new insights into rice endosperm development.

While FDA-approved liposomal drugs (e.g., Doxil®) have demonstrated improved toxicity profiles and targeted delivery, emerging evidence reveals paradoxical pro-angiogenic and immunosuppressive effects that compromise therapeutic outcomes. This review examines the critical yet underappreciated role of complement system activation in mediating these adverse effects. We present a comprehensive analysis of the dynamic interactions between liposomal formulations, complement proteins, and the tumor microenvironment. By elucidating these mechanisms, we identify key challenges and opportunities for optimizing nanocarrier design. Our synthesis provides a framework for developing next-generation liposomal therapeutics with enhanced efficacy and reduced immunogenic potential, offering important insights for translational cancer nanomedicine.

Cotton (Gossypium hirsutum), serving as a critical raw material for textile manufacturing, is highly vulnerable to drought stress during its growth cycle. Water deficit conditions directly impair boll development and ultimately reduce lint yield. As a crucial unsaturated fatty acid, linolenic acid (C18:3) plays a pivotal role in plant growth and drought response. However, the specific role of C18:3 in drought tolerance and the underlying regulatory network remain largely unelucidated. In this study, drought treatment significantly reduced C18:3 content in cotton leaves, while exogenous application of C18:3 enhanced drought tolerance. Gene expression analysis indicated that the fatty acid desaturase GhFAD3-2 may be involved in the drought-induced reduction of C18:3 content. Overexpression of GhFAD3-2 improved drought tolerance in cotton, whereas silencing GhFAD3-2 decreased drought tolerance, potentially by regulating C18:3, jasmonic acid, and flavonoid metabolism. Further investigation revealed that GhDREB1B acted as an upstream transcriptional activator of GhFAD3-2, directly binding to the promoter of GhFAD3-2 to activate its transcription in response to drought stress in cotton. The expression of GhDREB1B was significantly suppressed under drought stress, and silencing GhDREB1B resulted in decreased GhFAD3-2 expression, reduced C18:3 content, and consequently diminished drought tolerance in cotton. In conclusion, this study elucidates the role of the GhDREB1B-GhFAD3-2 module in regulating C18:3 biosynthesis in response to drought stress in cotton, providing new insights into the molecular mechanisms of drought response and potential breeding targets for cotton.

The Indo-Pacific humpback dolphin (Sousa chinensis; hereafter IPH dolphin), a coastal cetacean species primarily distributed in Chinese waters, serves as a flagship species for marine ecosystem conservation. Currently, this species faces sustained population declines and habitat degradation, and is listed as "Vulnerable" on the IUCN Red List. Herein, we de novo assembled a high-quality chromosome-level genome for the IPH dolphin and conducted conservation genomic analyses using whole-genome resequencing data from 82 individuals across four major geographic populations in Chinese waters (northern Beibu Gulf (NBG), eastern Zhanjiang (EZJ), Pearl River Estuary (PRE), and Xiamen (XM)) and one population from the Gulf of Thailand (THA). Our findings reveal that the four Chinese populations form three genetic clusters, with PRE and XM merging into one. Historical fluctuations in the effective population size (N_e) of IPH dolphins correlate with sea-level changes, while recent declines and critically low N_e now characterize all four Chinese populations. Gene flow was detected between NBG and EZJ, and between EZJ and PRE, indicating high historical population connectivity. Alarmingly, all four Chinese populations exhibited extremely low genetic diversity and elevated inbreeding levels. Genes carrying loss-of-function mutations in IPH dolphins were enriched in pathways related to DNA repair and cellular responses to organonitrogen compounds, potentially increasing cancer susceptibility and impairing the responses to aquatic organic pollutants. In conclusion, given the extremely low N_e and limited genetic evolutionary potential of IPH dolphins in Chinese waters, coupled with unfavorable marine environmental conditions, urgent conservation measures are warranted.

The associations between short-term exposure to PM_2.5 constituents and diabetes remain inconsistent and understudied. We conducted a nationwide case-crossover study across 153 hospitals in Chinese mainland. Daily average concentrations of five major PM_2.5 constituents, including black carbon (BC), organic matter (OM), sulfate (SO₄^2-), nitrate (NO₃^-), and ammonium (NH₄⁺), were assessed by satellite-based models. We applied single-constituent analysis and inverse-probability-of-treatment weighting (IPTW) to assess each constituent's independent effect. In addition, we developed a weighted quantile sum (WQS) regression for paired data with multiple controls to examine the joint impacts of the constituents and quantify each one's contribution. The single-constituent analysis suggested that an interquartile range increase in each of the five constituents was significantly associated with elevated risk of T2DM hospitalization, the effects ranging from 1.49%-2.14%. After adjusting for other constituents using IPTW methods, only OM and SO₄^2- remained significant associations with T2DM. The WQS analysis further confirmed SO₄^2- and OM as the dominant contributors. Our findings highlight the importance of targeted air pollution control measures for T2DM prevention.