外刊阅读 | TheScientist | 服药时间很重要吗？

Neural networks that mimic human learning form the basis of many state-of-the-art AI tools, from large language models to machine-learning algorithms capable of analysing large swathes of data, including the protein-structure-prediction model AlphaFold.

模仿人类学习方式的神经网络，构成了众多先进人工智能工具的基础，这些工具从大型语言模型到能够分析海量数据的机器学习算法，其中就包括蛋白质结构预测模型AlphaFold。

Why Timing Matters When Taking Medicines

为什么服药时间很重要

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Health outcomes in humans often show daily variations. For instance, morning vaccinations may trigger a more effective immune response than a jab in the afternoon.Similarly, people are more susceptible to infections at certain times of the day.Such variability is orchestrated by circadian clocks that regulate oscillations in gene expression. Experiments conducted in cells and lab animals have shown that the liver, which plays a role in vaccine responses and infections, displays a large number of such circadian-dependent genes.However, some aspects of drug metabolism and immune reactions are unique to humans and difficult to investigate due to a lack of experimental systems.

“We knew that the liver has its own circadian rhythm that is independent of the central clock in our brain,” said Liliana Mancio-Silva, a parasitologist at the Pasteur Institute. “We wanted to know whether we can mimic the liver circadian oscillations in vitro.”Mancio-Silva teamed up with biomedical engineer Sangeeta Bhatia at Massachusetts Institute of Technology to develop an in vitro human liver model, which they described in Science Advances. In characterizing the hepatocytes in their system, the researchers identified the genes involved in drug metabolism and susceptibility to infections that are under circadian control. The model, which mimics the circadian rhythm of the organ, provides researchers with a platform to study the influence of circadian genes on human liver functions and improve drug development. 

Equipped with a system to study cyclic variations in liver cells, the researchers wondered how circadian rhythms affected gene expression. They analyzed the transcriptomes of these cells and found that more than 380 genes were expressed cyclically and that a majority of these genes were related to drug metabolism and inflammatory and immune responses.One of these cyclically expressed genes, cytochrome P450 3A4 (CYP3A4) encodes a drug-metabolizing enzyme in the cytochrome P450 family, which is responsible for about three-quarters of all drug metabolism reactions in humans. They found that CYP3A4 enzymatic activity occurred in waves, suggesting that drug pharmacokinetics may differ depending on the time of the day. 

To test this, the team treated hepatic cells with either the lipid-lowering drug atorvastatin or the non-steroidal analgesic acetaminophen. These drugs are harmful to the liver at high doses due to their metabolism by CYP3A4 into toxic byproducts. In the treated cells, they observed that higher levels of CYP3A4 correlated with greater cell death, suggesting that adverse drug effects may be minimized by optimizing the time at which the drug is administered. The technological breakthrough in this paper is keeping human liver cells alive for 10 weeks, which enabled Mancio-Silva and her team to prove, for the first time, that drug-metabolizing enzyme activities in humans are cyclical. 

This observation did not surprise Mancio-Silva.“We know that malaria has a circadian component,” she said. Malaria-spreading mosquitoes bite humans and deliver the parasites at night when the human immune response is downregulated, she explained.These findings not only inform researchers how to better administer anti-malarial drug treatment, but they also highlight how experimental biologists must consider time as a factor when studying the liver. “These results also give us confidence in the liver model used,” Mancio-Silva said. “We can truly and faithfully recapitulate the human liver.”

Collectively, these findings indicate that mitochondrial metabolism is a key regulator of antigen processing in DCs and subsequent T cell activation.

综上所述，这些研究结果表明，线粒体代谢是树突状细胞（DCs）中抗原处理和随后T细胞活化的关键调节因子。

Vaccination is one of the most effective tools avail­able against infectious dis­ease. Nonetheless, opti­mizing vaccine efficacy remains a top priority for scientists, especially to better protect high-risk populations.

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