Functional evaluation of cytochrome P450 2D6 allelic isoforms

Human CYP2D6 is one of the most important human P450s based on the number of its drug substrates. It shows an extensive genetic polymorphism that influences its expression and function. There are more than 80 different CYP2D6 alleles and allelic variants that have been identified in human. However, only a part of alleles have been characterized with respect to enzyme activity and substrate specificity. In the first project, three alleles CYP2D6*24 (1297L), CYP2D6*27 (E410K) and CYP2D6*26 (I369T) were constructed and expressed. The enzymatic activities were evaluated by the metabolic rates for dextromethorphan O-demethylation and N-demethylation; codeine O-demethylation and N-demethylation. For DXM O-demethylation, CYP2D6*24 has the highest intrinsic clearance value, as estimated by Vmax/Km ratio, followed by *1, *26 and *27; For DXM N-demethylation, three allelic variants showed almost the same intrinsic clearance values as the wild type CYP2D6. For codeine O-demethylation, 2D6*26 and *27 have the same intrinsic clearance, it is around 2-fold higher than 2D6*1 as estimated by Vmax/Km ratio. For codeine N-demethylation, the variant CYP2D6*26 exhibited higher enzyme efficiency for codeine O-demethylation than codeine N-demethylation compared to the wild type and other alleles.;The human CYP2D subfamily includes CYP2D6, CYP2D7 and CYP2D8P, which locate at the CYP2D locus of chromosome 22. It was found that alternatively splicing of CYP2D pre-mRNA could occur and these splicing variants are tissue-specific. However, it is still unknown whether and how these alternatively splicing variants play important physiological or pathological roles in these tissues. In the second project, a human brain CYP2D7 variant was successfully constructed and expressed.;CYP2D6 polymorphism has been associated with various human cancer susceptibilities such as lung, breast, skin and prostate cancers. It has hypothesized that the existence of these alternatively splicing variants may impact the expression and functions of CYP2D6 in extrahepatic tissues, and the alternation of CYP2D6 might play an important role in determining cancer risk. However, the genotypes and function of these extrahepatic CYP2D6 are still unknown. In the third project, several alternatively splicing variants derived from different human tissues including liver, brain, skin, eye and prostate have been cloned and sequenced. Among these variants, a full-length skin variant were constructed and, expressed. (Abstract shortened by UMI.)

Just Fine-tune Twice: Selective Differential Privacy for Large Language Models

With the increasing adoption of NLP models in real-world products, it becomes more and more important to protect these models from privacy leakage. Because private information in language data is sparse, previous research formalized a Selective-Differential-Privacy (SDP) notion to provide protection for sensitive tokens detected by policy functions, and prove its effectiveness on RNN-based models. But the previous mechanism requires separating the private and public model parameters and thus cannot be applied on large attention-based models. In this paper, we propose a simple yet effective just-fine-tune-twice privacy mechanism to first fine-tune on in-domain redacted data and then on in-domain private data, to achieve SDP for large Transformer-based language models. We also design explicit and contextual policy functions to provide protections at different levels. Experiments show that our models achieve strong performance while staying robust to the canary insertion attack. We further show that even under low-resource settings with a small amount of in-domain data, SDP can still improve the model utility. We will release the code, data and models to facilitate future research

ViT-CX: Causal Explanation of Vision Transformers

Despite the popularity of Vision Transformers (ViTs) and eXplainable AI (XAI), only a few explanation methods have been proposed for ViTs thus far. They use attention weights of the classification token on patch embeddings and often produce unsatisfactory saliency maps. In this paper, we propose a novel method for explaining ViTs called ViT-CX. It is based on patch embeddings, rather than attentions paid to them, and their causal impacts on the model output. ViT-CX can be used to explain different ViT models. Empirical results show that, in comparison with previous methods, ViT-CX produces more meaningful saliency maps and does a better job at revealing all the important evidence for prediction. It is also significantly more faithful to the model as measured by deletion AUC and insertion AUC

Hydrodeoxygenation of p-cresol on unsupported Ni–P catalysts prepared by thermal decomposition method

AbstractUnsupported Ni–P catalysts were prepared from the mixed precursor of NiCl2 and NaH2PO2 by thermal decomposition method, and their catalytic activities were measured using the hydrodeoxygenation (HDO) of p-cresol as probe. The effects of the H2PO2−/Ni2+ molar ratio in the precursor and the thermal decomposition temperature on the catalyst purity, crystallite size and HDO activity were studied. The HDO of p-cresol on these Ni–P catalysts proceeded with two parallel pathways yielding methylbenzene and methylcyclohexane as final products. The higher HDO catalytic activity of the catalyst was attributed to its bigger crystallite size and purer phase of Ni2P