抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Cell-cell interactions orchestrate organismal development, homeostasis and single-cell functions. When cells do not properly interact or improperly decode molecular messages, disease ensues. Thus, the identification and quantification of intercellular signalling pathways has become a common analysis performed across diverse disciplines. The expansion of protein-protein interaction databases and recent advances in RNA sequencing technologies have enabled routine analyses of intercellular signalling from gene expression measurements of bulk and single-cell data sets. In particular, ligand-receptor pairs can be used to infer intercellular communication from the coordinated expression of their cognate genes. In this Review, we highlight discoveries enabled by analyses of cell-cell interactions from transcriptomic data and review the methods and tools used in this context.

/pdf/deciphering-cell-cell-interactions-and-communication-from-19hzux0gfi.pdf

Deciphering cell-cell interactions and communication from gene expression.

Branched chain amino acids (BCAAs) are building blocks for all life-forms. We review here the fundamentals of BCAA metabolism in mammalian physiology. Decades of studies have elicited a deep understanding of biochemical reactions involved in BCAA catabolism. In addition, BCAAs and various catabolic products act as signaling molecules, activating programs ranging from protein synthesis to insulin secretion. How these processes are integrated at an organismal level is less clear. Inborn errors of metabolism highlight the importance of organismal regulation of BCAA physiology. More recently, subtle alterations of BCAA metabolism have been suggested to contribute to numerous prevalent diseases, including diabetes, cancer, and heart failure. Understanding the mechanisms underlying altered BCAA metabolism and how they contribute to disease pathophysiology will keep researchers busy for the foreseeable future.

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Branched Chain Amino Acids.

Quantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids

The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP’s tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases.

/pdf/a-high-stringency-blueprint-of-the-human-proteome-5fev6rml90.pdf

A high-stringency blueprint of the human proteome

The ubiquitination mediated by ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3) cascade is crucial to protein degradation, transcription regulation, and cell signaling in eukaryotic cells. The high specificity of ubiquitination is regulated by the interaction between E3 ubiquitin ligases and their target substrates. Unfortunately, the landscape of human E3-substrate network has not been systematically uncovered. Therefore, there is an urgent need to develop a high-throughput and efficient strategy to identify the E3-substrate interaction. To address this challenge, we develop a computational model based on multiple types of heterogeneous biological evidence to investigate the human E3-substrate interactions. Furthermore, we provide UbiBrowser as an integrated bioinformatics platform to predict and present the proteome-wide human E3-substrate interaction network (
 http://ubibrowser.ncpsb.org
 ).

/pdf/an-integrated-bioinformatics-platform-for-investigating-the-2q3yico26z.pdf

An integrated bioinformatics platform for investigating the human E3 ubiquitin ligase-substrate interaction network.

A Cell-type-resolved Liver Proteome

It is still unclear whether there exist functional constraints on the evolution of protein ubiquitination sites, because most previous studies regarded all protein ubiquitination sites as a whole or only focused on limited structural properties. We tried to clarify the relation between functional constraints and ubiquitination sites evolution. We investigated the evolutionary conservation of human ubiquitination sites in a broad evolutionary scale from G. gorilla to S. pombe, and we found that in organisms originated after the divergence of vertebrate, ubiquitination sites are more conserved than their flanking regions, while the opposite tendency is observed before this divergence time. By grouping the ubiquitination proteins into different functional categories, we confirm that many functional constraints like certain molecular functions, protein tissue expression specificity and protein connectivity in protein-protein interaction network enhance the evolutionary conservation of ubiquitination sites. Furthermore, by analyzing the gains of ubiquitination sites at different divergence time and their functional characters, we validate that the emergences of ubiquitination sites at different evolutionary time were also affected by the uncovered functional constraints. The above results suggest that functional constraints on the adaptive evolution of ubiquitination sites increase the opportunity for ubiquitination to synthetically regulate various cellular and developmental processes during evolution.

/pdf/functional-constraints-on-adaptive-evolution-of-protein-9iphpqfz99.pdf

Functional constraints on adaptive evolution of protein ubiquitination sites.


 Traditional Chinese Medicine (TCM) not only maintains the health of peoples in Asia but also provides a great resource of active natural products for modern drug development. However, owing to its diverse constituents and the complex interactions with the human body, it is still challenging to clarify its effective constituents and molecular mechanism. This greatly hinders its widespread application worldwide and TCM-based modern drug development. The vast majority of constituents in TCM can produce pharmacological effects only after they are absorbed into bloodstream. Compared with ordinary constituents generally detected in vitro, these that are verified to reach the bloodstream, including original constituents absorbed into blood and metabolites of original constituents produced by the gastrointestinal tract, intestinal microflora, and liver, are more likely to be really effective ones responsible for the pharmacological effects. Here we developed DCABM-TCM (a Database of Constituents Absorbed into Blood and Metabolites of TCM), the first database systematically collecting blood constituents of TCM prescriptions and herbs, including prototypes and metabolites experimentally-detected in blood, together with the corresponding detailed detection conditions by manual literature mining. Currently DCABM-TCM has collected 4206 blood constituents of 192 prescriptions and 194 herbs, and also integrated various related annotations including physicochemical properties, ADMET properties, and associated targets, functional terms, pathways, and diseases etc. Furthermore, DCABM-TCM supported two analysis functions, the network pharmacology analysis for TCM molecular mechanism elucidation and the target/pathway/disease-based screening of candidate blood constituents, herbs or prescriptions for TCM-based drug discovery. DCABM-TCM is freely assessable by http://bionet.ncpsb.org.cn/dcabm-tcm/ and is browsable and searchable for each of 6 kinds of entities, including prescriptions, herbs, blood constituents, targets, pathways, and diseases. DCABM-TCM will contribute to not only the elucidation of effective constituents and molecular mechanism of TCMs but also the discovery of TCM-derived drug-like compounds which are both bioactive and bioavailable, the feature investigation of absorbable natural compounds, and the quality control of herbs.

/pdf/dcabm-tcm-a-database-of-constituents-absorbed-into-blood-and-4nz6bgxhlz.pdf

Feifei Guo

Papers

An integrated bioinformatics platform for investigating the human E3 ubiquitin ligase-substrate interaction network.

A Cell-type-resolved Liver Proteome

Functional constraints on adaptive evolution of protein ubiquitination sites.

DCABM-TCM, a Database of Constituents Absorbed into Blood and Metabolites of Traditional Chinese Medicine