White paper released for π-HuB, the international Human Proteome Navigator mega-science project

       Dynamics of the blood plasma proteome during hyperacute HIV-1 infection

       The structure of apolipoprotein B100 from human low-density lipoprotein

       ProHap enables human proteomic database generation accounting for population diversity

       Enhanced Parkin-mediated mitophagy mitigates adverse left ventricular remodelling after myocardial infarction: role of PR-364

       A "stable" survival analysis method for multi-center data

       Spatially resolved omics analysis of the tumor microenvironment reveals key steps of lung adenocarcinoma development

       The most complete mouse reference genome sequence to date

       Nature Biotechnology announces its top ten science-related news stories of 2024

       Science announces its top ten scientific breakthroughs of 2024

On December 11, Academician He Fuchu, a pioneer of the international proteomics field at the National Center for Protein Sciences, together with Professor Ruedi Aebersold of ETH Zurich, a leading figure in proteomics, and nearly a hundred other international scientists, published an important expert perspective in Nature. The human body contains trillions of cells of diverse types and complex functions. To understand human biology, we must understand the complexity of the proteome across the human body and its many potential states—complexity that can neither be predicted from the genome nor measured systematically with existing technologies. Recent advances in proteomic technologies and computational science now offer the opportunity to study the complex biology of the human body with unprecedented resolution and scale. Against this backdrop, the scientists introduce a large-scale scientific research project called π-HuB. By generating and using multimodal proteomic datasets, the project aims to deepen our understanding of human biology, advance disease risk assessment and diagnosis, discover new drug targets, optimize appropriate treatment strategies and realize intelligent healthcare—opening a new era of proteomics-driven, informed medicine.

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Dynamics of the blood plasma proteome during hyperacute HIV-1 infection

During hyperacute HIV-1 infection, the complex dynamics of protein expression in plasma and their relationship to acute retroviral syndrome, viral control and disease progression remain largely unknown. The research team of Esbjörnsson at Lund University in Sweden quantified 1,293 plasma proteins in 157 longitudinally linked plasma samples from 54 participants in four sub-Saharan African countries, collected before, during and after hyperacute HIV-1 infection, and identified six distinct longitudinal expression profiles, four of which showed a consistent decline in protein levels after HIV-1 infection. Proteins involved in inflammatory responses, immune regulation and cell motility changed significantly during the transition from pre-infection to one month post-infection. Specifically, decreased levels of ZYX and SCGB1A1 and increased levels of LILRA3 were associated with an increased risk of acute retroviral syndrome; increased levels of NAPA and RAN together with decreased ITIH4 were associated with viral control; and increased levels of HPN, PRKCB and ITGB3 were associated with an increased risk of disease progression. This study provides insight into the early host response to hyperacute HIV-1 infection and suggests potential biomarkers and mechanisms related to HIV-1 disease progression and viral load.

Low-density lipoprotein (LDL) plays a central role in lipid and cholesterol metabolism and is a key factor in the development of atherosclerosis, one of the leading causes of death worldwide. Apolipoprotein B100 (apoB100), one of the largest proteins encoded in the genome, is the principal structural and functional component of LDL, but its size and complex lipid associations have posed major challenges to structural studies. A research team at the University of Missouri used an integrated approach combining cryo-electron microscopy, AlphaFold2 and molecular dynamics refinement to present the first structure of apoB100, resolved to sub-nanometer resolution over most of its length. The structure consists of a large globular N-terminal domain and a continuous amphipathic β-sheet approximately 61 nm long that wraps around the LDL particle like a belt. Nine strategically positioned interstrand insertions are distributed almost symmetrically on either side of this "β-belt"; they extend onto the lipid surface and provide additional structural support through a network of long-range interactions. The researchers further compared the structure against a comprehensive list of more than 200 intramolecular cross-links and found a high degree of agreement between them. These results suggest how the different domains of apoB100 cooperate to maintain LDL shape and cohesion while accommodating different particle sizes. The findings advance our fundamental understanding of LDL synthesis, form and function, and will help accelerate the design of potential new therapies.

With advances in genomics, large human haplotype reference panels have become essential for interpreting human diversity within and between populations. Mass spectrometry-based proteomics, however, has not been able to benefit from this information. To address the problem, the team of Marc Vaudel at the University of Bergen in Norway introduced ProHap, a Python-based tool that builds protein sequence databases from the phased genotypes of a reference panel. ProHap allows researchers to account for haplotype diversity in proteomic searches. It can more accurately reflect the genetic variation present in a population, helps improve the accuracy of protein identification, and enables a better understanding of how genetic variation affects protein expression and modification—facilitating research into genotype-phenotype links and thereby advancing personalized and precision medicine.

Nearly 30% of survivors of myocardial infarction (MI) go on to develop heart failure (HF), partly because of injury caused by the accumulation of dysfunctional mitochondria. Organelle quality control through Parkin-mediated mitophagy plays a role in mediating myocardial injury and adverse remodeling in heart failure after ischemic injury. The team of Professor Jennifer Van Eyk at Cedars-Sinai Medical Center in the United States found that administering PR-364, a specific small-molecule Parkin activator, intravenously within 2 hours after MI reduced mortality, preserved ventricular ejection fraction and attenuated the progression of HF. To uncover the mechanism of PR-364, the researchers used a multi-omics strategy combined with classical functional experiments in an in vivo MI model and an in vitro cardiomyocyte model. In vitro cell data showed that activation of Parkin by PR-364 increased mitophagy and mitochondrial biogenesis, enhanced ATP production by improving the citric acid cycle, altered the pattern of calcium accumulation in mitochondria, and initiated translational reprogramming by increasing the expression of mitochondrial translation proteins. In mice, administration of PR-364 after MI led to widespread proteomic changes indicating up-regulated mitochondrial metabolism and mitochondrial translation in surviving myocardium. This study demonstrates that targeting Parkin-mediated mitophagy with PR-364 to protect surviving myocardial tissue after MI and prevent its progression to HF opens a new direction for the treatment of MI-related heart failure.

Survival analysis aims to estimate the effect of covariates on the expected time to an event. It is widely used in fields such as the life sciences and healthcare, has a major influence on decision-making, and can improve survival outcomes. Existing methods usually assume that the training and test data follow similar distributions, but when faced with the diverse data sources of the real world, unpredictable changes in actual data undermine their reliability. There is therefore an urgent need for survival analysis methods that can make predictions using stable features across different cohorts rather than relying on spurious correlations. To this end, the team of Cui Peng at Tsinghua University and the team of He Fuchu and Chang Cheng at the National Center for Protein Sciences (Beijing) jointly proposed a Stable Cox model for discovering stable biomarkers and identifying stable variables. The model jointly optimizes an independence-based sample reweighting module and a weighted Cox regression model. Through extensive evaluation on simulated data as well as real omics and clinical data, Stable Cox not only demonstrated strong generalization ability across different independent test sets, but also significantly distinguished patient subtypes based on the biomarkers it identified—of great importance for guiding treatment decisions and targeted drug development.

Spatially resolved omics analysis of the tumor microenvironment reveals key steps of lung adenocarcinoma development

The interaction between tumor cells and the microenvironment in which they reside is considered a key factor in tumor development. Researchers from the University of Tokyo, the National Cancer Center Hospital and Juntendo University used spatially resolved transcriptomic sequencing data combined with in situ RNA profiling for higher-resolution analysis, presenting spatial RNA profiles from 30 lung adenocarcinoma patients at the non-invasive stage and at the subsequent invasive stage. Detailed examination of each case, together with subsequent computational analysis based on the diverse profiles observed, revealed that marked changes in the phenotypic appearance of tumor cells are usually associated with changes in immune cell features. This phenomenon coincides with the induction of a series of cellular expression programs that enable tumor cells to transform and break through the immune cell barrier, allowing further progression. By combining spatial transcriptomics with spatial proteomics, this study achieved spatial resolution of the tumor microenvironment across multiple subtypes of lung adenocarcinoma, and separately elucidated the tumor evolution patterns of invasive adenocarcinoma and adenocarcinoma in situ/minimally invasive adenocarcinoma, providing a theoretical basis for building a more precise system of clinical diagnosis, treatment and prognosis in lung adenocarcinoma.

The most complete mouse reference genome sequence to date

At present, the mouse reference genome GRCm39 still contains large unresolved regions in repeat-associated euchromatin and heterochromatin. Recently, the team of Professor Yu Xiaochun at Westlake University obtained the most complete mouse reference genome to date. They sequenced and assembled the genome of mouse haploid embryonic stem cells, recovering ribosomal DNA arrays, pericentromeric and subtelomeric regions, and an additional 140 genes predicted to be protein-coding, filling 7.7% of the gaps in the mouse genome. These findings provide important technical references and resource data for genomics research.

Nature Biotechnology announces its top ten science-related news stories of 2024

1. Biotech financing: the darkness before dawn

2. The world's first CRISPR therapy is approved: who will benefit?

3. After the success of weight-loss drugs, companies race to develop ways to preserve skeletal muscle

4. Cancer-targeted antibody-drug conjugates drive a deal-making boom

5. TCR cell therapy finally takes on solid tumors

6. Can single-cell biology deliver on the promise of precision medicine

7. Foundation models learn the basic language of biology, building on ChatGPT technology

8. CAR-T moves into the treatment of autoimmune diseases

9. New mRNA drugs target toxic exons

10. Biotech companies bring multiplexed assays into animal models to accelerate drug development

Science announces its top ten scientific breakthroughs of 2024

1. A revolutionary long-acting injectable HIV prevention drug, lenacapavir, becomes available

2. CAR-T cell therapy for autoimmune diseases

3. The James Webb Space Telescope probes the cosmic dawn

4. RNA-based pesticides enter farm fields

5. The discovery of a nitrogen-fixing organelle reveals an evolutionary mystery

6. The emergence of a new type of magnet, the altermagnet

7. Multicellular organisms appeared early in ancient eukaryotes

8. Mantle waves shape the structure of continents

9. Starship lands successfully, catching the rocket with chopsticks

10. Ancient DNA reveals family connections