Academia Sinica

Sugars cover nearly all proteins present at the surface of the cells in our bodies, forming a shield around the proteins. Thus, these sugars influence how cells interact with their environment including pathogens, playing an important role in medical drug development. GlycoSHIELD, a new computational approach to study the sugar shields of proteins, is resource-reducing, time-efficient and user-friendly. Proteins not only carry out the functions that are critical for the survival of cells, but also influence the development and progression of diseases. To understand their role in health and disease, researchers study the three-dimensional atomic structure of proteins using both experimental and computational methods. Over 75 percent of proteins present at the surface of our cells are covered by glycans. These sugar-like molecules form very dynamic protective shields around the proteins. However, the mobility and variability of the sugars make it difficult to determine how these shields behave, or how they influence the binding of drug molecules. Mateusz Sikora, the project leader and head of the Dioscuri Centre for Modelling of Posttranslational Modifications, and his team in Krakow and partners at the Max Planck Institute of Biophysics in Frankfurt am Main, Germany, have addressed this challenge by using computers, working together with scientists at Inserm in Paris, Academia Sinica in Tapei and the University of Bremen. Their powerful new algorithm GlycoSHIELD enables a fast but realistic modeling of the sugar chains present on protein surfaces. Reducing computing hours and therefore power consumption by several orders of magnitude compared to conventional simulation tools, GlycoSHIELD paves the path towards green computing. From thousands of hours to a few minutes Protective glycan shields strongly influence how proteins interact with other molecules such as therapeutic drugs. For example, the sugar layer on the spike protein of the coronavirus hides the virus from the immune system by making it difficult for natural or vaccine-induced antibodies to recognize the virus. The sugar shields therefore play an important role in drug and vaccine development. Pharmaceutical research could benefit from routinely predicting their morphology and dynamics. Until now, however, forecasting the structure of sugar layers using computer simulations was only possible with expert knowledge on special supercomputers. In many cases, thousands or even millions of computing hours were required. With GlycoSHIELD, Sikora's team provides a fast, environmentally friendly open source alternative. "Our approach reduces resources, computing time and the technical expertise needed," says Sikora. "Anyone can now calculate the arrangement and dynamics of sugar molecules on proteins on their personal computer within minutes, without the need of expert knowledge and high-performance computers. Furthermore, this new way of making calculations is very energy efficient." The software can not only be used in research, but could also be helpful for the development of drugs or vaccines, for example in immunotherapy for cancer. A jigsaw puzzle made of sugar How did the team manage to achieve such a high increase in efficiency? The authors created and analyzed a library of thousands of most likely 3D poses of the most common forms of sugar chains on proteins found in humans and microorganisms. Using long simulations and experiments, they found that for a reliable prediction of glycan shields, it is sufficient that the attached sugars do not collide with membranes or parts of the protein. The algorithm is based on these findings. "GlyoSHIELD users only have to specify the protein and the locations where the sugars are attached. Our software then puzzles them on the protein surface in the most likely arrangement," explains Sikora. "We could reproduce the sugar shields of the spike protein accurately: they look exactly as what we see in the experiments!" With GlycoSHIELD it is now possible to supplement new as well as existing protein structures with sugar information. The scientists also used GlycoSHIELD to reveal the pattern of the sugars on the GABAA receptor, an important target for sedatives and anesthetics.

A new analysis sheds light on the molecular processes involved when a carnivorous species of fungus known as Arthrobotrys oligospora senses, traps and consumes a worm. A new analysis sheds light on the molecular processes involved when a carnivorous species of fungus known as Arthrobotrys oligospora senses, traps and consumes a worm. Hung-Che Lin of Academia Sinica in Taipei, Taiwan, and colleagues present these findings November 21 in the open access journal PLOS Biology. A. oligospora usually derives its nutrients from decaying organic matter, but starvation and the presence of nearby worms can prompt it to form traps to capture and consume worms. A. oligospora is just one of many species of fungi that can trap and eat very small animals. Prior research has illuminated some of the biology behind this predator-prey relationship (such as certain genes involved in A. oligospora trap formation) but for the most part, the molecular details of the process have remained unclear. To boost understanding, Lin and colleagues performed a series of lab experiments investigating the genes and processes involved at various stages of A. oligospora predation on a nematode worm species called Caenorhabditis elegans. Much of this analysis relied on a technique known as RNAseq, which provided information on the level of activity of different A. oligospora genes at different points in time. This research surfaced several biological processes that appear to play key roles in A. oligospora predation. When A. oligospora first senses a worm, the findings suggest, DNA replication and the production of ribosomes (structures that build proteins in a cell) both increase. Next, the activity increases of many genes that encode proteins that appear to assist in the formation and function of traps, such as secreted worm-adhesive proteins and a newly identified family of proteins dubbed "trap enriched proteins" (TEP). Finally, after A. oligospora has extended filamentous structures known as hyphae into a worm to digest it, the activity is boosted of genes coding for a variety of enzymes known as proteases -- in particular, a group known as metalloproteases. Proteases break down other proteins, so these findings suggest that A. oligospora uses proteases to aid in worm digestion. These findings could serve as a foundation for future research into the molecular mechanisms involved in A. oligospora predation and other fungal predator-prey interactions. The authors add, "Our comprehensive transcriptomics and functional analyses highlight the role of increased DNA replication, translation, and secretion in trap development and efficacy. Furthermore, a gene family that is largely expanded in the genomes of nematode-trapping fungi were found to be enriched in traps and critical for trap adhesion to nematodes. These results furthered our understanding of the key processes required for fungal carnivory."

Researchers have harnessed a combination of lab-grown cells to regenerate damaged heart muscle. The study addresses major challenges of using heart muscle cells, called cardiomyocytes, grown from stem cells -- takes a crucial step toward future clinical applications. Researchers at the University of Wisconsin-Madison and Academia Sinica of Taiwan have harnessed a combination of lab-grown cells to regenerate damaged heart muscle. The study, published in Circulation -- which addresses major challenges of using heart muscle cells, called cardiomyocytes, grown from stem cells -- takes a crucial step toward future clinical applications. Previous research has shown that transplanting cardiomyocytes made from induced pluripotent stem cells (iPSC) can replace muscle in the hearts of mammals. Researchers have struggled to bring the treatment to the clinic, in part because the implanted cells haven't developed enough life-sustaining blood vessels to survive very long. The new study confronted that challenge by combining the lab-grown cardiomyocytes with stem-cell-derived endothelial cells -- the cells that line blood. The combination therapy also holds promise for tackling arrhythmia, another significant obstacle in heart regeneration with stem-cell-derived cardiomyocytes. "Our findings suggest that human iPSC-derived endothelial cells can effectively augment the remuscularization of the heart by iPSC-derived cardiomyocytes, offering a promising avenue for future clinical applications," says Patrick Hsieh, a researcher with Academia Sinica's Institute of Biomedical Sciences who conducted the study while working as a visiting professor at the UW-Madison Stem Cell & Regenerative Medicine Center. Hsieh and study lead author Yu-Che Cheng collaborated with Tim Kamp, who serves as director of the Stem Cell & Regenerative Medicine Center, as well as a team of researchers at UW-Madison and the Wisconsin National Primate Research Center, to examine the therapeutic effect of co-transplantation in mice and non-human primates undergoing a heart attack. "The main advantage of iPSCs is their ability to be differentiated into many types of cells and serve as a valuable resource for cell therapy," says Cheng, who is a project manager at Academia Sinica. "In this study, we generated billions of endothelial cells and cardiomyocytes from the same iPSCs line to inject into mice and non-human primates." "The simple idea of the project was to enhance blood flow and promote survival of iPSC-cardiomyocytes using blood vessel-forming endothelial cells," Kamp says. "But the reality of generating the optimal cell preparations followed by precise delivery to the heart reflects tremendous effort by an international team of collaborators." The team would like to conduct further studies to refine their cell transplantation protocols and assess long-term safety and efficacy. Promising results, Hsieh believes, would lead to clinical trials with human patients with heart disease, a leading cause of death around the world. "As a cardiac surgeon now focusing on translational research, the most exciting aspect of this research is the potential to make a meaningful impact on the treatment of heart disease," Hsieh says. "Witnessing the significant improvements in cardiac function and tissue regeneration resulting from our combined cell therapy approach is both inspiring and promising for the future of cardiovascular medicine." This research was supported by grants from the Ministry of Science and Technology, Taiwan (111-2321-B-001-012, 111-2740-B-001-003, 110-2320-B-001-023), National Health Research Institutes (EX111-10907SI), U.S. National Academy of Medicine and Academia Sinica (AS-HLGC-109-05), National Institutes of Health (U01HL134764 and UL1TR002373) and the National Science Foundation (EEC-1648035).