Sugar has been called “evil,” “toxic,” and “poison.” But the body needs sugars, too. Sugar molecules help cells recognize and fight viruses and bacteria, shuttle proteins from cell to cell, and make sure those proteins function. Too much or too little can contribute to a range of maladies, including neurodegenerative diseases like Alzheimer’s, inflammation, diabetes, and even cancer.

About 85 percent of proteins, including those associated with Alzheimer’s and Parkinson’s, are beyond the reach of current drugs. One critical and abundant sugar (O-GlcNAc, pronounced o-glick-nack) is found on over 5,000 proteins, often those considered “undruggable.” But now, researchers at Harvard University have designed a new highly-selective O-GlcNAc pencil and eraser — tools that can add or remove the sugar from a protein with no off-target effects — to examine exactly what these sugars are doing and, eventually, engineer them into new treatments for the “undruggable.”

“We can now start studying particular proteins and see what happens when you add or remove the sugar,” said Daniel Ramirez, a co-author on the paper published in Nature Chemical Biology and a Ph.D. candidate in biological and biomedical sciences in the Graduate School of Arts and Sciences. “This is turning out to be very important for a lot of chronic diseases like cancer and diabetes and Alzheimer’s.”

Ramirez designed the original O-GlcNAc pencil, which was reported in ACS Chemical Biology.

All cells carry a multitude of sugars (called glycans), but they’re notoriously hard to study. Current tools either provide a wide-lens view (turning on or off all the O-GlcNAc in a cell) or an ultra-zoomed in view (turning on or off a single sugar on one amino acid on one protein). Neither of these perspectives can show what O-GlcNAc molecules are doing to a protein as a whole, the crucial insight that would enable researchers to connect the dots from O-GlcNAc to disease.

“With the protein-level approach, we’re filling in an important piece that was missing,” said Christina Woo, an associate professor of chemistry and chemical biology, who led the study. Her lab’s tool is like Goldilocks’ lukewarm bowl of porridge: Not too broad, not too specific. Just right.

“Once you have any protein of interest,” said first-author and postdoctoral scholar Yun Ge, “you can apply this tool on that protein and look at the outcomes directly.” Ge engineered the O-GlcNAc eraser, which, like the pencil, uses a nanobody as a protein homing device. The tool is adaptable, too; as long as a nanobody exists for a protein of choice, the tool can be modified to target any protein for which a homing nanobody exists.

The nanobody is a crucial component, but it has limitations: Whether or not it remains stuck to the target protein is still in question, and the molecule could alter the function or structure of the protein once stuck. If cellular changes can’t be definitively linked to the sugar on the protein, that muddies the data.

To skirt these potential limitations, the team engineered their pencils and erasers to be “catalytically dead,” said Woo. The neutered enzymes won’t make unwanted changes along the way to their target protein. And, they can both add and remove sugars, unlike previous tools, which cause permanent changes. Of course, once they connect a specific protein function to O-GlcNAc, they can then use those tools to zoom in and locate exactly where those sugars are latching onto and modifying the protein.

Already, a few of the Woo lab’s collaborators are using the pencil/eraser combo to study O-GlcNAc in live animals. One, for example, is using fruit flies to study how the sugar impacts a protein associated with Alzheimer’s disease. The sugar is also associated with Parkinson’s disease progression: “If you’re taking in less glucose,” said co-author Ramirez, “then you’re not able to produce this sugar inside the cells.” That means the body can’t attach the sugars to the proteins, which causes wide-reaching changes to the cells, aggravating the disease. In diabetes, excess sugars cause similar global disruption; and cancer cells tend to eat lots of sugars. Now, with the Woo lab’s pencil/eraser pair, researchers can identify exactly how these sugars impact various proteins and start to design drugs to reverse negative effects.

Next, the team plans to tweak their tool to achieve even greater control. With optogenetics, for example, they could switch sugars on or off with just a flash of light. Swapping out nanobodies for small molecules (used in traditional drug design), they could edge closer to new treatments. They’re also designing an eraser for the eraser — a tool with a kill switch — and plan to incorporate nanobodies that can target a naturally-occurring protein (for this study, they tagged proteins so the nanobody could find them). “We’re basically trying to make the system more natural and function the way the cell does,” said Ramirez.

Woo also plans to investigate how O-GlcNAc may influence traditionally “undruggable” proteins called transcription factors, which turn genes on and off. If O-GlcNAc plays a role in that process, the sugars could be engineered to study and regulate gene function, too.

“We really don’t know what people are going to find once we give them these tools,” said Ramirez. The tool may be new, but the potential is great: “We’re on the iPhone one, basically,” he continued, “but we’re already working on the next couple generations.”

“Vital exhaustion refers to excessive fatigue, feelings of demoralisation and increased irritability,” said study author Dr. Dmitriy Panov of the Institute of Cytology and Genetics, Novosibirsk, Russian Federation. “It is thought to be a response to intractable problems in people’s lives, particularly when they are unable to adapt to prolonged exposure to psychological stressors.”

This study examined the relationship between vital exhaustion and the risk of myocardial infarction in men with no history of cardiovascular disease. The study used data from the World Health Organization (WHO) MONICA Project.2 A representative sample of 657 men aged 25 to 64 years in Novosibirsk was enrolled in 1994.

Symptoms of vital exhaustion were assessed at baseline using the Maastricht Vital Exhaustion Questionnaire adopted by the MONICA protocol. Participants were classified according to their level of vital exhaustion: none, moderate, or high. Participants were followed-up for 14 years for the incidence of heart attack.

Overall, two-thirds (67%) of the men had vital exhaustion (15% had a high level and 52% had a moderate level) while 33% were unaffected. Nearly three-quarters (74%) of men with high blood pressure had vital exhaustion — high in 58% and moderate in 16%.

In the overall group of men, the researchers analysed the association between vital exhaustion at baseline and the risk of having a heart attack. Compared to those without vital exhaustion, men with moderate or high levels had a 2.7-fold greater risk of a heart attack within five years, a 2.25 higher risk within 10 years, and a 2.1 raised risk within 14 years (p for all <0.05).

When the analysis was controlled for social factors (education, occupation, and marital status) and age, the influence of vital exhaustion on heart attack risk decreased but remained statistically significant. For example, compared to those without vital exhaustion, men with moderate or high levels were 16% more likely to have a myocardial infarction over 14 years of follow-up compared to those without after adjusting for social factors and age (p <0.05).

In the adjusted analysis, the risk of a heart attack linked with exhaustion was higher in never married, divorced, and widowed men compared to married men — with hazard ratios of 3.7, 4.7, 7.0, respectively. The risk of a heart attack related to exhaustion was 2.2-fold higher in those with an elementary school education compared to men with a university degree. Middle-aged men were more affected than younger men: compared to 24-34-year-olds, the risk of a heart attack connected with exhaustion was 3.8-fold higher in 45-54-year-olds and 5.9-fold higher in 55-64-year-olds.

Regarding the influence of marital status on the relationship between exhaustion and heart attack, Dr. Panov said: “Living alone indicates less social support, which we know from our prior studies is an independent risk factor for myocardial infarction and stroke.”

He noted that the findings indicate a pattern whereby social disadvantage relates to vital exhaustion, which is associated with a greater risk of heart disease. “The relationship of exhaustion with threatening cardiovascular events should be taken into account when assessing risk,” he said.

Dr. Panov concluded: “Efforts to improve well-being and reduce stress at home and at work can help reduce vital exhaustion. Involvement in community groups is one way to increase social support and become less vulnerable to stress. Together with a healthy lifestyle, these measures should be beneficial for heart health.”

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Materials provided by European Society of Cardiology. Note: Content may be edited for style and length.

After an oil spill, oil droplets on the ocean surface can be transformed by a weathering process known as photooxidation, which results in the degradation of crude oil from exposure to light and oxygen into new by-products over time. Tar, a by-product of this weathering process, can remain in coastal areas for decades after a spill. Despite the significant consequences of this weathering pathway, photooxidation was not taken into account in oil spill models or the oil budget calculations during the Deepwater Horizon spill.

The UM Rosenstiel School research team developed the first oil-spill model algorithm that tracks the dose of solar radiation oil droplets receive as they rise from the deep sea and are transported at the ocean surface. The authors found that the weathering of oil droplets by solar light occurred within hours to days, and that roughly 75 percent of the photooxidation during the Deepwater Horizon oil spill occurred on the same areas where chemical dispersants were sprayed from aircraft. Photooxidized oil is known to reduce the effectiveness of aerial dispersants.

“Understanding the timing and location of this weathering process is highly consequential. said Claire Paris, a UM Rosenstiel School faculty and senior author of the study. “It helps directing efforts and resources on fresh oil while avoiding stressing the environment with chemical dispersants on oil that cannot be dispersed.”

“Photooxidized compounds like tar persist longer in the environment, so modeling the likelihood of photooxidation is critically important not only for guiding first response decisions during an oil spill and restoration efforts afterwards, but it also needs to be taken into account on risk assessments before exploration activities” added Ana Carolina Vaz, assistant scientist at UM’s Cooperative Institute for Marine and Atmospheric Studies and lead author of the study.

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Materials provided by University of Miami Rosenstiel School of Marine & Atmospheric Science. Original written by Diana Udel. Note: Content may be edited for style and length.