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.

In a study published Jan. 26 in Cancer Discovery, a journal of the American Association for Cancer Research, the investigators reported that this biologic process could help explain why cancers so often recur after treatment. The research was done in both organoids and mouse models made from patients’ samples of acute myeloid leukemia (AML) tumors. The findings were also verified by looking at samples from AML patients that were collected throughout the course of treatment and relapse.

“Acute myeloid leukemia can be put into remission with chemotherapy, but it almost always comes back, and when it does it’s incurable,” said senior author Dr. Ari M. Melnick, the Gebroe Family Professor of Hematology and Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “A longstanding question in the field has been, ‘Why can’t you get rid of all the cancer cells?’ A similar question can be posed for many other types of aggressive cancer in addition to AML.”

For years, cancer researchers have studied how tumors are able to rebound after they appear to be completely wiped out by chemotherapy. One theory has been that because not all cells within a tumor are the same at the genetic level — a condition called tumor heterogeneity — a small subset of cells are able to resist treatment and begin growing again. Another theory involves the idea of tumor stem cells — that some of the cells within a tumor have special properties that allow them to re-form a tumor after chemotherapy has been given.

The idea that senescence is involved does not replace these other theories. In fact, it could provide new insight into explaining these other processes, Dr. Melnick said.

In the study, the researchers found that when AML cells were exposed to chemotherapy, a subset of the cells went into a state of hibernation, or senescence, while at the same time assuming a condition that looked very much like inflammation. They looked similar to cells that have undergone an injury and need to promote wound healing — shutting down the majority of their functions while recruiting immune cells to nurse them back to health.

“These characteristics are also commonly seen in developing embryos that temporarily shut down their growth due to lack of nutrition, a state called embryonic diapause,” Dr. Melnick explained. “It’s not a special process, but normal biological activity that’s playing out in the context of tumors.”

Further research revealed that this inflammatory senescent state was induced by a protein called ATR, suggesting that blocking ATR could be a way to prevent cancer cells from adopting this condition. The investigators tested this hypothesis in the lab and confirmed that giving leukemia cells an ATR inhibitor before chemotherapy prevented them from entering senescence, thereby allowing chemotherapy to kill all of the cells.

Importantly, studies published at the same time from two other groups reported that the role of senescence is important not just for AML, but for recurrent cases of breast cancer, prostate cancer and gastrointestinal cancers as well. Dr. Melnick was a contributor to one of those other studies.

Dr. Melnick and his colleagues are now working with companies that make ATR inhibitors to find a way to translate these findings to the clinic. However, much more research is needed, because many questions remain about when and how ATR inhibitors would need to be given.

“Timing will be very critical,” he said. “We still have a lot to work out in the laboratory before we can study this in patients.”

Dr. Cihangir Duy, a former postdoctoral fellow in Dr. Melnick’s lab, was the study’s first author. Dr. Duy now leads his own lab at Fox Chase Cancer Center in Philadelphia.

Dr. Ari Melnick has been a paid consultant for KDAC Therapeutics, Epizyme, and Constellation Pharmaceuticals.

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Materials provided by Weill Cornell Medicine. Note: Content may be edited for style and length.

The study, published in the journal Science Advances, yields information on a important period in our planet’s formation, when a deep sea of incandescent magma stretched across Earth’s surface and extended hundreds of kilometres into its interior.

It is the gradual cooling and crystallisation of this ‘magma ocean’ that set the chemistry of Earth’s interior — a defining stage in the assembly of our planet’s structure and the formation of our early atmosphere.

Scientists know that catastrophic impacts during the formation of the Earth and Moon would have generated enough energy to melt our planet’s interior. But we don’t know much about this distant and fiery phase of Earth’s history because tectonic processes have recycled almost all rocks older than 4 billion years.

Now researchers have found the chemical remnants of the magma ocean in 3.6-billion-year-old rocks from southwestern Greenland.

The findings support the long-held theory that Earth was once almost entirely molten and provide a window into a time when the planet started to solidify and develop the chemistry that now governs its internal structure. The research suggests that other rocks on Earth’s surface may also preserve evidence of ancient magma oceans.

“There are few opportunities to get geological constraints on the events in the first billion years of Earth’s history. It’s astonishing that we can even hold these rocks in our hands — let alone get so much detail about the early history of our planet,” said lead author Dr Helen Williams, from Cambridge’s Department of Earth Sciences.

The study brings forensic chemical analysis together with thermodynamic modelling in search of the primeval origins of the Greenland rocks, and how they got to the surface.

At first glance, the rocks that make up Greenland’s Isua supracrustal belt look just like any modern basalt you’d find on the sea floor. But this outcrop, which was first described in the 1960s, is the oldest exposure of rocks on Earth. It is known to contain the earliest evidence of microbial life and plate tectonics.

The new research shows that the Isua rocks also preserve rare evidence which even predates plate tectonics — the residues of some of the crystals left behind as that magma ocean cooled.

“It was a combination of some new chemical analyses we did and the previously published data that flagged to us that the Isua rocks might contain traces of ancient material. The hafnium and neodymium isotopes were really tantalizing, because those isotope systems are very hard to modify — so we had to look at their chemistry in more detail,” said co-author Dr Hanika Rizo, from Carleton University.

Iron isotopic systematics confirmed to Williams and the team that the Isua rocks were derived from parts of the Earth’s interior that formed as a consequence of magma ocean crystallisation.

Most of this primeval rock has been mixed up by convection in the mantle, but scientists think that some isolated zones deep at the mantle-core boundary — ancient crystal graveyards — may have remained undisturbed for billions of years.

It’s the relics of these crystal graveyards that Williams and her colleagues observed in the Isua rock chemistry. “Those samples with the iron fingerprint also have a tungsten anomaly — a signature of Earth’s formation — which makes us think that their origin can be traced back to these primeval crystals,” said Williams.

But how did these signals from the deep mantle find their way up to the surface? Their isotopic makeup shows they were not just funnelled up from melting at the core-mantle boundary. Their journey was more circuitous, involving several stages of crystallization and remelting — a kind of distillation process. The mix of ancient crystals and magma would have first migrated to the upper mantle, where it was churned up to create a ‘marble cake’ of rocks from different depths. Later melting of that hybrid of rocks is what produced the magma which fed this part of Greenland.

The team’s findings suggest that modern hotspot volcanoes, which are thought to have formed relatively recently, may actually be influenced by ancient processes.

“The geochemical signals we report in the Greenland rocks bear similarities to rocks erupted from hotspot volcanoes like Hawaii — something we are interested in is whether they might also be tapping into the depths and accessing regions of the interior usually beyond our reach,” said Dr Oliver Shorttle, who is jointly based at Cambridge’s Department of Earth Sciences and Institute of Astronomy.

The team’s findings came out of a project funded by Deep Volatiles, a NERC-funded 5-year research programme. They now plan to continue their quest to understand the magma ocean by widening their search for clues in ancient rocks and experimentally modelling isotopic fractionation in the lower mantle.

“We’ve been able to unpick what one part of our planet’s interior was doing billions of years ago, but to fill in the picture further we must keep searching for more chemical clues in ancient rocks,” said co-author Dr Simon Matthews from the University of Iceland.

Scientists have often been reluctant to look for chemical evidence of these ancient events. “The evidence is often altered by the course of time. But the fact we found what we did suggests that the chemistry of other ancient rocks may yield further insights into the Earth’s formation and evolution — and that’s immensely exciting,” said Williams.