Most stars with a mass similar to the Sun form in multi-star systems together with other stars. So an understanding of multi-star system formation is important to an overall theory of star formation. However, the complexity and lack of high-resolution, high-sensitivity data left astronomers uncertain about the formation scenario. In particular, recent observations of protostars often reported structures called “streamers” of gas flows toward the protostars, but it has been unclear how these streamers form.

An international team led by Jeong-Eun Lee, a professor at Seoul National University, used the Atacama Large Millimeter/submillimeter Array (ALMA) to observe the trinary protostar system IRAS 04239+2436 located 460 light-years away in the constellation Taurus.

The team found that emissions from sulfur monoxide (SO) molecules trace three spiral arms around the three protostars forming in the system.

Comparison with simulations led by Tomoaki Matsumoto, a professor at Hosei University using the supercomputers “ATERUI” and “ATERUI II” in the Center for Computational Astrophysics at the National Astronomical Observatory of Japan (NAOJ) indicate that the three spiral arms are streamers feeding material to the three protostars. The combination of observations and simulations revealed, for the first time, how the streamers are created and contribute to the growth of the protostars at the center.

Video: https://youtu.be/_2d8p-NRuBc

Cyclopropanes are a key feature in many drugs currently approved by the U.S. Food and Drug Administration, including those used to treat COVID-19, asthma, hepatitis C, and HIV/AIDs. These structures can increase a drug’s potency, alter its ability to dissolve in the body, minimize its interactions with unintended targets, and otherwise fine-tune performance. Cyclopropanes are a ring of three connected carbon atoms, with one carbon attached to the rest of the drug molecule and the other two each attached to two hydrogen atoms.

“Cyclopropanes are an essential component of many drugs and adding them to drug candidates can be an important part of the drug discovery process,” said Ramesh Giri, professor of chemistry in the Eberly College of Science at Penn State and leader of the research team. “Previous efforts to improve the creation of cyclopropanes have focused on altering a mechanistic pathway devolved more than 60 years ago. We approached this from a different angle and identified a completely new pathway that is a simple, practical, and broadly applicable.”

The new method transforms a specific chemical structure on compounds called alkenes — used in the synthesis of many molecules — into cyclopropanes. The method takes advantage of “radical chemistry,” where intermediate steps of reactions leave some carbon atoms with unpaired electrons called free radicals that propel the reaction forward. This specific method uses visible light to initiate the reaction and uses common chemical ingredients, including oxygen.

Traditional methods to create cyclopropanes require highly reactive and difficult-to-acquire ingredients and must be conducted under controlled conditions, and the resulting compounds often have a very short shelf life. These unstable ingredients are critical to producing an intermediate compound in the process called a carbene — a highly reactive carbon atom with two unpaired electrons. The new method completely bypasses the carbene intermediate, producing the unpaired electrons one at a time as radicals.

“All of the ingredients used in this pathway are commercially available or easy to create in the lab and do not require any special safety precautions, and the end product can be stored for prolonged periods,” Giri said. “We can add all the ingredients together in one mixture while exposed to air with as little as 10% oxygen, and it proceeds in one step. The reaction is simple and safe enough that we are even planning to include it as part of an undergraduate chemistry lab.”

Another shortcoming of traditional methods is that they generally do not work with complex molecules. For this reason, cyclopropanes are typically installed early in the synthesis when the molecule is less complex, but following steps can cause the ring to open up, and later attempts to make derivatives of the molecule would require backtracking to those early steps. Using the new method, the researchers successfully transformed a variety of alkenes with a wide range of complexities into cyclopropanes, including pharmaceutically relevant compounds such as the steroid estrone, penicillin and vitamin B.

“We explored the entire range of molecule complexity that people might encounter during drug synthesis,” Giri said. “In some cases, traditional methods might be able to develop the same end product but in many more steps. In other cases, traditional methods would be unable to create these products, because the starting alkenes are too sensitive or too complex. The new method is not only safer, more efficient and more practical, but has a wider range of applications than traditional methods.”

Some of the ingredients in the reaction can also be swapped out to add additional chemical groups to the final product to achieve various therapeutic goals. One of the reaction’s ingredients is as a type of compound called a methylene. There are hundreds of different methylenes that are commercially available, each with a specific chemical group that makes it a methylene as well as other groups that differ and could theoretically be added to the alkene as a cyclopropane Is created. The researchers demonstrated the breadth of the new method using 19 different methylene compounds.

“The idea of using a visible light-based reaction and radical chemistry to transform alkenes into cyclopropanes using methylenes at first seems counterintuitive, which is why it was so important for us to thoroughly demonstrate this new catalytic method,” Giri said. “The key insight was introducing oxygen into the reaction, which helps create a radical that then interacts with the alkene. My lab has been studying other reactions that use alkenes to create a radical and wondered if the same idea could be applied to creating cyclopropanes.”

Next, Giri and his lab plan to scale up the method so that it is industrially viable.

“With future development and scaling up, this method has the potential to transform the way alkenes are cyclopropanated, which could have important implications for drug discovery, development, and creation,” he said.

In addition to Giri, the research team at Penn State includes postdoctoral researcher Dhruba Poudel, postdoctoral researcher at the time of the research Amrit Pokhrel, postdoctoral researcher at the time of the research Raj Kumar Tak, and postdoctoral research Majji Shankar. The U.S. National Institute of General Medical Sciences and Penn State supported this research.

STING is primarily on the lookout for DNA, which can indicate either a foreign invader such as a virus or damage to the host tissue or cell. When STING detects that danger signal, it can turn on at least three different pathways — one leading to interferon production, one to non-canonical autophagy (involved in recycling cell components and clearing pathogens), and a third to formation of the inflammasome, a complex of proteins that activates inflammatory responses. The mechanism by which STING stimulates interferon production is well characterized, but it has not been understood how it activates the other two processes.

Now, a team of MIT and Harvard Medical School researchers has discovered how STING activates those two pathways. They found that STING has a surprising and previously unknown function: It can act as an ion channel that allows protons to leak out of an organelle known as the Golgi body. This makes it the first human immune sensor that can translate danger signals into ion flow.

“Arriving at this new idea that STING is a proton channel required connecting prior findings by other labs that either STING or proton flux could activate the inflammasome and non-canonical autophagy, which led us to hypothesize that STING initiates or mediates proton flux to trigger both downstream processes,” says Nir Hacohen, a member of the Broad Institute of MIT and Harvard, a professor of medicine at Massachusetts General Hospital and Harvard Medical School, and a senior author of the study.

“Because of its importance to host immunity, there is a great interest in developing drugs that can activate or suppress STING activity, and the discovery of STING’s ion channel activity will provide new ways to think about designing therapeutics to modulate STING,” says Darrell Irvine, the Underwood-Prescott Professor at MIT with appointments in the departments of Biological Engineering and of Materials Science and Engineering; a member of MIT’s Koch Institute for Integrative Cancer Research and the Ragon Institute of MGH, MIT, and Harvard; and a senior author of the study.

MIT biology PhD student Bingxu Liu and Rebecca Carlson PhD ’23, a recent graduate of the Medical Engineering and Medical Physics program through the Harvard-MIT Division of Health Sciences and Technology, are the lead authors of the paper, which appears today in Science. Paul Blainey, the Karl Van Tassel Associate Professor of Biological Engineering at MIT and a member of the Broad Institute and the Koch Institute, is also an author of the paper.

A surprising role

STING (short for stimulator of interferon genes) is considered one of the major factors that triggers the immune response in the context of infection, autoimmunity, and cancer. Drugs that activate STING have been developed and tested in clinical trials as cancer immunotherapy drugs that would help stimulate the immune system to destroy tumors.

STING is a protein that can span membranes, and it is usually found embedded in the membrane of an organelle called the endoplasmic reticulum (ER). Once it detects DNA, it relocates to the Golgi body, where it begins to activate proteins that turn on genes required for interferon production.

“People know pretty well how STING induces interferon, but how STING induces autophagy and inflammasome formation has been an open debate in the field for the last 10 years,” Liu says.

Previous research has shown that both autophagy and formation of inflammasomes (large protein complexes that stimulate inflammation) can be provoked by protons leaking from cell organelles, which makes the inside of the cell more acidic. Because of that, the researchers wondered if STING might somehow induce proton leakage.

To explore this possibility, the researchers labeled the Golgi with a protein that fluoresces when the pH goes up. When they treated the cells with a molecule that activates STING, the Golgi became less acidic, meaning that it was losing protons. A genetic screen minimized the possibility of another ion channel controlling this ion flow, so the researchers hypothesized that STING itself was acting as a proton channel.

“In addition to its biological significance, this study is a notable example of the maturing functional genomics field, where pooled screening data are sufficiently reliable to set the direction of focused investigation — even from negative results, as was the case here,” Blainey says.

After running the structure of the STING protein through a computer model that can predict whether a given protein structure might contain a pore, the researchers found that the STING protein is predicted to contain a region that resembles a pore. Serendipitously, last year a company that was seeking STING agonists (molecules that activate STING) found a new molecule that was later shown by an academic group to bind in this precise location.

The MIT/Harvard team hypothesized that the agonist, known as C53, blocks the putative pore. When C53 was added to cells , protons did not leak out of the Golgi, and downstream pathways activating autophagy and inflammasome formation were not turned on, even if STING was activated through other means. However, interferon activation, which goes through a different pathway, still occurred.

“For the first time, we were able to decouple these downstream processes, where we can activate interferon with C53, but inhibit those other two pathways leading to autophagy and inflammasome formation,” Carlson says. “In the context of inflammatory diseases where STING is overactivated, we can now start asking which of those molecular mechanisms is most important and contributes the most to the phenotype that we’re seeing.”

Selective control

In future studies, the researchers hope to use C53 to determine the relative importance of these three pathways and try to figure out which ones would be most useful to stimulate or to block to treat a variety of diseases.

The U.S. Food and Drug Administration has not approved any STING agonist thus far, although multiple clinical trials are currently underway. One potential reason that other STING agonists have not made it beyond clinical trials is that the treatment can result in unwanted cell death mediated by STING. Drugs that stimulate interferon production but not cell death or other inflammatory pathways could offer a way to overcome that obstacle, according to the MIT/Harvard team.

The researchers hope to explore whether STING might play a role in influencing the behavior of other cellular activities known to be controlled by ion channels. “Now that we know that STING is an ion channel, we can propose other effects that we think could occur based on this knowledge that STING does transport protons,” Carlson says.

The research was funded by the U.S. National Institutes of Health, the Howard Hughes Medical Institute, a Fannie and John Hertz Foundation Fellowship, a U.S. National Science Foundation Graduate Research Fellowship, a European Molecular Biology Organization Fellowship, and a Cancer Research Institute/Bristol Myers Squibb Fellowship.

Where exactly these sinking processes take place is the subject of current research, and recent measurement programmes have located them to the east of Greenland. A team of scientists from the GEOMAR Helmholtz Centre for Ocean Research in Kiel, Germany, has now conducted a modelling study focusing on the Labrador Sea southwest of Greenland. In their study, now published in the journal Nature Communications, the researchers used complex computer simulations to show that fluctuations in the Labrador Sea can have a significant influence on the strength of sinking processes east of Greenland. An important link is a little-noticed system of deep currents that ensures rapid spreading of Labrador Sea water into the deep-sea basin between Greenland and Iceland.

“We oceanographers have long had our eyes on the Labrador Sea between Canada and Greenland,” says Professor Dr Claus Böning, who led the study. “Winter storms with icy air cool the ocean temperatures to such an extent that the surface water becomes heavier than the water below. The result is deep winter mixing of the water column, whereby the volume and density of the resulting water mass can vary greatly from year to year.”

In the model simulations of the past 60 years, the years 1990 to 1994 stood out, when the Labrador Sea cooled particularly strongly. “The unusually large volume of very dense Labrador Sea water that formed following extremely harsh winters led to significantly increased sinking between Greenland and Iceland in the following years,” explains Claus Böning. As a result, the model simulations calculated an increase in Atlantic overturning transport of more than 20%, peaking in the late 1990s. The measurements of the circulation in the North Atlantic, which have only been carried out continuously since 2004, would then fall exactly in the decay phase of the simulated transport maximum.

“According to our model results, the observed weakening of the Atlantic circulation during this period can therefore be interpreted, at least in part, as an aftereffect of the extreme Labrador Sea winters of the 1990s,” summarises Professor Dr Arne Biastoch, head of the Ocean Dynamics Research Unit at GEOMAR and co-author of the study. However, he clarifies: “Although we cannot yet say whether a longer-term weakening of the overturning is already occurring, all climate models predict a weakening as a result of human-induced climate change as ‘very likely’ for the future.

Ongoing observing programmes and further development of simulations are crucial for a better understanding of the key climate-relevant processes. And, of course, for future projections of the Gulf Stream system under climate change.