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‘Pac-Man with a ponytail’ proteins regulate everything from night vision to heartbeats – studying what GRKs look like could improve an array of drugs

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theconversation.com – Priyanka Naik, Ph.D. Candidate in Structural Biology, Purdue University – 2025-03-07 07:18:00

Rhodopsin kinase – GRK1 – is a GRK found in the retina of your eyes.
Priyanka Naik, CC BY-ND

Priyanka Naik, Purdue University

Each cell in your body relies on precise communication with other cells to function properly. At the center of this process are the molecular switches that turn communication signals in the body on and off. These molecules are key players in health and disease. One such molecular switch is G protein-coupled receptor kinases, or GRKs for short.

From vision to heart function and cell growth, GRKs play a vital role in maintaining physiological balance. When they go awry, they can contribute to cardiovascular disease, inflammatory illnesses like rheumatoid arthritis and multiple sclerosis, neurodegenerative diseases like Alzheimer’s, and multiple types of cancer.

Their involvement in a broad range of diseases makes GRKs an attractive drug target. Around 30% to 40% of all drugs currently on the market focus on these proteins. However, designing drugs that selectively target specific GRKs is a difficult task. Because they are structurally similar to each other and to other proteins, molecules binding to one GRK might also bind to many other enzymes and cause unwanted side effects.

A better understanding of how GRKs interact with their targets can help researchers develop better drugs. So my work in the Tesmer Lab at Purdue University focuses on uncovering more information on the structure of GRKs.

What do G protein-coupled receptor kinases look like?

What researchers know about the structure of GRKs has advanced significantly over the past two decades, revealing the intricate mechanisms by which they function.

The ability to physically look at proteins is highly useful for drug development. Seeing a protein’s structure is like looking at a jigsaw puzzle – you can find the missing piece by knowing its shape. Similarly, knowing a protein’s shape helps scientists design molecules that fit perfectly into it, making drugs more effective.

GRKs consist of several modules, or domains, that serve a particular purpose. Together, these modules assemble into a structure resembling a Pac-Man with a ponytail.

The kinase domain – the Pac-Man – is the catalytic center where the protein does its main job: adding a phosphate group to its target to control its activity. It has two subdomains – one small and one large lobe – connected by a hinge that can open and close. Like Pac-Man, this domain closes around reactants and reopens to release products.

Array of spiral ribbons arranged into roughly three sections
The three domains of GRKs resemble a Pac-Man with a ponytail. Shown here is GRK2.
Priyanka Naik, CC BY-ND

The RH domain – the ponytail – stabilizes the kinase domain. It guides and docks the GRK to its target protein.

Humans have seven GRKs, each specialized for different tissues and functions, and each unique in structure. Some regulate vision, while others affect your brain, kidney and immune functions, among others. Their structural differences dictate how they interact with their targets, and understanding these distinctions is key to designing drugs that can selectively target each one.

In 2003, researchers in the lab where I work uncovered the first known structure of a GRK – specifically, GRK2, which is involved in heart functions and cell proliferation – by using a technique called macromolecular crystallography. This involved bombarding a GRK2 sample with X-rays and tracing where they bounce off to determine where each atom of the protein is located.

Current state of GRK research

By determining how the three modules of GRK2 are arranged and where its target molecules would bind, my colleagues and I can design drugs that strongly interact with GRK2.

Irregularly shaped lump resembling a drumette
GRK2 with Paxil bound to its active site.
Priyanka Naik, CC BY-ND

For example, in 2012, one of my colleagues discovered that the antidepressant Paxil could inhibit GRK2. To build on this discovery, our team designed drugs with similar shapes to Paxil to identify ones that effectively and selectively inhibit GRK2. The goal was to develop treatments that could target GRK2-related diseases such as heart failure and breast cancer without interfering with other proteins, thereby minimizing side effects.

After determining what Paxil looks like when bound to GRK2, we designed a series of derivative compounds that better fit into GRK2’s active site – the missing jigsaw puzzle pieces. Some of these compounds were able to better block GRK2 compared with Paxil, improving the ability of heart muscle cells to contract. While the research is still in its early stages, our findings suggest that these compounds could potentially be used to treat heart failure.

An important missing piece of the story is what GRK2 looks like when bound to its primary target in the cells. These protein complexes are highly shape-shifting, making traditional imaging methods very difficult.

However, recent advances in imaging have made it possible to determine the structure of these molecules. Cryogenic electron microscopy, or cryo-EM, flash-freezes proteins and bombards them with electrons to capture their structure. These studies have thus far revealed what GRK1 and GRK2 look like when bound to two different target proteins, offering critical insights into how they work.

YouTube video
Cryo-EM was the subject of the 2017 Nobel Prize in chemistry.

My work focuses on uncovering how GRK2 function is different from GRK1. These proteins play different physiological roles – GRK1 primarily regulates vision, while GRK2 is involved in heart function and cell proliferation. Identifying structural differences in different GRKs will help researchers design drugs that only target the GRK of interest, thus preventing side effects.

By combining cutting-edge imaging techniques with decades of research, scientists in my lab and others hope to one day unlock the full therapeutic potential of GRKs, offering pinpointed treatments for a wide range of diseases.The Conversation

Priyanka Naik, Ph.D. Candidate in Structural Biology, Purdue University

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Simple strategies can boost vaccination rates for adults over 65 − new study

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theconversation.com – Laurie Archbald-Pannone, Associate Professor of Medicine and Geriatrics, University of Virginia – 2025-03-14 07:51:00

Simple strategies can boost vaccination rates for adults over 65 − new study

Many older adults are not up to date on their vaccines.
Morsa Images via Getty Images

Laurie Archbald-Pannone, University of Virginia

Knowing which vaccines older adults should get and hearing a clear recommendation from their health care provider about why a particular vaccine is important strongly motivated them to get vaccinated. That’s a key finding in a recent study I co-authored in the journal Open Forum Infectious Diseases.

Adults over 65 have a higher risk of severe infections, but they receive routine vaccinations at lower rates than do other groups. My colleagues and I collaborated with six primary care clinics across the U.S. to test two approaches for increasing vaccination rates for older adults.

In all, 249 patients who were visiting their primary care providers participated in the study. Of these, 116 patients received a two-page vaccine discussion guide to read in the waiting room before their visit. Another 133 patients received invitations to attend a one-hour education session after their visit.

The guide, which we created for the study, was designed to help people start a conversation about vaccines with their providers. It included checkboxes for marking what made it hard for them to get vaccinated and which vaccines they want to know more about, as well as space to write down any questions they have. The guide also featured a chart listing recommended vaccines for older adults, with boxes where people could check off ones they had already received.

In the sessions, providers shared in-depth information about vaccines and vaccine-preventable diseases and facilitated a discussion to address vaccine hesitancy.

In a follow-up survey two months later, patients reported that the most significant barriers they faced were knowing when they should receive a particular vaccine, having concerns about side effects and securing transportation to a vaccination appointment.

The percentage of patients who said they wanted to get a vaccine increased from 68% to 79% after using the vaccine guide. Following each intervention, 80% of patients reported they discussed vaccines more in that visit than they had in prior visits.

Of the 14 health care providers who completed the follow-up survey, 57% reported increased vaccination rates following each approach. Half of the providers felt that the use of the vaccine guide was an effective strategy in guiding conversations with their patients.

YouTube video
A pamphlet at the doctor’s office can empower older patients to ask about vaccines.

Why it matters

Only about 15% of adults ages 60-64 and 26% of adults 65 and older are up to date on all the vaccines recommended for their age, according to CDC data from 2022. These include vaccines for COVID 19, influenza, tetanus, pneumococcal disease and shingles.

Yet studies consistently show that getting vaccinated reduces the risk of complications from these conditions in this age group.

My research shows that strategies that equip older adults with personalized information about vaccines empower them to start the conversation about vaccines with their clinicians and enable them to be active participants in their health care.

What’s next

In the future, we will explore whether engaging patients on this topic earlier is even more helpful than doing so in the waiting room before their visit.

This might involve having clinical team members or care coordinators connect with patients ahead of their visit, either by phone or through telemedicine that is designed specifically for older adults.

My research team plans to conduct a pilot study that tests this approach. We hope to learn whether reaching out to these patients before their clinic visits and helping them think through their vaccination status, which vaccines their provider recommends and what barriers they face in getting vaccinated will improve vaccination rates for this population.

The Research Brief is a short take on interesting academic work.The Conversation

Laurie Archbald-Pannone, Associate Professor of Medicine and Geriatrics, University of Virginia

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3D printing will help space pioneers make homes, tools and other stuff they need to colonize the Moon and Mars

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theconversation.com – Sven Bilén, Professor of Engineering Design, Electrical Engineering and Aerospace Engineering, Penn State – 2025-03-13 07:51:00

3D printing could make many of the components for future structures on Mars.
3000ad/iStock via Getty Images Plus

Sven Bilén, Penn State

Throughout history, when pioneers set out across uncharted territory to settle in distant lands, they carried with them only the essentials: tools, seeds and clothing. Anything else would have to come from their new environment.

So they built shelter from local timber, rocks and sod; foraged for food and cultivated the soil beneath their feet; and fabricated tools from whatever they could scrounge up. It was difficult, but ultimately the successful ones made everything they needed to survive.

Something similar will take place when humanity leaves Earth for destinations such as the Moon and Mars – although astronauts will face even greater challenges than, for example, the Vikings did when they reached Greenland and Newfoundland. Not only will the astronauts have limited supplies and the need to live off the land; they won’t even be able to breathe the air.

Instead of axes and plows, however, today’s space pioneers will bring 3D printers. As an engineer and professor who is developing technologies to extend the human presence beyond Earth, I focus my work and research on these remarkable machines.

3D printers will make the tools, structures and habitats space pioneers need to survive in a hostile alien environment. They will enable long-term human presence on the Moon and Mars.

An astronaut holding a wrench poses for the camera.
NASA astronaut Barry Wilmore holds a 3D-printed wrench made aboard the International Space Station.
NASA

From hammers to habitats

On Earth, 3D printing can fabricate, layer by layer, thousands of things, from replacement hips to hammers to homes. These devices take raw materials, such as plastic, concrete or metal, and deposit it on a computerized programmed path to build a part. It’s often called “additive manufacturing,” because you keep adding material to make the part, rather than removing material, as is done in conventional machining.

Already, 3D printing in space is underway. On the International Space Station, astronauts use 3D printers to make tools and spare parts, such as ratchet wrenches, clamps and brackets. Depending on the part, printing time can take from around 30 minutes to several hours.

For now, the print materials are mostly hauled up from Earth. But NASA has also begun recycling some of those materials, such as waste plastic, to make new parts with the Refabricator, an advanced 3D printer installed in 2019.

Manufacturing in space

You may be wondering why space explorers can’t simply bring everything they need with them. After all, that’s how the International Space Station was built decades ago – by hauling tons of prefabricated components from Earth.

But that’s impractical for building habitats on other worlds. Launching materials into space is incredibly expensive. Right now, every pound launched aboard a rocket just to get to low Earth orbit costs thousands of dollars. To get materials to the Moon, NASA estimates the initial cost at around US$500,000 per pound.

Still, manufacturing things in space is a challenge. In the microgravity of space, or the reduced gravity of the Moon or Mars, materials behave differently than they do on Earth. Decrease or remove gravity, and materials cool and recrystallize differently. The Moon has one-sixth the gravity of Earth; Mars, about two-fifths. Engineers and scientists are working now to adapt 3D printers to function in these conditions.

An illustration of an astronaut looking at a base camp on Mars.
An artist’s impressions of what a Mars base camp might look like.
peepo/E+ via Getty Images

Using otherworldly soil

On alien worlds, rather than plastic or metal, 3D printers will use the natural resources found in these environments. But finding the right raw materials is not easy. Habitats on the Moon and Mars must protect astronauts from the lack of air, extreme temperatures, micrometeorite impacts and radiation.

Regolith, the fine, dusty, sandlike particles that cover both the lunar and Martian surfaces, could be a primary ingredient to make these dwellings. Think of the regolith on both worlds as alien dirt – unlike Earth soil, it contains few nutrients, and as far as we know, no living organisms. But it might be a good raw material for 3D printing.

My colleagues began researching this possibility by first examining how regular cement behaves in space. I am now joining them to develop techniques for turning regolith into a printable material and to eventually test these on the Moon.

But obtaining otherworldly regolith is a problem. The regolith samples returned from the Moon during the Apollo missions in the 1960s and 70s are precious, difficult if not impossible to access for research purposes. So scientists are using regolith simulants to test ideas. Actual regolith may react quite differently than our simulants. We just don’t know.

What’s more, the regolith on the Moon is very different from what’s found on Mars. Martian regolith contains iron oxide –that’s what gives it a reddish color – but Moon regolith is mostly silicates; it’s much finer and more angular. Researchers will need to learn how to use both types in a 3D printer.

YouTube video
See models of otherworldly habitats.

Applications on Earth

NASA’s Moon-to-Mars Planetary Autonomous Construction Technology program, also known as MMPACT, is advancing the technology needed to print these habitats on alien worlds.

Among the approaches scientists are now exploring: a regolith-based concrete made in part from surface ice; melting the regolith at high temperatures, and then using molds to form it while it’s a liquid; and sintering, which means heating the regolith with concentrated sunlight, lasers or microwaves to fuse particles together without the need for binders.

Along those lines, my colleagues and I developed a Martian concrete we call MarsCrete, a material we used to 3D-print a small test structure for NASA in 2017.

Then, in May 2019, using another type of special concrete, we 3D-printed a one-third scale prototype Mars habitat that could support everything astronauts would need for long-term survival, including living, sleeping, research and food-production modules.

That prototype showcased the potential, and the challenges, of building housing on the red planet. But many of these technologies will benefit people on Earth too.

In the same way astronauts will make sustainable products from natural resources, homebuilders could make concretes from binders and aggregates found locally, and maybe even from recycled construction debris. Engineers are already adapting the techniques that could print Martian habitats to address housing shortages here at home. Indeed, 3D-printed homes are already on the market.

Meanwhile, the move continues toward establishing a human presence outside the Earth. Artemis III, now scheduled for liftoff in 2027, will be the first human Moon landing since 1972. A NASA trip to Mars could happen as early as 2035.

But wherever people go, and whenever they get there, I’m certain that 3D printers will be one of the primary tools to let human beings live off alien land.The Conversation

Sven Bilén, Professor of Engineering Design, Electrical Engineering and Aerospace Engineering, Penn State

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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George Washington, a real estate investor and successful entrepreneur, knew the difference between running a business and running the government

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theconversation.com – Eliga Gould, Professor of History, University of New Hampshire – 2025-03-10 07:50:00

President George Washington delivers his first inaugural address in April 1789 in New York City.
Painting by T.H. Matteson, engraving by H.S. Sadd, via Library of Congress

Eliga Gould, University of New Hampshire

During his three presidential campaigns, Donald Trump promised to run the federal government as though it were a business. True to his word, upon retaking office, Trump put tech billionaire Elon Musk at the head of a new group in the executive branch called the Department of Government Efficiency.

DOGE, as Musk’s initiative is known, has so far fired, laid off or received resignations from tens of thousands of federal workers and says it has discovered large sums of wasted or fraudulently spent tax dollars. But even its questionable claim of saving US$65 billion is less than 1% of the $6.75 trillion the U.S. spent in the 2024 fiscal year, and a tiny fraction of the nation’s cumulative debt of $36 trillion. Because Musk’s operation has not been formalized by Congress, DOGE’s indiscriminate cuts also raise troubling constitutional questions and may be illegal.

Before they go too far trying to run the government like a business, Trump and his advisors may want to consider the very different example of the nation’s first chief executive while he was in office.

A man stands while behind him a man sits at a desk.
Elon Musk, left, and Donald Trump have undertaken an effort both describe as seeking to run government more like a business.
Andrew Harnik/Getty Images

The first businessman to become president

Like Trump, George Washington was a businessman with a large real estate portfolio. Along with property in Virginia and six other states, he had extensive claims to Indigenous land in the Ohio River Valley.

Partly because of those far-flung investments, the first president supported big transportation projects, took an active interest in the invention of the steamboat, and founded the Patowmack Company, a precursor to the builders of the Chesapeake and Ohio Canal.

Above all, Washington was a farmer. On his Mount Vernon estate, in northern Virginia, he grew tobacco and wheat and operated a gristmill. After his second term as president, he built a profitable distillery. At the time of his death, he owned nearly 8,000 acres of productive farm and woodland, almost four times his original inheritance.

Much of Washington’s wealth was based on slave labor. In his will, he freed 123 of the 300 enslaved African Americans who had made his successful business possible, but while he lived, he expected his workers to do as he said.

President Washington and Congress

If Washington the businessman and plantation owner was accustomed to being obeyed, he knew that being president was another matter.

In early 1790, near the end of his first year in office, he reflected on the difference in a letter to the English historian Catharine Macaulay. Macaulay had visited Mount Vernon several years before. She was eager to hear the president’s thoughts about what, in his reply, he described as “the last great experiment for promoting human happiness by reasonable compact.”

The new government, Washington wrote, was “a government of accommodation as well as a government of laws.”

As head of the executive branch, his own powers were limited. In the months since the inauguration, he had learned that “much was to be done by prudence, much by conciliation, much by firmness. Few, who are not philosophical Spectators,” he told his friend, “can realise the difficult and delicate part which a man in my situation (has) to act.”

Although Washington did not say why his situation was delicate, he didn’t need to. Congress, as everyone knew, was the most powerful branch of government, not the president.

The previous spring, Congress had shown just how powerful it was when it debated whether the president, who needed Senate confirmation to appoint heads of executive departments, could remove such officers without the same body’s approval. In the so-called Decision of 1789, Congress determined that the president did have that power, but only after Vice President John Adams broke the deadlock in the upper house.

The meaning of Congress’ vote was clear. On matters where the Constitution is ambiguous, Congress would decide what powers the president can legally exercise and what powers he – or, someday, she – cannot.

When it created a “sinking fund” in 1790 to manage the national debt, Congress showed just how far it could constrain presidential power.

Although the fund was part of the Treasury Department, whose secretary served at the president’s pleasure, the commission that oversaw it served for fixed terms set by Congress. The president could neither remove them nor tell them what to do.

Inefficient efficiency

William Humphrey, a member of the Federal Trade Commission, was unconstitutionally fired by Franklin Roosevelt in 1933.
Library of Congress

By limiting Washington’s power over the Sinking Fund Commission, Congress set a precedent that still holds, notably in the 1935 Supreme Court case of Humphrey’s Executor v. U.S.

To the displeasure of those, including Trump, who promote the novel “unitary executive” theory of an all-powerful president, the court ruled that President Franklin D. Roosevelt could not dismiss a member of the Federal Trade Commission before his term was up – even if, as Roosevelt said, his administration’s goals would be “carried out most effectively with personnel of my own selection.”

Like the businessman who currently occupies the White House, Washington did not always like having to share power with Congress. Its members were headstrong and independent-minded. They rarely did what they were told.

But he realized working with Congress was the only way to create a federal government that really was efficient, with each branch carrying out its defined powers, as the founders intended. Because of the Constitution’s checks and balances, the United States was – and is – a government based on compromise between the three branches. No one, not even the president, is exempt.

To his credit, Washington was quick to learn that lesson.The Conversation

Eliga Gould, Professor of History, University of New Hampshire

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