Publishing in the journal Cell Host & Microbe, the study describes an approach that provides step-by-step directions for the immune system to generate the elusive, yet necessary antibodies for a successful HIV vaccine.

“HIV is the fastest-evolving virus known. So it’s been a long-standing goal in HIV research to create a vaccine that can generate broadly neutralizing antibodies that can recognize diverse HIV strains,” said lead author Kevin Wiehe, Ph.D., associate professor in the Department of Medicine at Duke University School of Medicine and director of research at DHVI.

Wiehe and colleagues started with an engineered version of a broadly neutralizing antibody in its original state, before any mutations occurred. Knowing that the antibody will need to mutate to keep up with the ever-changing HIV virus, the researchers then added sequential mutations one-by-one to determine which mutations were essential for the antibody to broadly neutralize HIV.

Doing this allowed them to figure out what the exact points were along the route to arrive at broadly neutralizing antibodies. They then developed a vaccine which gave the immune system the turn-by-turn directions to follow that mutational route.

Using mice specially bred to encode for the original version of the antibody, the researchers demonstrated that the guidance system approach triggered the immune system to start churning out the sought-after antibodies.

“This paper shows that our mutation-guided vaccine strategy can work,” said Wiehe, adding that the technique could also be used in vaccines for other diseases. “This strategy potentially gives us a way to design vaccines to direct the immune system to make any antibody we want, which could be a broadly neutralizing antibody for all coronavirus variants, or an anti-cancer antibody.”

Wiehe said the next challenge will be to reproduce the study in primates and then humans.

In addition to Wiehe, study authors includes Kevin O. Saunders, Victoria Stalls, Derek W. Cain, Sravani Venkatayogi, Joshua S. Martin Beem, Madison Berry, Tyler Evangelous, Rory Henderson, Bhavna Hora, Shi-Mao Xia, Chuancang Jiang, Amanda Newman, Cindy Bowman, Xiaozhi Lu, Mary E. Bryan, Joena Bal, Aja Sanzone, Haiyan Chen, Amanda Eaton, Mark A. Tomai, Christopher B. Fox, Ying Tam, Christopher Barbosa, Mattia Bonsignori, Hiromi Muramatsu, S. Manir Alam, David Montefiori, Wilton B. Williams, Norbert Pardi, Ming Tian, Drew Weissman, Frederick W. Alt, Priyamvada Acharya, and Barton F. Haynes.

The study received funding support from the National Institute of Allergy and Infectious Diseases, a part of the National Institutes of Health (UM1AI144371, 1U19AI135902-01, P01AI131251-01).

The research links interpersonal discrimination to changes at the molecular level, revealing a potential root cause of disparities in aging-related illness and death.

“Experiencing discrimination appears to hasten the process of aging, which may be contributing to disease and early mortality and fueling health disparities,” said Adolfo Cuevas, assistant professor in the Department of Social and Behavioral Sciences at NYU’s School of Global Public Health and senior author of the study published in the journal Brain, Behavior, and Immunity-Health.

Research shows that people who experience discrimination based on their identity (e.g. race, gender, weight, or disability) are at increased risk for a range of health issues, including heart disease, high blood pressure, and depression. While the precise biological factors driving these poor health outcomes are not fully understood, chronic activation of the body’s stress response is a likely contributor. Moreover, a growing body of research connects persistent exposure to discrimination to the biological processes of aging.

To better understand the connection between discrimination and aging, Cuevas and his colleagues looked at three measures of DNA methylation, a marker that can be used to assess the biological impacts of stress and the aging process. Blood samples and surveys were collected from nearly 2,000 U.S. adults as part of the Midlife in the United States (MIDUS) study, a longitudinal analysis of health and well-being funded by the National Institute on Aging.

Participants were asked about their experiences with three forms of discrimination: everyday, major, and workplace. Everyday discrimination refers to subtle and minor instances of disrespect in daily life, whereas major discrimination focuses on acute and intense instances of discrimination (for example, being physically threatened by police officers). Discrimination in the workplace includes unjust practices, stunted professional opportunities, and punishment based on identity.

The researchers found that discrimination was linked to accelerated biological aging, with people who reported more discrimination aging faster biologically compared to those who experienced less discrimination. Everyday and major discrimination were consistently associated with biological aging, while exposure to discrimination in the workplace was also linked to accelerated aging, but its impact was comparatively less severe.

A deeper analysis showed that two health factors — smoking and body mass index — explained roughly half of the association between discrimination and aging, suggesting that other stress responses to discrimination, such as increased cortisol and poor sleep, are contributing to accelerated aging.

“While health behaviors partly explain these disparities, it’s likely that a range of processes are at play connecting psychosocial stressors to biological aging,” said Cuevas, who is also a core faculty at the Center for Anti-racism, Social Justice, & Public Health at NYU School of Global Public Health.

In addition, the link between discrimination and accelerated biological aging varied by race. Black study participants reported more discrimination and tended to exhibit older biological age and faster biological aging. However, White participants, who reported less discrimination, were more susceptible to the impacts of discrimination when they did experience it, perhaps due to less frequent exposure and fewer coping strategies. (Data on other racial and ethnic groups were not available in the MIDUS study.)

“These findings underscore the importance of addressing all forms of discrimination to support healthy aging and promote health equity,” added Cuevas.

In addition to Cuevas, study authors include Steven W. Cole of the University of California, Los Angeles; Daniel W. Belsky of Columbia University; and Anna-Michelle McSorley, Jasmine M. Shon, and Virginia W. Chang of the NYU School of Global Public Health.

The MIDUS study is supported by the John D. and Catherine T. MacArthur Foundation Research Network and the National Institute on Aging (P01-AG020166 and U19-AG051426). The study itself was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK137246 and R01DK137805).

The application of boron in organic chemistry dates back some seventy years and was awarded a Nobel Prize for Chemistry in 1979. In recent years, the interest in boron as a catalyst has grown, but as yet, its use in the chemical industry is limited. Roelfes: ‘So far, boron catalysis is too slow and it is not very suitable for enantioselective reactions.’ These types of reactions are used to create chiral molecules, which can exist in two versions that are mirror images of each other, like a left and a right hand. In many drugs, both ‘hands’ can have a different effect. It is, therefore, important to selectively produce the proper ‘hand’, especially for the pharmaceutical industry.

Expanded genetic code

‘To make this possible, we set out to introduce boron into an enzyme. Our group has a long history of designing enzymes that don’t exist in nature.’ The Roelfes group used an expanded genetic code to introduce a non-natural amino acid that contains a reactive boronic acid group into an enzyme. ‘Using this technique, we can determine at the DNA level where we place the amino acid in a protein.’

Once they made an enzyme with boronic acid at its reactive centre, they could use directed evolution to increase its efficiency, resulting in faster catalysis. ‘Furthermore, by placing the boronic acid in the chiral context of an enzyme, we were able to achieve highly enantioselective catalysis.’ The reaction that is described in the journal Nature is a ‘proof of principle’ and shows the way to harnessing the catalytic power of boron in enzymes.

Biocatalysis

Using enzymes to create organic compounds is important for the pharmaceutical industry. ‘In their push towards greener and more sustainable ways of producing drugs, they are looking at biocatalysis to replace conventional chemical reactions.’ At the University of Groningen, concerted efforts are being made towards this goal. ‘We have a number of research groups at the Faculty of Science and Engineering engaged in this kind of work, using different approaches to create biocatalytic solutions for the chemical industry.’ In this context, Roelfes and his team will continue to develop their boronic acid enzymes and create other such new-to-nature enzymes.

“More than one-third of people with neuropathy experience sharp, prickling or shock-like pain, which increases their rates of depression and decreases quality of life,” said study author Melissa A. Elafros, MD, PhD, of the University of Michigan in Ann Arbor and a member of the American Academy of Neurology. “People with neuropathy also have an increased risk of earlier death, even when you take into account other conditions they have, so identifying and treating people with or at risk for neuropathy is essential.”

The study involved 169 people from an outpatient internal medicine clinic serving mainly Medicaid patients in Flint, Michigan. The participants had an average age of 58 years and 69% were Black people. One-half of the people had diabetes, which can cause neuropathy. A total of 67% had metabolic syndrome, which is defined as having excess belly fat plus two or more of the following risk factors: high blood pressure, higher than normal triglycerides (a type of fat found in the blood), high blood sugar and low high-density lipoprotein (HDL) cholesterol, or “good” cholesterol. These risk factors are also associated with neuropathy.

All participants were tested for distal symmetric polyneuropathy. Information about other health conditions was also collected.

A total of 73% of the people had neuropathy. Of those, 75% had not been previously diagnosed with the condition. Nearly 60% of those with neuropathy were experiencing pain.

Of those with neuropathy, 74% had metabolic syndrome, compared to 54% of those who did not have neuropathy.

After adjusting for other factors that could affect the risk of neuropathy, researchers found that people with metabolic syndrome were more than four times more likely to have neuropathy than people who did not have the syndrome.

Researchers were also looking for any relationship between race and income and neuropathy, as few studies have been done on those topics. There was no relationship between low income and neuropathy. For race, Black people had a decreased risk of neuropathy. Black people made up 60% of those with neuropathy and 91% of those without neuropathy.

“The amount of people with neuropathy in this study, particularly undiagnosed neuropathy, was extraordinarily high with almost three fourths of the study population,” Elafros said. “This highlights the urgent need for interventions that improve diagnosis and management of this condition, as well as the need for managing risk factors that can lead to this condition.” A limitation of the study is that it is a snapshot in time; it did not follow people to see who developed neuropathy over time. It also did not look at reasons why people were not able to manage risk factors that can lead to neuropathy.

The study was supported by the National Institute of Neurological Disorders and Stroke, National Institute of Diabetes and Digestive and Kidney Diseases and National Center for Advancing Translational Sciences.