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.

Work of the group, led by Keng Ioi Vong, Ph.D., and Sangmoon Lee, M.D. Ph.D., both from the laboratory of Joseph G. Gleeson, M.D., at the UC San Diego School of Medicine Department of Neurosciences and the Rady Children’s Institute for Genomic Medicine, reveals the first link between spina bifida and a common chromosomal microdeletion in humans. The study demonstrates that individuals carrying this chromosomal deletion — present in one of 2,500 live births — demonstrate a risk of spina bifida more than 10 times greater than the general public.

The study also underscores the potential role of a common food supplement in reducing the risk of spina bifida. The findings were recently published in the journal Science.

Gleeson, Rady Professor in the Department of Neuroscience and director of neuroscience at Rady Children’s Institute for Genomic Medicine, is the senior author of the study. He explained that spina bifida, also known as meningomyelocele, affects one in every 3,000 newborns. Unfortunately, the causes are mostly unknown. A few mutations were reported but could only explain a tiny fraction of risk, Gleeson added.

To uncover the genetic causes of the disease, Gleeson’s UC San Diego lab joined with colleagues from across the globe to establish the Spina Bifida Sequencing Consortium in 2015. The consortium began focusing on a tiny deletion in chromosome 22. Chromosome microdeletions refer to a condition in which several genes in a chromosome are missing. The group’s target condition, known as 22q11.2del, has been implicated in a number of other disorders. They began looking for 22q11.2del in spinal bifida patients.

“All patients we recruited have the most severe form of spina bifida, and all underwent best-practice comprehensive genomic sequencing,” Gleeson said. “We identified 22q11.2del in 6 out of 715 patients. This may not seem a high percentage, but this is by far the most common single genetic variation that could contribute to spina bifida.”

He went on to say the group identified eight additional spina bifida patients who carried the deletion from a cohort of approximately 1,500 individuals recruited because of the presence of the common 22q11.2 deletion, Gleeson said.

The researchers then narrowed the cause among the many genes in the 22q11.2 deletion to a single gene known as CRKL. Gleeson explained that there are nine other genes in this chromosomal region that could have been the cause. He said the team began a process of elimination, “knocking out” each of the mouse genes one-by-one, when they received a fortuitous email from Dolores Lamb from Weil Cornell College of Medicine. Lamb had noted some of the mice in their vivarium that were missing Crkl and showed spina bifida. (Vong explained that researchers use all capital letters to describe the gene in humans, and lower-case for mice. )Lamb’s group heard about the Gleeson lab project throughs the Spina Bifida Association.

“This finding really got us excited because it meant that CRKL disruption might be sufficient for spina bifida,” said Vong, co-first author of the study. “We removed the mouse Crkl gene ourselves and confirmed that some of the mice developed neural tube defects, including spina bifida.” Most of the other genes in 22q11.2 deletion were subsequently excluded, he added.

They next turned their attention to how folic acid may modulate CRKL-mediated spina bifida. Vong noted that prior studies in humans demonstrated that folic acid (also known as vitamin B-9) supplementation prior to conception reduces the incidence of spina bifida and other neural tube defects by up to 30-50 percent, but the mechanisms are still a mystery.

“When we deprived the Crkl mutant female mice of folic acid in their chow, many more of their offspring had neural tube defects, and the severity increased dramatically,” Vong explained. “This suggests that folic acid taken by pregnant women may not only reduce the risk, but also the severity of neural tube defects in their offspring.”

“We hope our findings can help the research community to better understand causes of neural tube defects, especially the causes attributable to common genetic findings like 22q11.2 deletion,” Gleeson said. “We also hope our findings can contribute to healthy pregnancies, improved women’s health, and improved outcomes for children.”

Co-authors associated with the University of San Diego School of Medicine Department of Neurosciences, as well as with Rady Children’s Institute for Genomic Medicine, (in addition to Joseph G. Gleeson Sangmoon Lee and Keng Ioi Vong) are: Renee George, Bryn Gerding, Kiely N. James, Valentina Stanley, Nan Jiang, Kameron Alu, Naomi Meave, Fiza Jiwani, Isaac Tang, Ashna Nisal, Ishani Jhamb, Arzoo Patel, Aakash Patel, Jennifer McEvoy-Venneri, Chelsea Barrows, Celina Shen, Yoo-Jin Ha and Robyn Howarth. Other co-authors include Hal S. Meltzer, of the University of California San Diego Rady Children’s Hospital Department of Neurosurgery; Anna S. Nidhiry, of Rady Children’s Institute for Genomic Medicine; and the Spina Bifida Sequencing Consortium.

This work was supported by the Center for Inherited Disease Research grant HHSN268201700006I, the Yale Center for Genomic Analysis, the Broad Institute, the UC Irvine Genomics Core, the UCSD Institute for Genomic Medicine, the UCSD Transgenic Core, UCSD Microscopy Core grant P30 NS047101, and Columbia Microscopy Core grant S10 OD032447- 01. Other support came from the National Institutes of Health, including National Institute of Diabetes and Digestive and Kidney Diseases, and by support from the Howard Hughes Medical Institute and Rady’s Children Institute for Genomic Medicine to Joseph G. Gleeson.

To cut through the din, an interdisciplinary collaboration of researchers from MIT and elsewhere developed a sound-suppressing silk fabric that could be used to create quiet spaces.

The fabric, which is barely thicker than a human hair, contains a special fiber that vibrates when a voltage is applied to it. The researchers leveraged those vibrations to suppress sound in two different ways.

In one, the vibrating fabric generates sound waves that interfere with an unwanted noise to cancel it out, similar to noise-canceling headphones, which work well in a small space like your ears but do not work in large enclosures like rooms or planes.

In the other, more surprising technique, the fabric is held still to suppress vibrations that are key to the transmission of sound. This prevents noise from being transmitted through the fabric and quiets the volume beyond. This second approach allows for noise reduction in much larger spaces like rooms or cars.

By using common materials like silk, canvas, and muslin, the researchers created noise-suppressing fabrics which would be practical to implement in real-world spaces. For instance, one could use such a fabric to make dividers in open workspaces or thin fabric walls that prevent sound from getting through.

“Noise is a lot easier to create than quiet. In fact, to keep noise out we dedicate a lot of space to thick walls. [First author] Grace’s work provides a new mechanism for creating quiet spaces with a thin sheet of fabric,” says Yoel Fink, a professor in the departments of Materials Science and Engineering and Electrical Engineering and Computer Science, a Research Laboratory of Electronics principal investigator, and senior author of a paper on the fabric.

The study’s lead author is Grace (Noel) Yang SM ’21, PhD ’24. Co-authors include MIT graduate students Taigyu Joo, Hyunhee Lee, Henry Cheung, and Yongyi Zhao; Zachary Smith, the Robert N. Noyce Career Development Professor of Chemical Engineering at MIT; graduate student Guanchun Rui and professor Lei Zhu of Case Western University; graduate student Jinuan Lin and Assistant Professor Chu Ma of the University of Wisconsin at Madison; and Latika Balachander, a graduate student at the Rhode Island School of Design. The an open-access paper about the research appeared recently in Advanced Materials.

Silky silence

The sound-suppressing silk builds off the group’s prior work to create fabric microphones.

In that research, they sewed a single strand of piezoelectric fiber into fabric. Piezoelectric materials produce an electrical signal when squeezed or bent. When a nearby noise causes the fabric to vibrate, the piezoelectric fiber converts those vibrations into an electrical signal, which can capture the sound.

In the new work, the researchers flipped that idea to create a fabric loudspeaker that can be used to cancel out soundwaves.

“While we can use fabric to create sound, there is already so much noise in our world. We thought creating silence could be even more valuable,” Yang says.

Applying an electrical signal to the piezoelectric fiber causes it to vibrate, which generates sound. The researchers demonstrated this by playing Bach’s “Air” using a 130-micrometer sheet of silk mounted on a circular frame.

To enable direct sound suppression, the researchers use a silk fabric loudspeaker to emit sound waves that destructively interfere with unwanted sound waves. They control the vibrations of the piezoelectric fiber so that sound waves emitted by the fabric are opposite of unwanted sound waves that strike the fabric, which can cancel out the noise.

However, this technique is only effective over a small area. So, the researchers built off this idea to develop a technique that uses fabric vibrations to suppress sound in much larger areas, like a bedroom.

Let’s say your next-door neighbors are playing foosball in the middle of the night. You hear noise in your bedroom because the sound in their apartment causes your shared wall to vibrate, which forms sound waves on your side.

To suppress that sound, the researchers could place the silk fabric onto your side of the shared wall, controlling the vibrations in the fiber to force the fabric to remain still. This vibration-mediated suppression prevents sound from being transmitted through the fabric.

“If we can control those vibrations and stop them from happening, we can stop the noise that is generated, as well,” Yang says.

A mirror for sound

Surprisingly, the researchers found that holding the fabric still causes sound to be reflected by the fabric, resulting in a thin piece of silk that reflects sound like a mirror does with light.

Their experiments also revealed that both the mechanical properties of a fabric and the size of its pores affect the efficiency of sound generation. While silk and muslin have similar mechanical properties, the smaller pore sizes of silk make it a better fabric loudspeaker.

But the effective pore size also depends on the frequency of sound waves. If the frequency is low enough, even a fabric with relatively large pores could function effectively, Yang says.

When they tested the silk fabric in direct suppression mode, the researchers found that it could significantly reduce the volume of sounds up to 65 decibels (about as loud as enthusiastic human conversation). In vibration-mediated suppression mode, the fabric could reduce sound transmission up to 75 percent.

These results were only possible due to a robust group of collaborators, Fink says. Graduate students at the Rhode Island School of Design helped the researchers understand the details of constructing fabrics; scientists at the University of Wisconsin at Madison conducted simulations; researchers at Case Western Reserve University characterized materials; and chemical engineers in the Smith Group at MIT used their expertise in gas membrane separation to measure airflow through the fabric.

Moving forward, the researchers want to explore the use of their fabric to block sound of multiple frequencies. This would likely require complex signal processing and additional electronics.

In addition, they want to further study the architecture of the fabric to see how changing things like the number of piezoelectric fibers, the direction in which they are sewn, or the applied voltages could improve performance.

“There are a lot of knobs we can turn to make this sound-suppressing fabric really effective. We want to get people thinking about controlling structural vibrations to suppress sound. This is just the beginning,” says Yang.

This work is funded, in part, by the National Science Foundation (NSF), the Army Research Office (ARO), the Defense Threat Reduction Agency (DTRA), and the Wisconsin Alumni Research Foundation.

“Osteoporosis can occur for many reasons such as hormonal changes, aging, and lifestyle factors,” said Swanson, an associate professor in the Division of Endocrinology, Metabolism, and Diabetes. “But some patients I see don’t have an explanation for their osteoporosis.

“Therefore, it’s important to look for novel risk factors and consider what else changes across the lifespan like bone does — sleep is one of those,” she added.

How bone density and sleep change over time

In people’s early- to mid-20s, they reach what is called peak bone mineral density, which is higher for men than it is for women, Swanson said. This peak is one of the main determinants of fracture risk later in life.

After reaching this peak, a person’s bone density remains roughly stable for a couple of decades. Then, when women enter the menopausal transition, they experience accelerated bone loss. Men also experience bone density decline as they age.

Sleep patterns also evolve over time. As people get older, their total sleep time decreases, and their sleep composition changes. For instance, sleep latency, which is the time it takes to fall asleep, increases with age. On the other hand, slow wave sleep, which is deep restorative sleep, decreases as we age.

“And it’s not just sleep duration and composition that change. Circadian phase preference also changes across the lifespan in both men and women,” Swanson said, referring to people’s preference for when they go to sleep and when they wake up.

How can sleep relate to our bone health?

Genes that control our internal clock are present in all of our bone cells, Swanson said.

“When these cells resorb and form bone, they release certain substances into the blood that let us estimate how much bone turnover is going on at a given time,” she said.

These markers of bone resorption and formation follow a daily rhythm. The amplitude of this rhythm is larger for markers of bone resorption — which refers to the process of breaking down bones — than it is for markers of bone formation, she said.

“This rhythmicity is likely important for normal bone metabolism and suggests that sleep and circadian disturbance could directly affect bone health,” she said.

Researching the connection between sleep and bone health

To further understand this relationship, Swanson and colleagues researched how markers of bone turnover responded to cumulative sleep restriction and circadian disruption.

For this study, participants lived in a completely controlled inpatient environment. The participants did not know what time it was, and they were put on a 28-hour schedule instead of a 24-hour day.

“This circadian disruption is designed to simulate the stresses endured during rotating night shift work and is roughly equivalent to flying four time zones west every day for three weeks,” she said. “The protocol also caused participants to get less sleep.”

The research team measured bone turnover markers at the beginning and end of this intervention and found significant detrimental changes in bone turnover in both men and women in response to the sleep and circadian disruption. The detrimental changes included declines in markers of bone formation that were significantly greater in younger individuals in both sexes compared to the older individuals.

In addition, young women showed significant increases in the bone resorption marker.

If a person is forming less bone while still resorbing the same amount — or even more — then, over time, that could lead to bone loss, osteoporosis, and increased fracture risk, Swanson said.

“And sex and age may play an important role, with younger women potentially being the most susceptible to the detrimental impact of poor sleep on bone health,” she said.

Research in this area is ongoing, she added.

The researchers analyzed several sediment cores measuring up to 280 meters from the Chew Bahir Basin in southern Ethiopia, which act as a “record” of 620,000 years of East African climate history. The results of the study, which have just been published in “Nature Communications,” show that at the end of the African Humid Period, intense dry and wet events alternated regularly over a period of around 1,000 years before a dry climate prevailed around 5,000 years ago. A better understanding of the various tipping points and, above all, their typical early warning signals could prove essential for further climate change research and modeling.

The transition from the African Humid Period (AHP) to dry conditions in North Africa is the clearest example of climate tipping points in recent geological history. They occur when small perturbations trigger a large, non-linear response in the system and shift the climate to a different future state, usually with dramatic consequences for the biosphere. That was also the case in North Africa, where the grasslands, forests, and lakes favored by humans disappeared, causing them to retreat to areas like the mountains, oases, and the Nile Delta. This development is of particular relevance for researchers, not least because it is an impressive example of how quickly and extensively climate change can affect human societies.

Climate researchers have identified two main types of tipping points: With the first type, processes slow at an increasing rate and the climate has a hard time recovering from disturbances until a transition occurs. The second type is characterized by a flickering between stable humid and dry climates that occurs shortly before the transition. “The two types of tipping points differ with regard to the early warning signals that can be used to recognize them,” explains Martin Trauth. “Researching and better understanding them is important if we want to be able to predict possible future climate tipping points caused by humans. While the slowdown seen in the first type of tipping point leads to a decrease in variability, autocorrelation, and skewness, the flickering in the second type leads to the exact opposite — and, in some cases, to the impending tipping point not being recognized.”

In the large-scale project, led by Martin Trauth together with colleagues from the Universities of Cologne, Aberystwyth, and Addis Ababa and funded, among others, by the German Research Foundation (DFG), researchers are analyzing lake sediments obtained by means of scientific deep drilling in the Chew Bahir Basin, a former freshwater lake in eastern Africa. “For the current study, six shorter (9 to 17 meters) and two long (292 meters) drill cores were evaluated, which can be used to reconstruct the past 620,000 years of climate history in the region,” explains Dr. Verena Förster-Indenhuck from the University of Cologne.

“At the end of the AHP, we observed at least 14 dry events in the short cores from Chew Bahir, each of which lasted 20-80 years and recurred at intervals of 160±40 years,” says Trauth. “Later in the transitional phase, starting in 6,000 BC, seven wet events occurred in addition to the dry events, which were of a similar duration and frequency. These high-frequency, extreme wet-dry events represent a pronounced ‘climate flickering’ that can be simulated in climate models and can also be observed in earlier climate transitions in the environmental records from Chew Bahir. This indicates that transitions with flickering are characteristic of this region.”

The fact that very similar transitions can also be found in the older sections of the sediment cores also supports this. In particular, the changeover from humid to dry climate around 379,000 years ago looks like a perfect copy of the transition at the end of the African Humid Period. “This is interesting because this transition was natural, so to speak, as it occurred at a time when human influence on the environment was negligible,” says co-author Prof. Stefanie Kaboth-Bahr of Freie Universität Berlin. Thus, there are many arguments against human activity leading to an accelerated end of the AHP, as proposed by American colleagues. Conversely, people in the region where undoubtedly affected by the climate tipping: The traces of settlement in the Nile valley at the end of the African Humid Period attract millions of tourists to the region every year.