Insulin sensitivity is how responsive cells are to insulin, an essential hormone that controls blood glucose levels. An increase in insulin sensitivity means insulin can more effectively lower the blood glucose. Reduced insulin sensitivity or insulin resistance is a feature of Type 2 diabetes. Thus, improved insulin sensitivity can reduce the risk of developing Type 2 diabetes or improve its treatment.

GLP-1R agonists are medications that influence metabolism, such as decreasing blood sugar levels by promoting insulin secretion. Dipeptidyl peptidase 4 (DPP-4) inhibitors block the degradation of the body’s own endogenous GLP-1, as well as other peptide hormones such as glucose-dependent insulinotropic peptide (GIP).

“We know that GLP-1R agonists promote weight loss, but we were surprised to find that the GLP-1R agonist liraglutide also has rapid effects on insulin sensitivity, independent from weight loss,” said Mona Mashayekhi MD, PhD, assistant professor of Medicine in the Division of Diabetes, Endocrinology and Metabolism. “This effect requires activation of the GLP-1 receptor, but increasing the body’s own endogenous GLP-1 through the use of the DPP4 inhibitor sitagliptin does not achieve similar effects.”

“Our research suggests that liraglutide, and presumably other GLP-1R agonists, are having important metabolic effects in a way that’s different from increasing endogenous GLP-1 levels, even though they’re using the same receptor. Future research will focus on potential mechanisms of how GLP-1R agonists are improving insulin sensitivity independent of weight loss.”

Eighty-eight individuals with obesity and pre-diabetes were randomized for 14 weeks to receive the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin, or weight loss without drug using a low-calorie diet.

To further investigate the GLP-1R-dependent effects of the treatments, the GLP-1R antagonist exendin and a placebo were given in a two-by-two crossover study during mixed meal tests. Crossover studies allow the response of a subject to treatment A to be compared with the same subject’s response to treatment B.

Liraglutide was shown to rapidly improve insulin sensitivity as well as decrease blood glucose within two weeks of beginning treatment and before any weight loss.

“GLP-1R agonists are an exciting class of medications, given their strong glucose-lowering effects combined with tremendous weight-loss benefits, and they have transformed how we manage diabetes and obesity in the clinic,” Mashayekhi said. “Since the number of medications in this class is rapidly expanding, a deeper understanding of the mechanisms of benefit is crucial so we can design the right drugs for the desired effects in the right patients.”

The investigators’ prior research demonstrated that liraglutide, but not sitagliptin or diet, improves measures of heart disease and inflammation. This matches the clinical findings of reduced cardiovascular disease with GLP-1R agonist treatment.

Future studies will continue to explore both receptor- and weight loss-dependent effects of GLP-1R agonists in humans.

This research was supported by the American Heart Association (17SFRN33520017), National Center for Advancing Translational Sciences (5UL1TR002243), and the National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007061) This work utilized the cores of the Vanderbilt Diabetes Research and Training Center funded by grant DK020593 from the National Institute of Diabetes and Digestive and Kidney Disease. Novo Nordisk provided liraglutide and matching placebo.

“Despite more than a century of study on the mechanobiology of bone development, the cellular and molecular basis largely has remained a mystery,” said the study’s senior author, Joel Boerckel, PhD, an associate professor of Orthopaedic Surgery. “Here, we identify a new population of cells that are key to turning the body’s early cartilage template into bone, guided by the force-activated gene regulating proteins, YAP and TAZ.”

By combing through the genes expressed by individual cells in developing mouse limbs, through single-cell sequencing, Boerckel and the study’s first author, former Penn Bioengineering doctoral student Joseph Collins, PhD, along with their colleagues, found and described a class of cells that they named “‘vessel-associated osteoblast precursors (VOPs),” which “invade” early cartilage alongside blood vessels. Since osteoblasts are the cells required to form (and fix) bones, these cells would essentially be the grandparents to bones, with osteoblasts being bones’ parents.

And, importantly, a pair of proteins called YAP and TAZ that are sensitive to the natural movement of the body — which the team’s previous work has shown is crucial to early bone development and regeneration — serve as guides to the VOPs, passing on signals they glean from the body’s mechanobiology.

The researchers found that YAP and TAZ help direct blood vessel integration into the cartilage, a vital aspect of bone development. They were able to demonstrate this role by first genetically removing YAP and TAZ from human cell models, which appeared to stop angiogenesis, the process by which new blood vessels form. Then, the researchers treated those human cell models with a special variety of protein called CXCL12, which restored YAP and TAZ and restarted normal angiogenesis.

The study is a result of a long-time collaboration with Dr. Niamh Nowlan of University College Dublin, whose laboratory focuses on how mechanical forces direct skeletal development in animal models and in human patients.

It’s also appropriate that Boerckel, Collins, and their team are using their exploration of bone development as a lens to further the understanding of mechanobiology.

“The study of bone development is the birthplace of mechanobiology,” Boerckel said. “For example, Wolff’s Law of Bone Transformation, says that trabecular — spongy — bone adapts in a manner depending on the stresses placed on it, but Julius Wolff spent more time in his 1894 book focused on bone development than on trabecular bone.”

With the information the Penn researchers gleaned from their study on both bone development and mechanobiology, they believe they can now inform some of the knowledge and, hopefully, treatment of genetic and congenital musculo-skeletal conditions. That includes brittle bone disease — in which the body doesn’t make collagen correctly, causing bones that can break easily — or arthrogryposis — a condition in which joints develop improperly due to limited fetal movement.

“We are now working on using these findings to target these cells and pathways, either by direct mechanical or pharmacologic means, to restore cellular function and proper bone development in utero, potentially preventing these types of conditions,” Boerckel said.

This research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR073809, R01 AR074948, P30AR069619, NSF CMMI 1548571) and the European Research Council (336306).

According to its inventors, new devices made possible by this innovation will benefit from dynamically adjustable fluorescent and spectroscopic properties, ease of manufacturing, and potential for scaling to areas large enough to cover vehicles, billboards and even buildings. The bio-inspired creation is the subject of a study published recently in Nature Communications.

Hapalochlaena lunulata is a species of octopus native to the Western Pacific Ocean and Indian Ocean. It uses a neurotoxin venom to stun its prey and can ward off predators with a flash of its blue rings. These iridescent circles on a brown background on the creature’s skin are what drew the attention of the UCI researchers.

“We are fascinated by the mechanisms underpinning the blue-ringed octopus’ ability to rapidly switch its skin markings between hidden and exposed states,” said senior co-author Alon Gorodetsky, UCI professor of chemical and biomolecular engineering. “For this project, we worked to mimic the octopus’ natural abilities with devices from unique materials we synthesized in our laboratory, and the result is an octopus-inspired deception and signaling system that is straightforward to fabricate, functions for a long time when operated continuously, and can even repair itself when damaged.”

The architecture of the innovation calls for a thin film consisting of wrinkled blue rings surrounding brown circles — much like those on the octopus — sandwiched between a topmost transparent proton-conducting electrode and an underlying acrylic membrane, with another identical electrode underneath.

Further technical creativity by the researchers occurs at the molecular level as they explored the use of acenes, which are organic compounds made up of linearly fused benzene rings. Designer nonacene-like molecules (with nine linearly fused rings) used by the team help give the platform some of its outstanding capabilities, according to Gorodetsky.

“For our devices, we conceptualized and designed a nonacene-like molecule with a unique architecture,” said co-lead author Preeta Pratakshya, who recently received her Ph.D. in UCI’s Department of Chemistry. “Acenes are organic hydrocarbon molecules with a host of advantageous characteristics, including ease of synthesis, tunable electronic characteristics, and controllable optical properties.”

She added, “Our nonacene-like molecules are exceptional among acenes because they can survive years of storage in air and over a day of continuous irradiation with bright light in air. No other expanded acene displays this combined long-term stability under such harsh conditions.”

According to Gorodetsky, the type of molecules used to fabricate the colored blue ring layer are what endow the devices with their most favorable features, including adjustable spectroscopic properties, the facilitation of straightforward benchtop manufacturing and ambient-atmosphere stability under illumination.

“Our co-author Sahar Sharifzadeh, a Boston University professor of electrical and computer engineering, demonstrated that the stimuli-responsive properties of the molecules can be computationally predicted, which opens paths for the in silico design of other camouflage technologies,” Gorodetsky said.

In their laboratory tests, many of which happened in UCI’s California Institute for Telecommunications and Information Technology, the team found that the bioinspired devices could change their visible appearance over 500 times with little or no degradation, and they also could autonomously self-repair without user intervention.

The invention was demonstrated to possess a desirable combination of capabilities in the ultraviolet, visible light, and near-infrared parts of the electromagnetic spectrum, according to Gorodetsky. This would enable the devices to disguise other objects from detection or to clandestinely signal observers.

“The photophysical robustness and general processability of our nonacene-like molecule — and presumably its variants — opens opportunities for future investigation of these compounds within the context of traditional optoelectronic systems such as light-emitting diodes and solar cells,” added Gorodetsky.

Joining Gorodetsky and Pratakshya in this study were Chengyi Xu, Panyiming Liu, Reina Kurakake, and Robert Lopez in UCI’s Department of Materials Science and Engineering; David Josh Dibble and Anthony Burke in UCI’s Department of Chemical and Biomolecular Engineering; Philip Denison in UCI’s Department of Chemistry; and Aliya Mukazhanova and Sharifzadeh of Boston University. The Office of Naval Research, the Defense Advanced Research Projects Agency, and the National Science Foundation provided funding support.

Enter the synaptonemal complex (SC), a zipper-like protein structure that lines up and anchors the two parental chromosomes together, end-to-end, to facilitate successful genetic exchanges. Failure to regulate this exchange is a leading cause of age-related infertility in humans and could compromise fertility across the tree of life. Humans, fungi, plants, worms and anything that reproduces sexually uses the SC to make reproductive cells, known as gametes. Despite its importance, we don’t understand how proteins within the SC regulate chromosomal interactions because this multi-step process happens in internal organs and has been impossible to recreate in a lab.

In a new study, University of Utah biologists developed a method for illuminating the intricate interactions of the SC in the nematode C. elegans. The authors identified a trio of protein segments that guide chromosomal interactions, and pinpointed the location where they interact with each other. Their novel method uses a technique known as genetic suppressor screening, which can serve as a blueprint for research on large cellular assemblies that resist traditional structural analysis.

“This is a way to lock in on systems in cells that are too ‘loosie-goosey’ to use methods that rely on crystallization,” said Ofer Rog, associate professor of biology at the U and senior author of the study. “A lot of the interactions in cells are loosely bonded together. The problem is that you can’t look at it under an electron microscope because nothing is stable enough — everything is constantly moving. Our approach allows you to study even the interactions that are relatively weak or transient.”

The study published on Dec. 6, 2023, in the journal Proceedings of the National Academy of Sciences (PNAS).

The birds and the bees… and the nematodes

Let’s dig into meiosis. Chromosomes are thread-like structures made of DNA that carry genetic information when cells divide and from generation to generation. Regular cells have a certain number of chromosomes; humans have 46 and C. elegans have 12. Chromosomes come in pairs called homologous chromosomes that carry the genes we inherited from each of our parents — one from our mom, one from our dad. When meiosis begins, homologous chromosomes arrange themselves into elongated structures organized along a backbone called the axis. The axes of homologous pairs are aligned lengthwise to each other while at the same time, the synaptonemal complex (SC) forms between the parallel axes. The homologous pairs have matching genes arranged in the same order, with small variations within the genes — these are the variations that make each individual unique.

“You can think of it like a zipper,” Rog explained. “The axes of the chromosomes are like the two sides of your shirt. The synaptonemal complex is kind of like the teeth of the zippers that lock onto each other and can pull and align the two sides of the shirt correctly.”

Scientist previously knew that the SC of C. elegans formed between homologs, but the U biologists are the first to pinpoint the exact position where the SC interacts with itself to facilitate genetic exchanges.

“When you exchange information between the chromosomes, you want to make sure that at the end you still have two complete chromosomes,” said Rog. “The way the cell does it is that the two chromosomes are perfectly aligned. So, when you exchange segments between them, you’re not losing any information in the process.

How to analyze loosie-goosey structures

The researchers bred 50,000 nematodes that had temperature-sensitive defects in the SC. At high temperatures, the worms were unable to form the SC protein zipper needed to join the chromosomes together. Without the zipper, the gene exchanges during meiosis either didn’t happen at all or didn’t occur at the right number. Lisa Kursel, postdoctoral researcher and lead author of the study ran the experiments.

“We grew the worms at the permissive, cooler temperature, then exposed them to a chemical that caused millions of mutations along their chromosomes and watched to see if any of the mutated worms could reproduce at the warmer temperature,” Kursel said. The chemically induced mutations that corrected the nematode’s infertility are known as suppressor mutations. “Then we’d know if the suppressor mutations restored their fertility.”

To identify the animals with mutations that made them fertile again, the researchers put the nematodes on agar plates filled with yummy bacteria. The agar plates that had fertile nematodes were soon empty as their progeny ate the food. The agar plates with sterile worms died off before they could clean their plate, allowing the bacteria to flourish.

Once they had fertile nematodes, they could test if the mutation “fixed” the protein zipper. They then screened every single base pair on the DNA — 100 million base pairs — and identified which mutations restored the worms’ ability to reproduce. They found that all the helpful mutations occurred in short segments of three proteins, SYP-1, SYP-3, SYP-4. Moreover, the mutations carried distinct signatures of interaction. For example, while the original mutations changed the electric charge from positive to negative, the helpful mutations flipped the charge back.

“This was a strong indication that SYP-1, SYP-3 and SYP-4 interact with each other like magnets, with positive and negative regions attracted to each other,” said Rog. Such “sticky” interactions could also help tether the chromosomes together.

Jesus Aguayo Martinez, a senior biology major and co-author of the study, looked at the behavior of the suppressor mutation in nematodes without the original SC-disrupting mutation.

“We thought that since the original mutation alone produced a fertility defect, then the nematodes with the suppressor mutation alone would also have a fertility defect. That wasn’t the case,” said Aguayo Martinez. “Surprisingly, normal worms and worms with only the suppressor mutations produced similar numbers of progeny.”

Next steps

Uncovering the SC’s role in meiosis may help to better understand fertility in humans. The SC has a similar role across all eukaryotes, from nematodes to fungi to plants to humans. Previous research by the Rog Lab at the U showed that the structure itself looks the same and acts similarly to bring in parental chromosomes to facilitate exchanges. However, the actual sequences of the protein components are different between organisms. Such a pattern is unusual: Most cellular structures that carry essential, basic functions like cell division, genome duplication or metabolism are highly conserved, and could in fact be swapped between different organisms.

“A question that we think a lot about is what is special about the SC? Why can it do the same thing and look the same way, but consist of different building blocks?” Rog asked.

Kursel, Aguayo Martinez, Rog and other members of the lab are doing more analysis on the evolution of the SC across species, and of other cellular structures that defy the common wisdom of evolution.

This work was funded by the National Institute for General Medical Sciences grant R35GM128804. Kursel was supported by the Developmental Biology Training Grant from the U.S. National Institute of Child Health and Human Development, and Aguayo Martinez was supported by a University of Utah Biology Research Scholar Award.

In a paper published this week in the Proceedings of the National Academy of Sciences, a team of scientists demonstrated that kelp forests can do more than supply food to tiny, hungry crustaceans living in the sand. They can also influence the dynamics of the sandy beach food web.

“The amount of kelp on the reef changes through time in a way where the peaks and low points in abundance across several kelp forests are matched together,” said lead author Jonathan Walter, a senior researcher at the University of California, Davis, and its Center for Watershed Sciences. “That’s what we refer to as synchrony. It is related to the ability of systems to persist in the face of changing environmental conditions. A little asynchrony allows systems to be resistant to fluctuations and therefore more stable.”

The study uncovers the role of synchrony in the beach food web, with broader implications as the climate shifts in ways that might change how linked ecosystems perform their functions.

Revealing synchrony’s role in these ecosystems fills a key knowledge gap in our understanding of the connection of reef and beach.

“The kelp forest and the beach are both highly dynamic ecosystems,” said co-author Jenny Dugan, a coastal marine ecologist at UC Santa Barbara. “How the dynamics of those two ecosystems interact and behave is the key question here, especially with the beach system so dependent on the kelp forest.”

In sync

Though a natural and ubiquitous phenomenon, synchrony and its implications are not yet fully understood.

The research team sought to understand whether and how kelp wrack (detritus) could affect the beach ecosystem’s dynamics. For instance, how might species respond to the changing environment, and how resilient is the beach ecosystem to disturbances?

To address these questions, the study used long-term data from UCSB’s Santa Barbara Coastal Long Term Ecological Research site, which is supported by the National Science Foundation. The team’s model was built on a time series of wind, wave, wrack, and beach-width data at five sandy beaches over 11 years.

It revealed patterns of synchrony — where the abundance of kelp wrack on beaches could be explained by kelp abundance in the forest, wave action, and beach width fluctuating together. At the longest timescales, kelp forest biomass and beach width were the biggest drivers of kelp wrack on the beaches.

Beach melodies

“We found time lags in this synchrony that were important,” Dugan said. “It wasn’t as simple as everything changing at the same time — it was like separate songs or melodies that came together in different ways. This made the patterns more complex, which is why it required the type of analyses we used.”

Importantly, the researchers found this synchrony crossed from ocean to shore. The abundance of predatory shorebirds, like sandpipers and plovers, lagged behind the deposition of wrack on beaches.

“Once on the beach, kelp wrack feeds a highly productive community of small invertebrates — crustaceans and insects — that are in turn a favorite food of shorebirds,” Dugan explained. The cross-system synchrony is particularly notable because the beach ecosystem relies so heavily on kelp subsidies, she added.

Dynamic nature

“The dynamic nature of kelp forests, in terms of their high productivity and turnover, is unique for ecosystems structured around foundation species,” said co-author and coastal ecologist Kyle Emery, a researcher in the UCSB Marine Science Institute. “It allows us to observe change many times over compared to other foundation species and gives us the ability to observe many different system states, processes and functions. This enabled us to more rapidly analyze these questions of cross-ecosystem synchrony.”

The study was funded by the Santa Barbara Coastal Long Term Ecological Research, National Science Foundation, McDonnell Foundation and Humboldt Foundation.

“Given that signs of Alzheimer’s disease start to accumulate in the brain several decades before symptoms begin, understanding the connection between sleep and cognition earlier in life is critical for understanding the role of sleep problems as a risk factor for the disease,” said study author Yue Leng, PhD, of the University of California, San Francisco. “Our findings indicate that the quality rather than the quantity of sleep matters most for cognitive health in middle age.”

The study involved 526 people with an average age of 40. They were followed for 11 years.

Researchers looked at participants’ sleep duration and quality. Participants wore a wrist activity monitor for three consecutive days on two occasions approximately one year apart to calculate their averages. Participants slept for an average of six hours.

Participants also reported bedtimes and wake times in a sleep diary and completed a sleep quality survey with scores ranging from zero to 21, with higher scores indicating poorer sleep quality. A total of 239 people, or 46%, reported poor sleep with a score greater than five.

Participants also completed a series of memory and thinking tests.

Researchers also looked at sleep fragmentation, which measures repetitive short interruptions of sleep. They looked at both the percentage of time spent moving and the percentage of time spent not moving for one minute or less during sleep. After adding these two percentages together, researchers found that participants had an average sleep fragmentation of 19%.

Researchers then divided participants into three groups based on their sleep fragmentation score.

Of the 175 people with the most disrupted sleep, 44 had poor cognitive performance 10 years later, compared to 10 of the 176 people with the least disrupted sleep.

After adjusting for age, gender, race, and education, people who had the most disrupted sleep had more than twice the odds of having poor cognitive performance when compared to those with the least disrupted sleep. There was no difference in cognitive performance at midlife for those in the middle group compared to the group with the least disrupted sleep.

“More research is needed to assess the link between sleep disturbances and cognition at different stages of life and to identify if critical life periods exist when sleep is more strongly associated with cognition,” Leng said. “Future studies could open up new opportunities for the prevention of Alzheimer’s disease later in life.”

The amount of time people slept and their own reports of the quality of their sleep were not associated with cognition in middle age.

A limitation of the study was that due to the small sample size, researchers were unable to fully investigate potential race or gender differences.

The study was funded by the National Institute on Aging and the National Heart, Lung, and Blood Institute.