This peptide originates from within a long non-coding RNA (lncRNA) called LOUP. According to the researchers, the human genome encodes over 20,000 lncRNAs, making it the largest group of genes produced from the genome. But despite this abundance, scientists know little about why lncRNAs exist or what they do. This is why lncRNA is sometimes referred to as the “dark matter of the genome.”

The study, published May 23 in the Proceedings of the National Academy of Sciences (PNAS), is one of the very few in the existing literature to chip away at the mysteries of lncRNA. It also presents a new strategy for conducting high-throughput screening to rapidly identify functional lncRNAs in immune cells. The pooled-screen approach allows researchers to target thousands of genes in a single experiment, which is a much more efficient way to study uncharacterized portions of the genome than traditional experiments which focus on one gene at a time.

The research was led by immunologist Susan Carpenter, a professor and Sinsheimer Chair of UC Santa Cruz’s Molecular, Cell, and Developmental Biology Department. She studies the molecular mechanisms involved in protection against infection. Specifically, she focuses on the processes that lead to inflammation to determine the role that lncRNAs play in these pathways.

“Inflammation is a central feature of just about every disease,” she said. “In this study, my lab focused on trying to determine which lncRNA genes are involved in regulating inflammation.”

This meant studying lncRNAs in a type of white blood cell known as a monocyte. They used a modification of the CRISPR/Cas9 technology, called CRISPR inhibition (CRISPRi), to repress gene transcription and find out which of a monocyte’s lncRNAs play a role in whether it differentiates into a macrophage — another type of white blood cell that’s critical to a well-functioning immune response.

In addition, the researchers used CRISPRi to screen macrophage lncRNA for involvement in inflammation. Unexpectedly, they located a region that is multifunctional and can work as an RNA as well as containing an undiscovered peptide that regulates inflammation.

Understanding that this specific peptide regulates inflammation gives drugmakers a target to block the molecular interaction behind that response in order to suppress it, Carpenter said. “In an ideal world, you would design a small molecule to disrupt that specific interaction, instead of, say, targeting a protein that might be expressed throughout the body,” she explained. “We’re still a long way from targeting these pathways with that level of precision, but that’s definitely the goal. There’s a lot of interest in RNA therapeutics right now.”

Co-authors of the study from UC Santa Cruz include Haley Halasz, Eric Malekos, Sergio Covarrubias, Samira Yitiz, Christy Montano, Lisa Sudek, and Sol Katzman, along with researchers at UCSF and MIT. The research was supported with funding from the National Institute of General Medical Sciences (R35GM137801 to Carpenter) and the National Institute of Allergy and Infectious Diseases (F31AI179201 to Malekos).

Innovative methods have also been bolstered with new tools, and a growth in the use of robotics since the 1980s has moved health care forward significantly. Assistant Professor Zhenhua Tian has pressed forward another step in the march of progress using robotics and noninvasive acoustics, and his team’s work has been published in Science Advances.

Robot-assisted surgery

Surgery using robots has been invasive since its invention because cutting is involved and often other instruments are inserted into the incision. However, because robotic-assisted tools can be smaller, the cuts also tend to be smaller than traditional surgeries, making robotics a preferred choice. This form of surgery has proven its benefits and has grown in use over time, with advantages to patients including

• Less discomfort and bleeding
• Less time in the hospital
• Faster recovery periods

In fact, according to the American College of Surgeons, 1.8 percent of surgeries included a robot in 2012. By 2018, that percentage had risen to 15.1 percent and continues to rise through advancements in robotics. Some of the most common procedures involving robotics include appendectomies, hysterectomies, and gastric bypasses.

Noninvasive sound treatment

While robotic-assisted surgery has its share of advantages, Tian’s team has taken that idea a step beyond its current state: Team members are developing a method of moving small targets, such as cells and medicine, within a body that is noninvasive. That means the method requires no cuts.

The secret is found in acoustic energy emitters that Tian’s team uses to surround and capture particles, working like invisible tweezers. The emitters create 3D acoustic vortex fields that can pass through barriers such as bone and tissue, crossing over one another to form tiny ring-shaped acoustic traps. Micro- to millimeter-sized objects caught at the center of an acoustic trap can be moved and rotated. Tian received a 2024 National Science Foundation Faculty Early Career Development Program (CAREER) award for the acoustic vortex development.

“The ability to move cells and drugs around inside veins without breaking the skin creates new opportunities in medicine,” said Tian. “As we continue the work on this research, I anticipate we will find a host of new applications.”

By mounting an acoustic vortex emitter onto a robotic platform, the acoustic vortex beam can be moved at the micrometer scale. Accordingly, the particle trapping area can be precisely set in a 3D space, and moving a particle after its capture can be engineered. When moving a tiny object along the winding path of a blood vessel, this can be a critical feature.

More than medicine

While Tian’s team is able to move a small object behind a solid structure, the acoustic vortex beams can move particles within both gases and liquids as well. Although the current approach targets small particles within those substances, integrating the acoustic energy emitters together with robotics has applications beyond surgery and very small particles. Contactless, robotic manipulation has potential in many other applications across engineering, biology, and chemistry research. Some of those include

• Controlling microrobots
• Handling delicate bioparticles, such as exosomes and cells
• Transporting hazardous reagent droplets
• Controlling self-assembly of colloidal materials
• Arranging nanomaterials for composite fabrication

“When we were recently participating in a STEM expo, the children who visited us enjoyed putting small beads into the invisible acoustic fields generated by our devices, but we would like to offer the opportunity for them to move larger objects,” said Tian. “Next year, we hope to have a larger emitter that can hold a ping pong ball. It will be interesting to see how we plug that approach into our other research.”

Healthier lives and improved well-being are among the United Nations’ global Sustainable Development Goals. Positively, a recent study shows that life expectancy worldwide is projected to increase by about 4.5 years by 2050. Much of this is thanks to public health efforts to prevent disease and improved survival from illnesses, such as cardiovascular disorders. However, heart disease is still the leading cause of death worldwide, with 26 million people estimated to be affected by heart failure.

Once heart failure has occurred, it has a tendency to reoccur along with other health issues, such as kidney and muscle problems. Researchers in Japan wanted to understand what causes this recurrence and the deterioration of other organs, and whether it can be prevented.

“Based on our earlier research, we hypothesized that recurrence may be caused by stress experienced during heart failure accumulating in the body, particularly in hematopoietic stem cells,” explained Project Professor Katsuhito Fujiu from the Graduate School of Medicine at the University of Tokyo. Hematopoietic stem cells are found in bone marrow and are the source of blood cells and a type of immune cell called macrophages, which help to protect heart health.

By studying mice with heart failure, the researchers found evidence of stress imprinting on the epigenome, that is, chemical changes occurred to the mice’s DNA. An important signaling pathway, called the transforming growth factor beta, which is involved in regulating many cellular processes, was suppressed in the hematopoietic stem cells of mice with heart failure, leading to the production of dysfunctional immune cells.

This change persisted over an extended period of time, so when the team transplanted bone marrow from mice with heart failure into healthy mice, they found that the stem cells continued to produce dysfunctional immune cells. The latter mice later developed heart failure and became prone to organ damage.

“We termed this phenomenon stress memory because the stress from heart failure is remembered for an extended period and continues to affect the entire body. Although various other types of stress might also imprint this stress memory, we believe that the stress induced by heart failure is particularly significant,” said Fujiu.

The good news is that by identifying and understanding these changes to the TGF-β signaling pathway, new avenues are now open for potential future treatments. “Completely new therapies could be considered to prevent the accumulation of this stress memory during hospitalization for heart failure,” said Fujiu. “In animals with heart failure, supplementing additional active TGF-β has been shown to be a potential treatment. Correcting the epigenome of hematopoietic stem cells could also be a way to deplete stress memory.”

Now that it has been identified, the team hopes to develop a system that can detect and prevent the accumulation of stress memory in humans, with a long-term goal of being able to not only prevent the recurrence of heart failure, but also catch the condition before it can fully develop.

“The massive use of antibiotics and antimicrobials in people and animals has led to these substances appearing in unexpected environmental samples,” said Irantzu Vergara, researcher in the UPV/EHU’s IBeA group. Drugs that do not end up fully metabolised in the body reach the environment through various routes (such as manure, sewage sludge used as fertilisers, etc.), are leached into the soil and may end up transferring to crops or earthworms, which are at the base of the food chain. “Although no short-term toxicity has been demonstrated in humans, the unintended consumption of antibiotics in the diet can cause problems for allergic individuals; and the effects of long-term exposure remain unknown. However, the biggest problem associated with this contamination is the spread of multi-resistant bacteria; it is difficult to find an effective treatment in the event of infection, which is responsible for 33,000 deaths per year across Europe,” explained Vergara.

To address this problem, the IBeA research group has developed two analytical methods enabling very low concentrations of antimicrobials in vegetables and earthworms to be detected: “Although high drug concentrations can be expected in manure, much lower concentrations are expected after these substances have transferred to plants or earthworms, so sensitive methods are needed to detect them,” said Vergara.

The methods developed by Vergara in the UPV/EHU labs enable a wide range of antimicrobial drugs to be simultaneously determined, as well as various products deriving from their transformation. As the researcher explained, “the drugs can be excreted in their original form or transformed after being metabolised (after undergoing certain changes in the body). What is more, these are very sensitive compounds which, under conditions of temperature, humidity, light, etc., can be very easily degraded and transformed in the environment.”

The methods constitute a significant breakthrough, as “until now there have been no analytical methods to simultaneously study a wide range of antimicrobials in plants and earthworms, and they did not focus on the analysis of transformation products, either. Each family of antibiotics has different physicochemical properties, and it is very important that the same analytical method can be used to analyse all of them. We have also achieved pretty low detection limits, which allow us to detect very low concentrations of these substances in the environment.”

Samples of vegetables taken in different locations across the Basque Autonomous Community

In the case of vegetables, the research group took samples from different locations of the Basque Country, from both organic and non-organic agriculture. “We set out to measure the scale of the antibiotics problem in the Basque Autonomous Community. The analytical studies conducted revealed data on the existence of antimicrobial drugs and their derivatives in vegetables: we found that there is a transfer of both antimicrobials and degradation products between soil and vegetables. In other words, there is a problem of antimicrobial contamination in the Basque Country,” she added.

In the case of earthworms, however, they conducted an experiment under controlled conditions of exposure, in other words “this is a study designed and conducted in the laboratory using earthworms. We wanted to check whether, in the case of contaminated soil, the earthworms that feed on this soil are able to accumulate antimicrobials in their bodies. The study did in fact reveal an accumulation of these antimicrobials in the body, which generate a large variety of previously unreported transformation products.”

Vergara stressed the need to “continue multidisciplinary research along these lines, as this is a problem that is going to affect everyone over the coming decades.” Water treatment plants currently do not have fully effective treatments to remove residual drugs, and this water is often used for irrigation. “As there is such a large, constant input of antimicrobials into the environment, the bacteria are getting used to coexisting with them and generating resistance,” she explained. The researcher warned that “in fact, there are already cases in which there are no effective treatments for people who become infected with multi-resistant bacteria. It is important to drive forward research in order to minimise the problem or to start to look for solutions in the short to medium term.”

Known as piezoelectricity, the ability to trade between mechanical stress and electric charge can be harnessed widely in capacitors, actuators, transducers and sensors like accelerometers and gyroscopes for next-generation electronics. However, integrating these materials into miniaturized systems has been difficult due to the tendency of electromechanically active materials to — at the submicrometer scale, when the thickness is just a few millionths of an inch — get “clamped” down by the material they are attached to, which significantly dials down their performance.

Rice University researchers and collaborators at the University of California, Berkeley have found that a class of electromechanically active materials called antiferroelectrics may hold the key to overcoming performance limitations due to clamping in miniaturized electromechanical systems. A new study published in Nature Materials reports that a model antiferroelectric system, lead zirconate (PbZrO₃), produces an electromechanical response that can be up to five times greater than that of conventional piezoelectric materials even in films that are only 100 nanometers (or 4 millionths of an inch) thick.

“We’ve been using piezoelectric materials for decades,” said Rice materials scientist Lane Martin, who is the corresponding author on the study. “Recently there has been a strong motivation to further integrate these materials into new types of devices that are very small — as you would want to do for, say, a microchip that goes inside your phone or computer. The problem is that these materials are typically just less usable at these small scales.”

According to current industry standards, a material is considered to have very good electromechanical performance if it can undergo a 1% change in shape — or strain — in response to an electric field. For an object that measures 100 inches in length, for instance, getting 1 inch longer or shorter represents 1% strain.

“From a materials science perspective, this is a significant response, since most hard materials can only change by a fraction of a percent,” said Martin, the Robert A. Welch Professor, professor of materials science and nanoengineering and director of the Rice Advanced Materials Institute.

When conventional piezoelectric materials are scaled down to systems less than a micrometer (1,000 nanometers) in size, their performance generally deteriorates significantly due to the interference of the substrate, which dampens their ability to change shape in response to electric field or, conversely, to generate voltage in response to a change in shape.

According to Martin, if electromechanical performance were rated on a scale of 1-10 — where 1 is lowest performance and 10 is the industry standard of 1% strain — then clamping is typically expected to bring conventional piezoelectrics’ electromechanical response down from a 10 to the 1-4 range.

“To understand how clamping impacts motion, first picture being in a middle seat on an airplane with no one on either side of you — you’d be free to adjust your position if you get uncomfortable, overheated, etc.,” Martin said. “Now picture the same scenario, except now you’re seated between two huge offensive linemen from Rice’s football team. You’d be ‘clamped’ between them such that you really couldn’t meaningfully adjust your position in response to a stimulus.”

The researchers wanted to understand how very thin films of antiferroelectrics — a class of materials that remained understudied until recently due to a lack of access to “model” versions of the materials and to their complex structure and properties — changed their shape in response to voltage and whether they were likewise susceptible to clamping.

First, they grew thin films of the model antiferroelectric material PbZrO ₃ with very careful control of the material thickness, quality and orientation. Next, they performed an array of electrical and electromechanical measurements to quantify the responses of the thin films to applied electric voltage.

“We found the response was considerably larger in the thin films of antiferroelectric material than what is achieved in similar geometries of traditional materials,” said Hao Pan, a postdoctoral researcher in Martin’s research group and lead author on the study.

Measuring shape change at such small scales was not an easy feat. In fact, optimizing the measurement setup required so much labor the researchers documented the process in a separate publication.

“With the perfected measurement setup, we can get a resolution of two picometers — that’s about a thousandth of a nanometer,” Pan said. “But just showing that a shape change happened doesn’t mean we understand what’s going on, so we had to explain it. This was one of the first studies to reveal the mechanisms behind this high performance.”

With support from their collaborators at the Massachusetts Institute of Technology, the researchers used a state-of-the-art transmission electron microscope to observe the nanoscale material shapeshift with atomic resolution in real time.

“In other words, we watched the electromechanical actuation as it was happening, so we could see the mechanism for the large shape changes,” Martin said. “What we found was that there is an electric voltage-induced change in the crystal structure of the material, which is like the fundamental building unit or single type of Lego block from which the material is built. In this case, that Lego block gets reversibly stretched with applied electric voltage, giving us a big electromechanical response.”

Surprisingly, the researchers found that not only does clamping not interfere with material performance, but it in fact enhances it. Together with collaborators at Lawrence Berkeley National Laboratory and Dartmouth College, they recreated the material computationally in order to get another view of how the clamping affects the actuation under applied electric voltage.

“Our results are the culmination of years of work on related materials, including the development of new techniques to probe them,” Martin said. “By figuring out how to make these thin materials work better, we’re hoping to enable the development of smaller and more powerful electromechanical devices or microelectromechanical systems (MEMS) — and even nanoelectromechanical systems (NEMS) — that use less energy and can do things we never thought possible before.”