“We hope that this risk score can be useful to clinicians on the ground — primary care physicians, endocrinologists, nephrologists, and cardiologists — who are caring for patients with diabetes and thinking about what strategies can be used to help them,” said co-first author Muthiah Vaduganathan, MD, MPH, a cardiologist at the Brigham.

“Our risk score provides a novel prediction tool to identify patients who face a heart failure risk in the next five years,” said co-first author Matthew Segar, MD, MS, a resident physician at UT Southwestern. “By not requiring specific clinical cardiovascular biomarkers or advanced imaging, this risk score is readily integrable into bedside practice or electronic health record systems and may identify patients who would benefit from therapeutic interventions.”

To develop the risk score — called WATCH-DM — the team leveraged data from 8,756 patients with diabetes enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. These data included a total of 147 variables, including demographics, clinical information, laboratory data and more. The investigators used machine-learning methods capable of handling multidimensional data to determine the top-performing predictors of heart failure.

Over the course of almost five years, 319 patients (3.6 percent) developed heart failure. The team identified the 10 top-performing predictors of heart failure, which make up the WATCH-DM risk score: weight (BMI), age, hypertension, creatinine, HDL-C, diabetes control (fasting plasma glucose), QRS duration, myocardial infarction and coronary artery bypass grafting. Patients with the highest WATCH-DM scores faced a five-year risk of heart failure approaching 20 percent.

The study draws strength from its large sample size and the high rate of heart failure, but the authors note that their findings may be constrained by certain limitations. ACCORD was conducted between 1999 and 2009, and predictors of heart failure may have evolved since the trial’s conclusion. In addition, while the risk score was accurate in predicting one form of heart failure — that with reduced ejection fraction — it fell short for predicting a second form of heart failure — that with preserved ejection fraction. Future studies will be needed to develop specific risk scores for predicting the latter among the general population and among patients with diabetes.

Importantly, the WATCH-DM risk score is now available as an online tool for clinicians to use. As a next step, the research team is working to integrate the risk score into electronic health record systems at both the Brigham and UT Southwestern to facilitate its practical use.

In addition to the tool’s usefulness for clinicians, Vaduganathan also sees a key message from the study for patients with diabetes who are concerned about their risk of heart failure.

“It’s important to look at these 10 variables and reflect on them,” said Vaduganathan. “For individual patients, these are important messages to think about when assessing personal risk. BMI was one of the top predictors of heart failure risk, which reinforces the idea that long-term excess weight may increase future risk for heart failure. We hope this work highlights ways to intervene — both through lifestyle changes and through the use of SGLT2 inhibitors — to delay or even entirely prevent heart failure.”

“This risk tool is an important step in the right direction to promote prevention of heart failure in patients with type 2 diabetes. It can be readily used as part of clinical care of patients with type 2 diabetes and integrated with the electronic medical records to inform physicians about the risk of heart failure in their patients and guide use of effective preventive strategies,” said Ambarish Pandey, MD, MSCS, a preventive cardiologist at UT Southwestern and the senior author of this study.

Funding for this work was provided by The Texas Health Resources Clinical Scholars Program, KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health [NIH]/National Center for Advancing Translational Sciences award UL 1TR002541) and the Texas Health Resources Clinical Scholars Program. Vaduganathan serves on advisory boards for AstraZeneca and Boehringer Ingelheim.

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At the Optical Society’s (OSA) Laser Congress, held 29 September — 3 October 2019 in Vienna, Austria, researchers from the University of Mississippi, U.S.A., will report a new laser-based sensor that effectively detects buried objects even while the detector is in motion. This new device offers a significant improvement over existing technologies, which cannot be operated on the go and lose accuracy in the presence of external sources of sound or vibration.

Laser Doppler vibrometers (LDVs) combined with vibration excited in the ground have shown promise for detecting landmines and other buried objects, but their sensitivity to environmental vibrations mean they must be operated from a special stable platform. The device, called a Laser Multi Beam Differential Interferometric Sensor (LAMBDIS), provides comparable detection capabilities but is far less sensitive to motion, allowing it to be used aboard a moving vehicle.

“The lingering scourge of landmines presents a serious challenge to rapid and accurate interrogation of large areas from moving vehicles,” said lead researcher Dr. Vyacheslav Aranchuk. “Our new device overcomes this challenge by using a series of laser beams and then combining their signals to create a rapid-detection scheme that also is robust enough to compensate for motion and other ‘noise’ that could overwhelm other techniques. LAMBDIS provides measurement of vibration fields with high sensitivity, while having low sensitivity to the whole body motion of the object, or sensor itself, allowing for the operation from a moving vehicle.”

Measurements without a reference beam

To detect buried objects, LDVs are used in conjunction with an audio source such as a loudspeaker, or a seismic source such as a mechanical shaker. The sound or seismic waves cause the ground to vibrate. The LDV can detect subtle differences in the vibration pattern where an object is buried, provided that the detector is stationary and the environment is sufficiently vibration-free.

Operation of traditional LDVs is based on interference of light reflected from an object with a reference beam internal to the LDV. As a result, motion of the LDV itself can cause LDV signals to be significantly higher than, and indistinguishable from, signals caused by object vibration.

In the new work, the researchers used a linear array of 30 laser beams directed onto the interrogated area.

Optical elements, including a receiver lens and a shearing interferometer, are used to combine the light reflected from different points on the ground on a photodetector array (PDA) resulting in interference signals on the PDA outputs. The frequency of the signals is proportional to the vibration velocity between illuminated points due to the Doppler effect. Processing of the PDA signals reveals vibrations between illuminated points on the surface.

“Unlike LDVs, the LAMBDIS doesn’t use an internal reference beam, but detects a Doppler shift by using interference of light reflected from different points on the object,” said Aranchuk. “Due to the lack of a reference beam, the Doppler frequency caused by the sensor motion is practically the same for all reflected beams and is automatically subtracted from the interference signals. As a result, LAMBDIS has very low sensitivity to the motion of the sensor itself, while having high sensitivity to relative vibration between points on the object.”

Successful field tests

Researchers report the LAMBDIS device performed well under a wide range of conditions in laboratory and field tests. LAMBDIS was able to detect buried objects 7.5 meters to 20 meters away and from a vehicle traveling at 3.8 meters per second (about 8.5 miles per hour) with comparable results to a stable platform-mounted LDV. Researchers tested the device both with airborne and seismic sound sources and with different scanning angles, suggesting the device could provide accurate results in a variety of real-world conditions.

In addition to detecting landmines, LDVs are commonly used to inspect automobiles and aircraft components, to assess bridge and structure vibrations, to calibrate equipment and study materials, and in dental and biomedical applications. LAMBDIS could benefit such applications in cases where environmental noise or movement hinders the use of LDV devices.

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In this work supported by NIH’s National Institute of General Medical Sciences, the researchers set out to explore specific mechanics of cell division, what Verma calls “the rules of faithful and complete division,” in fruit fly cells. In particular, they want to understand how structures called microtubules help to define where the cell splits in half during the division process.

Maresca explains, “This has been studied for a long time, since microscopy made it possible to see cells divide, but very intensely for 40 or 50 years. What are the cues that tell a cell where to divide? How does the cell know where to put the division plane? It’s the ultimate conclusion of mitosis, the actual division of the cell into two.”

In normal cell division, chromosomes line up near the center of the cell, where a structure called the spindle aligns copies of each chromosome by interacting with a bridge-like structure called the kinetochore. When all the chromosomes have been aligned, microtubules pull the chromosome copies apart like a zipper. The cell then physically divides at a location positioned between the segregated chromosomes to produce two daughter cells, each with a complete copy of the genome.

In imaging the microtubules, often described as nano-scale highways, the biologists noticed that the spatial cue for locating the division plane requires microtubules, Maresca says. “They grow out to touch the edges inside the cell membrane. Vikash found that the growing tips of the tubes, the ‘plus-ends’ that touch the membrane, say to the cell, ‘This is where to divide.’ Regulatory proteins get recruited to the site contacted by the plus-ends kicking into gear and a whole new pathway assembles a ring that will constrict like a purse string to split one large cell into two smaller ones.”

Timing plays a role, as well, the researchers found. “It seems that all the microtubule tips have the special ability to trigger the purse-string pathway,” Maresca says, “but over time, something changes and only the tips in the middle of the cell retain that ability.” Referring to work published in eLife in February, he adds, “We found what we think is a very important spatial cue for how the cell positions its division plane.”

Visualizing the behavior of microtubules during cell division in detail is typically hampered by the fact that so many microtubules are growing and shrinking at the same time throughout the cell, Verma says. “It’s like many highways converging at the same place and time in the spindle. It looks like a Los Angeles freeway map.” But by using a powerful technique called total internal reflection fluorescence (TIRF) microscopy, Verma could more easily visualize the dynamic properties of individual microtubules. Maresca adds, “We went from a stressful L.A. traffic jam into a Sunday-drive-on-a-country-road view.”

That is when they witnessed the branching. Using multi-color TIRF microscopy, the researchers could now clearly see and quantitatively define the branching microtubule nucleation process. To the best of their knowledge, this had never been visualized before in real time in animal cells. “It was very exciting,” Verma recalls.

Maresca says, “When you see such beautiful things right before your eyes, you just have to follow it. This project started out as an investigation of how cells define where they divide, but we saw this branching phenomenon so often and so clearly that we realized we had to look at it more closely. We don’t think you could have seen the branching process as well in other model systems as you can in our fruit fly cells. It highlights the fact that every model system has its strengths and its weaknesses and, in this case, our cells and the phase at which we were imaging them just offered a uniquely beautiful, birds-eye view of branching. We could actually see all of this happening in real time before our eyes.”

Once they could visualize the entire process of branching nucleation in a cell, he adds, “We knew we could next ‘tag’ proteins that regulate the process with different colors to further quantify fundamental parameters of the phenomenon. All of a sudden we realized that this is the first time one could see this happening in living animals cells.”

Branching nucleation is fundamental and conserved, one of the essential parts of mitosis, but it’s been difficult to directly visualize in other model systems, Maresca points out. “The course of this project was a reminder that some of the most exciting work we do as scientists is unplanned and, especially for microscopists, begins with seeing something in the cell unfold right before your eyes.”

For most of the last 25 million years, eastern Australia was home to a now-extinct group of marsupials called palorchestids. These animals are well known for their large size, strange tapir-like skulls, and large claws, but so far there has been no detailed study of their limb morphology. In this study, Richards and colleagues examined more than 60 fossil specimens of palorchestids of varying geologic ages to characterize the function and evolution of their arms and legs.

Over the course of their evolution, palorchestids grew larger and stranger. Using limb proportions as a proxy for body size, these authors estimated that the latest and largest of the palorchestids may have weighed over 1,000kg. Furthermore, their forelimbs were extremely muscular and were likely adapted for grabbing or scraping at leaves and branches. Uniquely among known mammals, the elbow joints of the largest palorchestids appear to have been immobile and fixed at roughly a 100-degree angle, so that the arms served as permanently flexed food-gathering tools.

This study provides the first formal description of limb morphology in palorchestid marsupials and reveals a group of giant herbivores that probably filled a niche no longer occupied in modern Australian ecosystems. Fossil remains are still missing for certain parts of the palorchestid body, such as the shoulders and wrists, but the authors are hopeful that more material may be found in existing museum collections.

The authors add: “This study has allowed us for the first time to appreciate just how huge these mega-marsupial palorchestids were, while also providing the first comprehensive view of a strange limb anatomy unprecedented in the mammalian world. This research reveals yet more about the diversity of unique large marsupials that once roamed Australia not so long ago.”

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“With this new method we are able to package together in one lentiviral capsid both essential components (Cas9 protein and guide RNA) for the CRISPR mediated gene editing,” said Baisong Lu, Ph.D, assistant professor of regenerative medicine at WFIRM and one of the lead authors of the paper. “Previously, the two components had to be delivered separately which was not as convenient.”

CRISPR (clustered regularly interspaced short palindromic repeats) technology is used to alter DNA sequences and modify gene function. CRISPR/Cas9 is an enzyme that is used like a pair of scissors to cut two strands of DNA at a specific location to add, remove or repair bits of DNA. But CRISPR/Cas9 is not 100 percent accurate and could potentially cut unexpected locations, causing unwanted results.

Now the WFIRM team can package the two components — Cas9 protein (the enzyme) and the guide RNA — as ribonucleoproteins inside the lentiviral capsid, creating a lentiviral capsid-based bionanoparticle system for delivering CRISPR/Cas9. Lentiviral vector is a widely used gene delivery vehicle in research labs and is already widely used for delivering the CRISPR/Cas9 machinery for efficient genome editing. However, using lentiviral vector to deliver CRISPR/Cas9 will result in long-term expression of the endonuclease, which is undesired for safety reasons. The new system offers the delivery efficiency of conventional lentiviral vectors, but enables transient Cas9 expression. Thus, the new CRISPR/Cas9 delivery system is more efficient and safer.

The research has led the team to hypothesize that a “similar strategy should be translatable to other editor proteins for gene disruption,” said Anthony Atala, M.D., director of WFIRM and a co-author of the paper. “We may be able to utilize this to package and deliver other RNPs into mammalian cells, which has been difficult to achieve so far.”

The research is part of an ongoing effort to improve in vivo gene editing efficiency which will be useful in research and clinical applications by improving safety and avoiding possible immune responses.

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A key player in the immune response is T follicular helper cells. These Tfh cells are essential in vaccination responses, but they can be harmful actors in an autoimmune disease like lupus.

Now, a preclinical study published in Science Immunology shows how the interplay of two interleukin signaling proteins, IL-6 and IL-2, affects the development of Tfh cells. This interplay may either maintain or disrupt the balancing act of the immune system. Thus, the research may help guide future disease treatment.

“We believe these findings have important therapeutic implications,” said André Ballesteros-Tato, Ph.D., associate professor in the University of Alabama at Birmingham Department of Medicine’s Division of Clinical Immunology and Rheumatology and leader of the research.

“For example, it is well-known that abnormal expansion of Tfh cells correlates with disease severity in systemic lupus erythematosus patients. Unfortunately, there are currently no therapies to selectively deplete Tfh cells in vivo. Based on our data, it is tempting to speculate that blockade of IL-6 with IL-6-neutralizing antibodies — in combination with recombinant IL-2 administration — will synergize to efficiently prevent Tfh cell responses in autoimmune patients, thereby avoiding the production of self-reactive antibodies.”

Both IL-6-neutralizing antibodies and recombinant IL-2 are Food and Drug Administration-approved drugs.

“The findings in this study are quite exciting,” said S. Louis Bridges, Jr., M.D., Ph.D., director of the UAB Division of Clinical Immunology and Rheumatology. “Both IL-6 and IL-2 are key molecules in immune responses and autoimmune diseases. This research helps to elucidate the complex interactions of these cytokines and how they influence Tfh cells. The novel findings in this paper may ultimately lead to better ways to treat diseases such as lupus.”

Development of Tfh cells takes place this way — Tfh cells react with antigens presented outside of B cell follicles in the lymph nodes or spleen. The activated Tfh cells then move into the follicles, where the Tfh cells interact with B cells to produce a germinal center — a factory that multiplies and transforms B cells into high-specificity, antibody-producing cells.

The study began from an apparent paradox for the UAB researchers and colleagues in Virginia and Maryland. As Tfh cells become germinal center-Tfh cells, they need sustained T-cell receptor stimulation to maintain the germinal center-Tfh state. Yet that same stimulation is known to induce expression of the interleukin-2 receptor and production of the interleukin IL-2, which together should create a feedback loop of IL-2 signaling that is known to inhibit Tfh cells. Therefore, Ballesteros-Tato and colleagues sought to understand how Tfh cells evade this potent inhibition.

They and others previously have shown that treatment with recombinant IL-2 prevents Tfh cell responses in mice. In the Science Immunology paper, using a model of influenza infection in mice, they found that IL-6 protects Tfh cells from the deleterious effect of IL-2 by interrupting the feedback loop. This effect allows Tfh cells to receive T-cell receptor stimulation without responding to IL-2. Part of the proof of this interplay was showing that blockade of IL-6 signaling rendered Tfh cells more susceptible to IL-2-mediated depletion, at lower levels of IL-2.

The researchers found that IL-6 protection was not needed in the first week of the immune response, apparently because other immune cells that consume IL-2 are present, lowering IL-2 levels. The IL-6 protection became essential after the Tfh cells entered B cell follicles to start germinal center development. There, the IL-2 produced by Tfh cells, Ballesteros-Tato says, is not consumed, which likely lets IL-2 levels rise past a threshold that requires IL-6 protection.

The research revealed underlying mechanistic details. The researchers found that IL-6 inhibited upregulation of the IL-2 beta receptor subunit, also called CD122, by preventing association of the STAT5 transcription factor with the Il2rb gene for that receptor subunit. This allowed the germinal center-Tfh cells that received sustained T-cell receptor signaling and were producing IL-2 to circumvent the T-cell receptor/IL-2-inhibitory feedback loop because the receptor cannot function.

Altogether, these results have identified a regulatory mechanism that controls the generation of germinal center-Tfh cells. Instead of one interleukin or another controlling the response of Tfh cells in an on-off fashion, IL-6 signaling fine-tunes the threshold of IL-2 responsiveness; thus, the relative levels of the two interleukins determine the fate of the Tfh cells.

This model, Ballesteros-Tato says, clarifies previous conflicting studies regarding the role of IL-6 in controlling Tfh cell responses.

The research team includes scientists from North Carolina State University, the Department of Energy’s Oak Ridge National Laboratory (ORNL), the Chinese Academy of Sciences and the Ohio State University.

In solids with magnetic ions (e.g., manganese), thermal perturbations of spins either can align with each other (ferromagnets or antiferromagnets), or not align (paramagnets). However, spins are not entirely random in paramagnets: they form short-lived, short-range, locally ordered structures — paramagnons — which exist for only a millionth of a billionth of a second and extend over only two to four atoms. In a new paper describing the work, the researchers show that despite these shortcomings, even paramagnons can move in a temperature difference and propel free electrons along with them, creating paramagnon drag thermopower.

In a proof-of-concept finding, the team observed that paramagnon drag in manganese telluride (MnTe) extends to very high temperatures and generates a thermopower that is much stronger than what electron charges alone can make.

The research team tested the concept of paramagnon drag thermopower by heating lithium-doped MnTe to approximately 250 degrees Celsius above its Néel temperature (34 degrees Celsius) — the temperature at which the spins in the material lose their long-range magnetic order and the material becomes paramagnetic.

“Above the Néel temperature, one would expect the thermopower being generated by the spin waves to drop off,” says Daryoosh Vashaee, professor of electrical and computer engineering and materials science at NC State and co-corresponding author of the paper describing the work. “However, we didn’t see the expected drop off, and we wanted to find out why.”

At ORNL the team used neutron spectroscopy at the Spallation Neutron Source to determine what was happening within the material. “We observed that even though there were no sustained spin waves, localized clusters of ions would correlate their spins long enough to produce visible magnetic fluctuations,” says Raphael Hermann, a materials scientist at ORNL and co-corresponding author of the paper. The team showed that the lifetime of these spin waves — around 30 femtoseconds — was long enough to enable the dragging of electron charges, which requires only about one femtosecond, or one quadrillionth of a second. “The short-lived spin waves, therefore, could propel the charges and create enough thermopower to prevent the predicted drop off,” Hermann says.

“Before this work, it was believed that magnon drag could exist only in magnetically ordered materials, not in paramagnets,” says Joseph Heremans, professor of mechanical and aerospace engineering at the Ohio State University and co-corresponding author of the paper. “Because the best thermoelectric materials are semiconductors, and because we know of no ferromagnetic semiconductor at room temperature or above, we never thought before that magnon drag could boost the thermoelectric efficiency in practical applications. This new finding changes that completely; we can now investigate paramagnetic semiconductors, of which there are a lot.”

“When we observed the sudden rise of Seebeck coefficient below and near the Néel temperature, and this excess value extended to high temperatures, we suspected something fundamentally related to spins must be involved,” says Huaizhou Zhao, a professor at the Chinese Academy of Science in Beijing and co-corresponding author of the paper. “So we formed a research team with complementary expertise which laid the groundwork for this discovery.”

“Spins enable a new paradigm in thermoelectricity by alleviating the fundamental tradeoffs imposed by Pauli exclusion on electrons,” Vashaee says. “Just as in the discovery of the spin-Seebeck effect, which led to the new area of spincaloritronics, where the spin angular momentum is transferred to the electrons, both the spin waves (i.e., magnons) and the local thermal fluctuations of magnetization in the paramagnetic state (i.e., paramagnons) can transfer their linear momentum to electrons and generate thermopower.”

The research appears in Science Advances and is supported by the National Science Foundation, the Air Force Office of Scientific Research, and the U.S. Department of Energy Office of Science, Basic Energy Sciences, Materials Sciences and Engineering Division. Graduate students and co-first authors Yuanhua Zheng of the Ohio State University, Tianqi Lu of the Chinese Academy of Sciences and Mobarak H. Polash of NC State contributed equally to the work. The Spallation Neutron Source at ORNL is a DOE Office of Science User Facility.