About 150,000 nontraumatic amputations occur annually, according to the 2021 American Heart Association policy statement: Reducing Nontraumatic Lower-Extremity Amputations by 20% by 2030: Time to Get to Our Feet. Between 8 and 10 million people in the United States have PAD. The condition disproportionately affects Black people, American Indian people and those of low socioeconomic status.

The condition occurs when the arteries that transport blood from the heart throughout the body narrow, reducing blood and oxygen flow. It usually affects the legs and feet causing symptoms while walking, such as cramping, weakness, fatigue, aching and pain or discomfort that subside within 10 minutes of rest. Previous research found that walking for exercise, particularly on a treadmill while supervised by a staff member, improves walking ability and walking distance among people with PAD. What remained unclear were the potential effects of walking at a pace that induced symptoms such as leg pain on speed, strength and balance.

This study examined the effects of home-based walking for exercise among 264 people with PAD who were participating in a randomized clinical trial, called the Low-Intensity Exercise Intervention in PAD (LITE), which included 305 people overall. From September 2015 to December 2019, participants enrolled in the LITE study at four U.S. medical centers (Northwestern University, Tulane University, University of Minnesota and University of Pittsburgh). Their average age was 69 years, 48% were women and 61% were Black adults.

Researchers randomly assigned participants to one of three groups for 12 months. The first group (38%) walked at home at a comfortable pace; the second group (41%) walked at home at a pace that induced leg symptoms; while the third group (21%) did not walk for exercise. Both walking exercise groups wore an ActiGraph, a device that monitored the intensity of their walking and the time walked.

Personalized thresholds for the ActiGraph intensity that corresponded to walking for exercise at a pace that induced leg symptoms (high intensity) and that corresponded to walking for exercise at a comfortable pace without leg symptoms (low intensity) were defined for each individual randomized to an exercise intervention. Participants randomized to exercise wore their ActiGraph device during walking exercise activity and uploaded data on exercise frequency, intensity and duration to the study website.

At the study’s start and at 6 and 12 months, participants completed three tests of leg function: walking speed over a four-meter distance (13 feet) at usual pace, walking speed over a four-meter distance at fastest pace and the short physical performance battery (SPPB) consisting of four-meter walking velocity at usual pace, a standing balance test and the time for five repeated chair rises.

The key findings were:

• At six months, participants whose walking pace induced leg pain or discomfort walked 11 feet per minute faster, and at 12 months, they walked more than 16 feet per minute faster than participants whose walking pace did not induce leg pain or discomfort. Compared to non-exercisers, participants in the group that walked for exercise at a pace inducing leg pain or discomfort walked nearly 13 feet per minute faster at six months, however, this increase was not statistically significant at 12 months.
• At 12 months, people who walked for exercise with leg pain or discomfort scored almost 1 point higher on the sum of the three leg function tests (the short physical performance battery), out of a total of 13 points (0-12), compared to people who walked at a comfortable pace with no leg pain. For those walking for exercise at a comfortable pace, there was no improvement in walking speed at six months or 12 months compared to non-exercisers.

“We were surprised by the results because walking for exercise at a pace that induces pain in the legs among people with PAD has been thought to be associated with damage to leg muscles,” said senior study author Mary M. McDermott, M.D., the Jeremiah Stamler Professor of Medicine in the division of general internal medicine and geriatric medicine and of preventive medicine at Northwestern University’s Feinberg School of Medicine in Chicago. “Based on these results, clinicians should advise patients to walk for exercise at a pace that induces leg discomfort, instead of at a comfortable pace without pain.”

This underscores the benefits of walking for exercise at a pace that induces leg pain or discomfort. “This finding is consistent with “no pain, no gain” with regard to walking exercise in PAD,” McDermott said.

“Exercise that induces leg pain is beneficial, though difficult,” McDermott said. “We now are working to identify interventions that can make the higher intensity exercise easier — and still beneficial — for people with PAD.”

It is important to note that study participants walked at home, so the results may not apply to walking on a treadmill in the presence of a health professional, which is the standard of care and first line therapy according to clinical practice guidelines. In addition, the outcomes in this report were not pre-specified outcomes for this clinical trial. Therefore, these findings must be confirmed in future research.

In May 2022, the American Heart Association and 24 collaborating organizations launched the PAD National Action Plan, a guide to assist in the prevention of PAD complications, treatment of cardiovascular risk and improvement of quality of life for those living with the disease.

“PAD is a lifelong medical condition, but people with PAD can lead active and long lives,” said American Heart Association volunteer expert and PAD National Action Plan writing group member Joshua Beckman, M.D., director of Vascular Medicine Section and professor of medicine Vanderbilt University in Nashville, Tennessee. “If you notice walking is becoming more difficult, keeping up with others is hard, or you have pain when you walk, talk with a doctor and describe when it happens and how it feels.”

This association between reduced hippocampal activity and risk of PTSD was particularly strong in individuals who had greater involuntary defensive reactions to being startled.

This research, published in the JNeurosci, suggests that individuals with greater defensive reactions to potentially threatening events might have a harder time learning whether an event is dangerous or safe. They also are more likely to experience severe forms of PTSD, which include symptoms such as always being on guard for danger, self-destructive behavior like drinking too much or driving too fast, trouble sleeping and concentrating, irritability, angry outbursts, and nightmares.

“These findings are important both to identify specific brain responses associated with vulnerability to develop PTSD, and to identify potential treatments focused on memory processes for these individuals to prevent or treat PTSD,” said senior author Vishnu Murty, PhD, assistant professor of psychology and neuroscience at Temple University.

This research is part of the national Advancing Understanding of RecOvery afteR traumA (AURORA) Study, a multi-institution project funded by the National Institutes of Health, non-profit funding organizations such as One Mind, and partnerships with leading tech companies. The organizing principal investigator is Samuel McLean, MD, MPH, professor of psychiatry and emergency medicine at the University of North Carolina School of Medicine and director of the UNC Institute for Trauma Recovery.

AURORA allows researchers to leverage data from patient participants who enter emergency departments at hospitals across the country after experiencing trauma, such as car accidents or other serious incidents. The ultimate goal of AURORA is to spur on the development and testing of preventive and treatment interventions for individuals who have experienced traumatic events.

AURORA scientists have known that only a subset of trauma survivors develop PTSD, and that PTSD is associated with increased sensitivity to threats and decreased ability to engage neural structures retrieving emotional memories. Yet how these two processes interact to increase risk for developing PTSD is not clear. To better understand these processes, Murty and colleagues characterized brain and behavioral responses from individuals two weeks following trauma.

Using brain-imaging techniques coupled with laboratory and survey-based tests for trauma, researchers found that the individuals with less activity in their hippocampus and greatest defensive responses to startling events following trauma had the most severe symptoms.

“In these individuals, greater defensive reactions to threats may bias them against learning information about what is happening so that they can discern what is safe and what is dangerous,” said Büşra Tanriverdi, the lead researcher on the study and graduate student at Temple. “These findings highlight an important PTSD biomarker focused on how people form and retrieve memories after trauma.”

“These latest findings add to our list of AURORA discoveries that are helping us understand the differences between individuals who go on to develop posttraumatic stress disorder and those who do not,” said McLean, an author on the paper. “Studies focusing on the early aftermath of trauma are critical because we need a better understanding of how PTSD develops so we can prevent PTSD and best treat PTSD.”

“Since initiating our financial support of the AURORA Study in 2016, we remain steadfast in our commitment to helping AURORA investigators make important discoveries and to bridge the gaps that exist in mental health research funding and patient support,” said Brandon Staglin, president of One Mind.

In the study, published this week in Nature Genetics, researchers used CRISPR technology to test the impact of every human gene on SARS-CoV-2 infections in human lung cells. Their findings revealed new pathways that the virus relies on to infect cells, as well as the antiviral pathways that help protect against viral infection. Notably, they showed that mucins — the main component of mucus found in the lungs — seem to help block the SARS-CoV-2 virus from entering our cells.

“Our data suggest that mucins play a key role in restricting SARS-CoV-2 infection by acting as a barrier to viruses that are attempting to access our lung epithelial cells,” said Scott Biering, the study’s co-lead author and a postdoctoral researcher in Eva Harris’s lab at UC Berkeley’s School of Public Health. “Further, our data suggest that mucin expression levels in an individual’s lungs may impact COVID-19 disease progression.”

Patrick Hsu — cofounder of the Arc Institute and Berkeley assistant professor of bioengineering, Deb Faculty Fellow and Innovative Genomics Institute Investigator — is the principal investigator of the study, which brought together researchers from 10 institutions. Harris, professor of public health at UC Berkeley, and Silvana Konermann, assistant professor at Stanford University School of Medicine, were co-senior authors of the study. Other collaborators contributed from Stanford University, the University of North Carolina at Chapel Hill, Yale School of Medicine and Cornell University, and spanned disciplines ranging from immunology, bioengineering, epidemiology, molecular biology and genetics.

Together, the researchers were trying to determine how the SARS-CoV-2 virus enters human cells and replicates so efficiently during illness. They also wanted to identify specific defense mechanisms in human cells that might be able to fight infection, which could inspire new therapeutic strategies.

Researchers discovered that MUC1 and MUC4, types of mucins found in lung cell membranes, defend lung cells from infection. This finding is important because previous studies had suggested that an accumulation of mucus could be the reason why some people became seriously ill with COVID-19 — since the mucus can make it difficult for people to breathe — and proposed using drugs to deplete mucus. This Berkeley-led study suggests that such a strategy could interfere with mucins that provide a valuable defense mechanism against SARS-CoV-2 infection.

Still, mucins are complex, and more research is needed to fully understand them. The researchers discovered that other mucins — MUC5AC and MUC5B — which are secreted into the mucus lining of the lungs, either do nothing to stop SARS-CoV-2 infection or can even promote viral infection.

According to Biering, both the type and amount of mucus that each person produces may result in different outcomes for SARS-CoV-2 infection — and lead to different treatment strategies.

“Somebody who produces a lot of the right type of mucus could be very protected. But somebody who produces a lot of the wrong type of mucus might have more risk of infection,” said Biering. “And somebody who produces very little of the right type also could be at more risk.”

This is also the first study in which researchers looked at how the SARS-CoV-2 virus interacts with human lung cells, marking a critical advancement in COVID-19 research.

“It is well known that virus infection can be promoted or inhibited by our own proteins,” said Biering. “But this is the first time that a systematic investigation of these host cell proteins has been conducted in human lung epithelial cells for SARS-CoV-2 infection.”

Past studies of SARS-CoV-2 infection have used cell types that do not naturally contain the receptors or other pathways that the virus uses to infect our lungs. For this study, researchers wanted to use a more relevant cell type, human epithelial cells called Calu-3, found on the inner surface of the lung. Though this cell line is extremely challenging to work with, researchers managed to gain a more accurate understanding of the biology involved in human SARS-CoV-2 infections.

“[Using Calu-3 cells] was a huge advancement, given that these are very representative of the first cells the virus contacts and infects in humans, and it revealed new pathways not seen in other cell lines,” said co-lead author Sylvia Sarnik, an assistant specialist in Hsu’s lab at the time of the study. “Overall, this study is a step forward in understanding viral infection pathways and paves the way for research toward better treatments in the future.”

The researchers conducted genome-wide CRISPR gain-of-function and loss-of-function screening to eliminate or overexpress every gene in the human genome. Then they measured the impact of these gene expression changes on SARS-CoV-2 infection in human lung epithelial cells. Importantly, many of the genes highlighted by this screen have yet to be investigated experimentally, providing a starting point for future work.

“You can run these massively parallel ‘Hunger Games’-style experiments on human cells to see which genes you can change to tune the ability of our lung cells to survive or grow when the virus infects them,” said Hsu.

“Our screen successfully identified hundreds of genes that were important for replication of SARS-CoV-2 and hundreds of genes that could restrict SARS-CoV-2,” said Biering. “In this study, we chose to focus on understanding the role of these mucin proteins.”

The researchers identified mucin glycoproteins as key restriction factors for infection in cells, both in mouse models and potentially in humans.

Researchers also studied how mucins would interact with other respiratory viruses, including influenza A virus, human parainfluenza virus, common cold coronaviruses and respiratory syncytial virus. As with SARS-CoV-2, the results were unpredictable.

“What we showed was mucins are broadly antiviral, but the story is actually much more complicated than that,” said Hsu. “In fact, in some viruses, we found that mucin overexpression actually seemed to increase infectivity.”

Future work will be critical to better understand how viruses interact with mucins, but, for now, these findings provide an important starting point. “This study helped us learn more about the virus and opened new avenues for research to further investigate druggable targets,” said Sarnik.

Fast Grants, the National Institutes of Health and the Centers for Disease Control and Prevention helped support this research.

A dense, collapsed star spinning 707 times per second — making it one of the fastest spinning neutron stars in the Milky Way galaxy — has shredded and consumed nearly the entire mass of its stellar companion and, in the process, grown into the heaviest neutron star observed to date.

Weighing this record-setting neutron star, which tops the charts at 2.35 times the mass of the sun, helps astronomers understand the weird quantum state of matter inside these dense objects, which — if they get much heavier than that — collapse entirely and disappear as a black hole.

“We know roughly how matter behaves at nuclear densities, like in the nucleus of a uranium atom,” said Alex Filippenko, Distinguished Professor of Astronomy at the University of California, Berkeley. “A neutron star is like one giant nucleus, but when you have one-and-a-half solar masses of this stuff, which is about 500,000 Earth masses of nuclei all clinging together, it’s not at all clear how they will behave.”

Roger W. Romani, professor of astrophysics at Stanford University, noted that neutron stars are so dense — 1 cubic inch weighs over 10 billion tons — that their cores are the densest matter in the universe short of black holes, which because they are hidden behind their event horizon are impossible to study. The neutron star, a pulsar designated PSR J0952-0607, is thus the densest object within sight of Earth.

The measurement of the neutron star’s mass was possible thanks to the extreme sensitivity of the 10-meter Keck I telescope on Maunakea in Hawai’i, which was just able to record a spectrum of visible light from the hotly glowing companion star, now reduced to the size of a large gaseous planet. The stars are about 3,000 light years from Earth in the direction of the constellation Sextans.

Discovered in 2017, PSR J0952-0607 is referred to as a “black widow” pulsar — an analogy to the tendency of female black widow spiders to consume the much smaller male after mating. Filippenko and Romani have been studying black widow systems for more than a decade, hoping to establish the upper limit on how large neutron stars/pulsars can grow.

“By combining this measurement with those of several other black widows, we show that neutron stars must reach at least this mass, 2.35 plus or minus 0.17 solar masses,” said Romani, who is a professor of physics in Stanford’s School of Humanities and Sciences and member of the Kavli Institute for Particle Astrophysics and Cosmology. “In turn, this provides some of the strongest constraints on the property of matter at several times the density seen in atomic nuclei. Indeed, many otherwise popular models of dense-matter physics are excluded by this result.”

If 2.35 solar masses is close to the upper limit of neutron stars, the researchers say, then the interior is likely to be a soup of neutrons as well as up and down quarks — the constituents of normal protons and neutrons — but not exotic matter, such as “strange” quarks or kaons, which are particles that contain a strange quark.

“A high maximum mass for neutron stars suggests that it is a mixture of nuclei and their dissolved up and down quarks all the way to the core,” Romani said. “This excludes many proposed states of matter, especially those with exotic interior composition.”

Romani, Filippenko and Stanford graduate student Dinesh Kandel are co-authors of a paper describing the team’s results that has been accepted for publication by The Astrophysical Journal Letters.

How large can they grow?

Astronomers generally agree that when a star with a core larger than about 1.4 solar masses collapses at the end of its life, it forms a dense, compact object with an interior under such high pressure that all atoms are smashed together to form a sea of neutrons and their subnuclear constituents, quarks. These neutron stars are born spinning, and though too dim to be seen in visible light, reveal themselves as pulsars, emitting beams of light — radio waves, X-rays or even gamma rays — that flash Earth as they spin, much like the rotating beam of a lighthouse.

“Ordinary” pulsars spin and flash about once per second, on average, a speed that can easily be explained given the normal rotation of a star before it collapses. But some pulsars repeat hundreds or up to 1,000 times per second, which is hard to explain unless matter has fallen onto the neutron star and spun it up. But for some millisecond pulsars, no companion is visible.

One possible explanation for isolated millisecond pulsars is that each did once have a companion, but it stripped it down to nothing.

“The evolutionary pathway is absolutely fascinating. Double exclamation point,” Filippenko said. “As the companion star evolves and starts becoming a red giant, material spills over to the neutron star, and that spins up the neutron star. By spinning up, it now becomes incredibly energized, and a wind of particles starts coming out from the neutron star. That wind then hits the donor star and starts stripping material off, and over time, the donor star’s mass decreases to that of a planet, and if even more time passes, it disappears altogether. So, that’s how lone millisecond pulsars could be formed. They weren’t all alone to begin with — they had to be in a binary pair — but they gradually evaporated away their companions, and now they’re solitary.”

The pulsar PSR J0952-0607 and its faint companion star support this origin story for millisecond pulsars.

“These planet-like objects are the dregs of normal stars which have contributed mass and angular momentum, spinning up their pulsar mates to millisecond periods and increasing their mass in the process,” Romani said.

“In a case of cosmic ingratitude, the black widow pulsar, which has devoured a large part of its mate, now heats and evaporates the companion down to planetary masses and perhaps complete annihilation,” said Filippenko.

Spider pulsars include redbacks and tidarrens

Finding black widow pulsars in which the companion is small, but not too small to detect, is one of few ways to weigh neutron stars. In the case of this binary system, the companion star — now only 20 times the mass of Jupiter — is distorted by the mass of the neutron star and tidally locked, similar to the way our moon is locked in orbit so that we see only one side. The neutron star-facing side is heated to temperatures of about 6,200 Kelvin, or 10,700 degrees Fahrenheit, a bit hotter than our sun, and just bright enough to see with a large telescope.

Filippenko and Romani turned the Keck I telescope on PSR J0952-0607 on six occasions over the last four years, each time observing with the Low Resolution Imaging Spectrometer in 15-minute chunks to catch the faint companion at specific points in its 6.4-hour orbit of the pulsar. By comparing the spectra to that of similar sun-like stars, they were able to measure the orbital velocity of the companion star and calculate the mass of the neutron star.

Filippenko and Romani have examined about a dozen black widow systems so far, though only six had companion stars bright enough to let them calculate a mass. All involved neutron stars less massive than the pulsar PSR J0952-060. They’re hoping to study more black widow pulsars, as well as their cousins: redbacks, named for the Australian equivalent of black widow pulsars, which have companions closer to one-tenth the mass of the sun; and what Romani dubbed tidarrens — where the companion is around one-hundredth of a solar mass — after a relative of the black widow spider. The male of this species, Tidarren sisyphoides, is about 1% of the female’s size.

“We can keep looking for black widows and similar neutron stars that skate even closer to the black hole brink. But if we don’t find any, it tightens the argument that 2.3 solar masses is the true limit, beyond which they become black holes,” Filippenko said.

“This is right at the limit of what the Keck telescope can do, so barring fantastic observing conditions, tightening the measurement of PSR J0952-0607 likely awaits the 30-meter telescope era,” added Romani.

Other co-authors of the ApJ Letters paper are UC Berkeley researchers Thomas Brink and WeiKang Zheng. The work was supported by the National Aeronautics and Space Administration (80NSSC17K0024, 80NSSC17K0502), the Christopher R. Redlich Fund, the TABASGO Foundation, and UC Berkeley’s Miller Institute for Basic Research in Science.