Now, Dr. Jaewon Sim and her colleagues at Michigan State University have published a study in Science Immunology that suggests part of the answer may lie in the body's immune response. The researchers uncovered a previously unknown link between an underappreciated immune cell and the group of male hormones that includes testosterone. Their findings may help explain one biological reason for sex differences in chronic pain.

"It is well established that women tend to experience more severe, more frequent, and longer-lasting pain than men," says Sim. "However, the biological mechanisms underlying these differences have remained relatively understudied."

For Sim, the motivation behind the research extended beyond understanding biology.
​
She says this knowledge gap has contributed to persistent misconceptions about women's pain, such as the belief that women exaggerate their pain or have a lower pain tolerance.

"We found an urgent need to challenge these misconceptions through rigorous scientific research."

Their findings offer one step toward filling that gap, revealing biological mechanisms that may shape how pain resolves differently between the sexes.

Pain is more than just a warning signal

Pain is the body's natural alarm system. When tissues are damaged, specialized nerve cells called nociceptors send signals to the brain, prompting us to protect the injured area. Normally, these pain signals diminish as healing occurs. But tissue repair is only one factor that shapes how we experience pain. Hormones, immune responses, stress, and emotions, along with previous experiences, all shape how pain is experienced and whether it resolves or persists.

Many people think pain simply disappears once an injury heals.

According to Sim, that idea is only partly true. "In acute pain, pain usually disappears once the painful stimulus is removed, or the injured tissue has healed. However, once the transition from acute to chronic pain occurs, which is surprisingly common, it becomes a major health problem."

In some people, pain persists long after the original injury has healed, becoming a chronic condition in its own right. Scientists increasingly recognize that this can happen when the body's natural processes for resolving pain are delayed or disrupted. Rather than viewing pain as something that passively fades away, researchers are increasingly recognizing that the body actively works to resolve it through communication between the nervous and immune systems.

As Sim explains, "Our findings suggest that the body has its own active pain-resolution mechanisms that help prevent the transition from acute to chronic pain. By understanding how these natural mechanisms work, we may be able to develop treatments that prevent this harmful transition, rather than simply treating it after it occurs, which makes treatment difficult."

Understanding these natural pain-resolution mechanisms meant answering two key questions: Which immune cells are responsible for switching pain off, and what regulates their activity?

The immune system's role in pain recovery

Sim says the immune system has been part of pain research for decades, but many studies have focused on how it promotes or worsens pain. Instead, her team asked whether it might also help switch pain off.

To investigate this, the MSU researchers focused on monocytes, immune cells that circulate in the bloodstream of both males and females. Sim says that monocytes have been relatively understudied in pain research because they were traditionally viewed as precursors of macrophages (immune cells that engulf pathogens, clear damaged cells, and help coordinate tissue repair). However, the team found that monocytes themselves were the predominant immune cells in inflamed skin, and removing them significantly impaired pain resolution.

The researchers also discovered that these monocytes produce interleukin-10 (IL-10), an anti-inflammatory molecule that does more than reduce inflammation.

According to Sim, "IL-10-producing monocytes serve as the body's natural 'pain-resolving' cells. They produce IL-10, an anti-inflammatory molecule that not only ameliorates inflammation but signals to pain-sensing neurons to deactivate neuronal activity."

These findings suggest that monocytes do more than help fight infection or repair damaged tissue. They also communicate with the nervous system, helping switch off pain signals as healing progresses.

But identifying the cells involved was only the first step. The researchers next needed to understand why pain resolution differs between females and males and where that difference originates.

The connection between male hormones and the immune system

Having identified IL-10-producing monocytes as key players in pain resolution, the researchers next asked what controls their activity.

They found that androgens, a group of hormones that includes testosterone, increased both the number of pain-resolving monocytes and the amount of IL-10 they produced.

These findings suggest that androgens may contribute to differences in pain recovery between males and females by increasing the number of IL-10-producing monocytes. The researchers also found that increasing these pain-resolving monocytes helped speed up pain resolution in both males and females, suggesting that this pathway could be a potential target for future treatments.

The researchers then made a surprising discovery: pain-sensing nerve cells from both males and females responded similarly to IL-10. The key difference was how much IL-10 the immune system produced. This suggests that differences in IL-10 production, rather than differences in how the pain-sensing neurons respond, may help explain why pain resolves differently between males and females.

What comes next?

Although the findings reveal an important biological pathway, translating them into new treatments will require addressing several challenges.

One possibility is developing therapies that activate the IL-10 pain-resolution pathway, but researchers will need to find a way to sustain the effects once they're in the human body.

Dr. Jaewon Sim suggests that hormone therapy may be one way to achieve this sustained activation. Because androgens regulate this pathway, hormone therapy could potentially keep pain-resolving immune cells active and producing IL-10 for longer. Hormone-based therapies have also shown some promise in pain research. A 2015 study involving 12 women with fibromyalgia reported reductions in musculoskeletal pain following treatment with topical testosterone.

However, hormone-based treatments have important limitations because they affect many biological functions beyond pain. Future treatments will need to target the pain-resolution pathway more precisely while minimizing unintended effects elsewhere in the body.

Another challenge is determining when to activate these pain-resolving immune cells. Because pain resolution is a carefully coordinated process, timing may be just as important as the treatment itself.

Sim explains, "Even beneficial mechanisms may lose their effectiveness, or even become harmful, if they are activated at the wrong time."

When asked whether hormonal changes during menstruation, pregnancy, and menopause might influence pain through other immune pathways, Sim said her team did not observe a significant effect of female hormones on IL-10 production by monocytes or on pain resolution in this study.

Whether female hormones regulate other pain-associated immune pathways remains an open question.
"Investigating additional immune pathways will be a potential direction for future research."

A new perspective on women's pain

​For many years, scientists viewed pain largely as a signal of injury that gradually disappeared as damaged tissues healed. This study challenges that view by showing that recovery is an active biological process involving close communication between the immune and nervous systems.

As Sim explains, "What makes our study different is that we uncovered how the immune system can actively resolve pain."

The findings suggest that differences in the immune system's production of IL-10 may be one reason pain takes longer to resolve in women. While the IL-10 pathway is only one piece of the puzzle, the findings offer new insights into why pain recovery differs between females and males. They also suggest that, rather than simply suppressing immune activity, future treatments may be able to harness the immune system's natural pain-resolving functions, opening the door to new strategies for preventing chronic pain.

Looking ahead, Sim hopes these findings will also improve how pain is perceived and treated in clinical practice.

"A better understanding of sex differences can help dispel harmful misconceptions, prevent women's pain from being dismissed and men's pain from being misdiagnosed, and lead to more effective, personalized treatment," she says.
​
Ultimately, the study offers one possible explanation for why pain may take longer to resolve in women: differences in the immune system's ability to produce the signals that help switch pain off. Delayed pain resolution can increase the likelihood of pain becoming chronic. Understanding these immune differences may help researchers develop better ways to prevent and treat chronic pain. 

By Johina Maria
​Edited by Lauren Koenig

A giant gas planet

Light years away from Earth, the giant gas planet, officially named HIP 99770b, orbits a dusty star much brighter than our sun. Both planets receive a similar amount of sunlight from their host stars. Unlike Jupiter, however, this planet is older than most other worlds discovered so far. Because of its age and slightly cloudy atmosphere, scientists may be able to study this planet to learn how gaseous planets evolve. ​

The hunt for exoplanets

Usually, hunting exoplanets involves scanning the sky, rather than zeroing in on any particular known target.

Planet hunters use a variety of methods to find exoplanets like the radial velocity method, transit photometry or direct imaging. These techniques are also used by surveys, like NASA’s popular TESS Mission, which conduct a blind search for exoplanets. 

The Radial Velocity Method

The Radial Velocity Method is an indirect method to find exoplanets by looking at the colour of the stars as seen from earth. Planets tug at their stars, which slowly affects their speed. Using a spectrograph, the stars subsequently appear redder or bluer depending on whether they are being pushed away from us or towards us - a phenomenon known as the Doppler effect. If there is no change in the star’s colour overtime, we know that there is nothing else exerting gravity nearby. But if there is a slight change in colour, we can conclude the star hosts a small companion - an exoplanet - in close orbit. This radial velocity method was the most popular method to find Jovian exoplanets until 2012. ​

Direct Imaging 

Direct imaging provides the most high-quality, detailed images compared to other methods. These blind search surveys scan the sky for exoplanets and find a few target exoplanets that can be imaged from the earth using ground based telescopes. Many astrophysicists choose which exoplanets to photograph solely based on survey information that reveals how old they are and their mass  this is so they can understand how planets have evolved over time and to study the habitability of earth-like worlds with almost earth-like masses. Just because a planet meets a researcher’s age or mass requirements though, doesn’t mean it will also be easy to capture in a photo.

High-precision astrometry

Fortunately, high-precision astrometry is yet another method that can help overcome the obstacles faced by researchers using direct imaging. High-precision astrometry can pick out stars that host exoplanets by tracing their motion across the sky. Compared to solo stars which tread along under their own pace, stars with exoplanets demonstrate an accelerated speed due to the planet’s gravitational pull. 

Once host stars are identified, their position in the sky and motion can be used to pinpoint the exact location of their resident planets. Then these exoplanets can be imaged directly from the earth to accurately find their mass, age and other intricate information. 

The benefits of high-precision astrometry are being demonstrated by the European Space Agency’s Gaia survey, which is currently mapping the galaxy in intricate detail and providing precise measurements for the position, distance and motion of stars throughout the universe. According to the European Space Agency, this technique enables them to measure the distances of the nearest stars within 0.001% accuracy — a feat similar to measuring the diameter of a human hair from 1000 km away.

Currie and the rest of the research team realized that combining high-precision astrometry with direct imaging would give them the advantages of both - precision of position and accuracy of information.

What this means for planet hunters

Blind search surveys may potentially be able to be abandoned in favor of Curry’s new method, ultimately allowing researchers to learn about exoplanets in striking new detail. HIP 99770b, the cloudy Jovian exoplanet, is a testament that this coupled method works. It allows for targeted searches, drastically cutting costs on exoplanet hunting missions, making exoplanet hunting more accessible than before. 

Researchers may also soon be able to look deeper into space with the advent of even better imaging technology, such as TMT International Observatory’s planned Thirty Meter Telescope, which could open up a whole new pool of exoplanets to be explored. As the search for habitable exoplanets continues, Curry’s method brings us one step closer towards discovering other Earth-like planets that could sustain human life.  ​

​When we think about some of the biggest scientific questions that remain unsolved in the 21st century, we might think about Dark Matter, Quantum Entanglement, and even The Multiverse - concepts that the majority of us might feel distanced from on a daily basis. But what if I told you that amongst those abstract ideas, something as natural and familiar to us as aging can be found on that list? To this day, aging remains one of the biggest mysteries in science.

References

(1) Johannes Gutenberg Universitaet Mainz. “Why we did not evolve to live forever: Unveiling the mystery of why we age.” Science Daily, 15 September 2017, https://www.sciencedaily.com/releases/2017/09/170915144151.htm. Accessed 8 July 2021. 

(2) The Brunet Lab. “Research Interests.” The Brunet Lab at Stanford University, http://web.stanford.edu/group/brunet/research%20interests.html. Accessed 10 July 2021.
 
(3) Harvard Radcliffe Institute. “Anne Brunet.” Harvard Radcliffe Institute, https://www.radcliffe.harvard.edu/people/anne-brunet. Accessed 27 July 2021.

​(4) Stanford University, creator. Stanford Faculty - Meet Anne Brunet. Stanford University, 2014. YouTube, https://www.youtube.com/watch?v=qjCApNPevVU. Accessed 1 July 2021.
 
(5) Simons Foundation. “Anne Brunet, Ph.D.” Simons Foundation, https://www.simonsfoundation.org/people/anne-brunet/. Accessed 4 July 2021
 
(6) Zhang, Siwen, et al. “Caenorhabditis elegans as a Useful Model for Studying Aging Mutations.” Frontiers, 2020, https://www.frontiersin.org/articles/10.3389/fendo.2020.554994/full. Accessed 9 August 2021.
 
(7) Valdesalici, Stefano, and Alessandro Cellerino. “Extremely short lifespan in the annual fish Nothobranchius furzeri.” PubMed, 2003, https://pubmed.ncbi.nlm.nih.gov/14667379/. Accessed 9 August 2021.
 
(8) Yeo, Robin W., et al. “Chromatin accessibility dynamics of neurogenic niche cells reveal a reversible decline in neural stem cell migration during aging.” 2021, bioRxiv, p. 67 https://www.biorxiv.org/content/10.1101/2021.03.29.437585v1.full. Accessed 27 June 2021.
 
(9) National Human Genome Research Institute. “​Chromatin.” National Human Genome Research Institute, https://www.genome.gov/genetics-glossary/Chromatin. Accessed 10 July 2021.
 
(10) Robertson, Sally. “What is the Actin Cytoskeleton?” News Medical Life Sciences, 2019, https://www.news-medical.net/life-sciences/What-is-the-Actin-Cytoskeleton.aspx. Accessed 4 July 2021.

But hurricane seasons like 2020 may become the norm due to global climate change and scientists are working to understand how it contributes to trends in the frequency and intensity of tropical cyclones. Other scientists, are working to understand how societies can manage these risks.
 
New research published in the journal PNAS found that when tropical cyclones strike regional areas with strong, local public services and countries with more effective national governments, they result in fewer deaths, even when taking into account average income and socioeconomic status. This is the first time scientists have been able to disentangle the physical effects of a hurricane from the economic factors that determine how an area will cope during a tropical cyclone disaster.
 
National and Local Data
 
The study's authors, Elizabeth Tennant and Elisabeth A. Gilmore, looked at cyclone data from over 1,000 tropical cyclone disasters that took place from 1979-2016, making it one of the most comprehensive studies to date.  During those years, more than 418,000 people from 85 countries lost their lives to tropical cyclones.
 
To gauge government effectiveness, Tennant and Gilmore used data from the World Governance Indicators project, which capture the quality of public policies and government service delivery. “We were able to look at each storm and determine how intense it was and how many people were exposed,” said Tennant, lead author of the study and a postdoctoral associate at Cornell. Adding in government effectiveness and socioeconomic data then creates a “clearer picture of the relationships between a place, its characteristics, and the outcomes from a disaster event,” said Tennant.
 
Most hurricane research has taken a bird’s eye view when it comes to investigating the effects of hurricanes at the national level. A tropical cyclone, however, is only considered destructive when it coincides with areas where people live. For that reason, Tennant and Gilmore pursued a more nuanced investigation into the quality of local institutions that contribute to hurricane survival.
 
The researchers scored regional vulnerability to hurricanes based on an area’s infant mortality data, which reflects the availability of healthcare and other social safety nets that people rely on to provide help during a natural disaster. If a hurricane hits a community with depleted resources, the consequences will be far worse than if its hits another location that’s more prepared, even within the same country.
 
While this conclusion is intuitive, setting up a model to address this type of variation may help both scientists and governments alike precisely target areas that need shoring up. “Good data and models are essential for studying a wide range of natural hazards, including extreme events, which we expect to increase in frequency and severity under climate change,” said Tennant.  
 
Risk Preparation
 
While this study doesn’t evaluate any particular policies, it does show that when people think about hurricanes, they need to also think about the governments and institutions in power and their approach to tropical cyclone risk. “One of the reasons why we looked at governance and average income, as opposed to hazard-specific features such as the number of cyclone shelters, is because we are interested in the foundational characteristics that help societies adapt to these hazards,” said Tennant.
 
Many people feel barraged and exhausted by the past few months, but it seems unlikely that the entangled nature of modern crises will simplify anytime soon. Science-backed data that supports building the capacity of institutions and governments in this realm may help prepare for similar shocks and stress events, said Tennant. “This is particularly important in this evolving landscape of risk under climate change, globalization, and public health crises.”

​Have you ever been asked if you’re more of a night owl or a morning lark? The choice might actually be a trick question. Scientists are learning that many species are going about their day (and night) far differently than once thought.
 
Mountain lions in Argentina, who typically grab a bite under the cover of darkness, are hunting more during the day and boldly out in the open, according to new research led by Dr. Justine Smith published August 27 in Ecology.

​It turns out this unexpected behavior is the mountain lions’ most recent move in a long-standing strategy game with their prey, vicuñas, the wild cousin of llamas and alpacas. Once vicuñas learned to avoid places where mountain lions hunt at night, the cats realized their best chance at getting a meal meant learning to hunt during the daytime. In spite of mountain lions showing a capacity for being behaviorally flexible, mountain lions that live alongside humans in other parts of the world still have the losing hand unless active measures are taken to share space and natural resources.  

​Tracking and Setup
 
Argentina’s San Guillermo National Park is where Smith, a specialist in human-wildlife conflict at University of California, Davis, does her research. Home to only one main predator and one main prey animal, the park is the next best thing to studying animals in a controlled lab setting. This is a rare thing when studying animals in their native habitat because the complexity of the natural world often makes it difficult to link cause and effect.
 
Smith and her team fitted mountain lions and vicuñas with GPS collars that transmitted data showing where and when the animals moved around the park for nearly three years. They then developed a modeling technique to identify which data points indicate interactions between mountain lions and vicuñas. When the GPS collars sent back signals showing both animals spent several hours in the same place, Smith knew it’s not because they were enjoying quality time together – most likely, the mountain lion was dining on a hard-earned meal.

​
​The vicuñas in San Guillermo National Park usually meet their end at the jaws of a mountain lion. They are the cats’ favorite item on the menu by far; mountain lions actually kill double what they kill in other places with similarly sized prey, although the reason is still unclear.

​Strategy Games
 
The game of cat and mouse, or vicuña in this case, plays out over three distinct landscapes: plains, canyons, and meadows. Mountain lions, who are ambush predators, prefer to hunt at night and in canyons, where they hide behind boulders and are nearly invisible while they stalk their prey. When the time is right, they can leap out from behind a rocky outcrop and catch an unsuspecting vicuña by surprise.
 
To avoid making this fatal mistake, the vicuñas prefer to entrench themselves in the wide-open plains. There is no cover here for a mountain lion. Watchful vicuñas can make a break for it before a mountain lion arrives within striking distance.
 
But safety comes at a cost - the barren plains offer little sustenance for the vicuñas. Eventually, both vicuñas and mountain lions must leave their preferred home base to find food. The only place left to pitch battle is the meadows.
 
While meadows don’t offer the protection of the plains, vicuñas make the best of a bad situation by visiting this food source during daytime hours. Here they can gorge on sweet grass, taking comfort in the general rule of nature that ambush predators are unwilling to risk exposure under the bright light of day. The mountain lions in this park, however, defied the expectations of both the vicuñas and the researchers. With no more food available at night, mountain lions had no choice but to switch up their schedule and begin hunting vicuñas during off peak hours. Relying on the cover of darkness is also not their only trick. Mountain lions are incredibly adept at blending into short, sparse grasslands, seemingly invisible until they ambush the next oblivious vicuña.
 
In the end, neither animal has the perfect strategy in which they can take advantage of their greatest strengths, but both are life-long learners. “It’s not that animals have consistent behaviors and are stuck in those behaviors,” said Smith. The relationship between predator and prey is always evolving.    

​Multiplayer Challenge
 
Smith’s study pushes the boundaries of what we know about animal behavior by looking at how mountain lions evaluate risk and reward and change their behavior accordingly.
 
“This system showed us that when the prey have good information and can only be in risky places during the daytime, it forces the predator to change its strategy,” said Smith. “You now see this new hunting behavior in the daytime…and how prey behavior could change this well-established behavioral profile.”
 
This flexibility might benefit mountain lions in North America as more of their habitat becomes developed by humans. “It’s helpful to know that they’re capable of a lot of different hunting strategies,” Smith stated. If big cats are adaptable, there is greater potential for finding ways to solve human-wildlife conflict.
 
Unfortunately, humans typically put more constraints on where animals feel comfortable, said Smith, who was part of another project showing that mountain lions in California's Central Coast need to hunt more prey to make up for increased activity at night. More animals are becoming nocturnal in order to avoid coming into contact with people, who are most active during the day. Prey animals, like deer, also flock to suburbs where big cats are unwelcome. Mountain lions therefore become more limited both by where and when they can find food. Once there is no common ground between predators and prey, no amount of creativity can help mountain lions survive a wilderness that’s out-of-stock.

Anyone familiar with the history of antibiotics would know that streptomycin was discovered by Professor Selman A. Waksman in 1943. However, Waksman’s claim was countered by his PhD student, Albert Schatz, who requested better public recognition and part of the royalties from the streptomycin patent (1). While reading about the history of streptomycin in Encyclopaedia Britannica, I noticed the name Elizabeth Bugie. Yet, there was no information about her work and why she was listed in this entry. This made me stop and wonder:

Who was Elizabeth Bugie and what part did she play in the discovery of streptomycin?
Why she didn’t become famous for her role?
Is she just one of the many women in science lost to history?

I contacted one of her daughters, Professor Eileen Gregory, who has had a lengthy career as a microbiologist at Rollins College in Winter Park, Florida. She provided me with an article published in the Pittsburgh Post-Gazette about Elizabeth Bugie's death in 2001. In the article, Gregory and her sister, Patricia Camp, talk about their mother’s involvement in the discovery of streptomycin. According to Camp, her mother’s colleagues told her it wasn’t important that her name be on the patent because she would one day get married and have a family. Bugie said later to her daughters, “If women's lib had been around, my name would have been on the patent."

Gregory also helped me to uncover the rest of the story by connecting me with Dr. Douglas Eveleigh from Rutgers University, where streptomycin was discovered. He recently worked with Dr. Joan Bennett to co-author a chapter entitled “Women Microbiologists at Rutgers in the Early Golden Age of Antibiotics” in the book Women in Microbiology published by the American Society for Microbiology. This chapter helps unravel the story about several women who played a key part in contributing to the development of antibiotics – including Elizabeth Bugie.
 
Elizabeth Bugie (October 5,1920 – April 10, 2001) was a master’s degree student at Waksman’s laboratory at Rutgers University who previously completed a bachelor’s degree in microbiology at New Jersey College for Women (today’s Douglass Residential College). Waksman was an established scientist in the field of microbiology and his goal was to find the second clinically effective antimicrobial substance after penicillin. His laboratory efforts led to the discovery of streptomycin - the first antibiotic effective against tuberculosis that was non-toxic to humans. The results were published in the Proceedings of the Society for Experimental Biology where Schatz is listed as the first author, Bugie the second, and Waksman is last author (3). In spite of her authorship on the paper, Bugie’s name was noticeably absent from the patent submission. Waksman alone received the Nobel prize and took all credit for the discovery. Schatz sued him to get his share from the royalties arising from the patent and full recognition for the discovery. Neither acknowledged Bugie as more than just an assistant researcher whose work only confirmed their results (1, 4). Interestingly, his claim contrasts with the fact that Bugie was awarded royalties for her work: although small, she received 0.2% of the streptomycin discovery royalties. Out of the remainder, 3% is given to Schatz, and 10% to Waksman (4, 5).

Bugie was an important member of Waksman’s laboratory. She was an excellent microbiologist who worked on the development of other antimicrobial substances (5). Her master’s degree focused on the optimisation of the production of flavicin and chaetomin isolated from Aspergillus flavus and Chaetomium cochliodes (6) and resulted in two peer-reviewed publications (7, 8). She also isolated and characterised micromonosporin – a pigmented glycoprotein active against gram positive bacteria (9). A notable part of Bugie’s work was her research of antimicrobials against plant pathogens like the ‘elm killing’ fungus Dutch elm disease (10). After leaving Rutgers University she joined the nearby Merck laboratory where she evaluated the activity of penicillin and pyrazinoic acid amide against Mycobacterium tuberculosis (5). “Her studies formed a strong fundamental basis for the early antibiotic studies,” Eveleigh summarized in a personal correspondence.

Most importantly, Bugie pursued lab work because of her love for science and gratitude for the opportunity to conduct research (4). After graduating, she married another notable microbiologist, Francis Joseph Gregory, who was a member of the Waksman team. Bugie changed her last name to Gregory and did what was expected of women during these years – raised a family. She later returned to school to graduate in library sciences (4).

Bugie’s degree choice was quite unusual for that time, so I asked her daughter, Eileen Gregory, what was the reason behind it.

Gregory kindly answered, “I believe that it was my grandfather, Charles A. Bugie, who is responsible for my mother achieving as much as she did. My grandfather believed that education was the key to a successful life. He never had the opportunity to study beyond high school and wanted to make sure that my mother had opportunities that he did not have. He established and ran his own steel company, but I remember him mostly as someone who could build anything and was constantly taking things apart to see how they worked. My mother inherited this curiosity about how things worked and like my grandfather, could fix anything. She had a very analytical mind and loved a challenge. I think that if the field had been open to women she might have pursued a career in engineering or physics. Biology was an acceptable science field for women at that time so that is what she ended up studying.”

I asked Gregory if her mother left any life advice that helped in pursuing her own career. She said, “Like my father, my mother encouraged my sister and I to enter a profession that we enjoyed. I actually started my college career as a theater major. Both my parents supported me in this decision but asked that I just take at least one science course. I took a course in introductory microbiology and found it fascinating and changed majors immediately. I felt that this was a field that I would not only enjoy, but in which I could be successful.”
 
Elizabeth Bugie was an astonishing person who didn’t care for fame, but her contribution to the discovery of antibiotics saved millions of people and is quietly documented in numerous sources. For this, she should be recognized.

I hope that readers will not only learn something new about the history of science, but will remember the wise advice she gave to her daughters.

Acknowledgements: I would like to sincerely thank Professor Eileen Gregory and Professor Douglas Eveleigh for helping me to write this article.
 
References
1. Ginsberg, Judah. 2005. Selman Waksman and Antibiotics. National Historic Chemical Landmark. The American Chemical Society https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/selmanwaksman.html#discovery-of-streptomycin-controversy

2. Encyclopaedia Britannica – Streptomycin
https://www.britannica.com/science/streptomycin

3. Schatz A, Bugie E, Waksman SA. 1944. Streptomycin, a substance exhibiting antibiotic activity against gram positive and gram negative bacteria. Proc Soc Exp Biol Med 55:66 – 69.
http://journals.sagepub.com/doi/abs/10.3181/00379727-55-14461

4. Snowbeck, Christopher. 14 April 2001. Obituary: Elizabeth Gregory: did McCandless woman get fair shake for role in discovery of streptomycin? Pittsburgh Post-Gazette, Pittsburgh, PA.
http://old.post-gazette.com/obituaries/20010414gregory2.asp

5. Eveleigh, Douglas E. and Joan W. Bennett. 2018. Women Microbiologists at Rutgers in Golden Age of Antibiotics. In: Women in Microbiology (eds. Rachel J. Whitaker and Hazel A. Barton), Chapter 34. American Society for Microbiology, Washington, DC.
http://www.asmscience.org/content/book/10.1128/9781555819545.chap34


6. Bugie, Elizabeth J. 1944. Production of antibiotic substances by Aspergillus flavus and Chaetomium cochliodes. M.Sc. Thesis. Rutgers, The State University of New Jersey, New Brunswick, N.J.
https://rutgers.primo.exlibrisgroup.com/discovery/fulldisplay?vid=01RUT_INST:01RUT&docid=alma991014836289704646

7. Waksman, SA, Bugie, E. 1943. Strain specificity and production of antibiotic substances. II. Aspergillus flavus-oryzae Group. Proc. Natl. Acad. Sciences, U.S. 29:282-288.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1078613/

8. Waksman SA, Bugie E.1944. Chaetomin, a new antibiotic substance produced by Chaetomium cochliodes: I. Formation and properties. J Bacteriol. 48:527-30.
https://www.ncbi.nlm.nih.gov/pubmed/16560863

9. Waksman SA, Geiger WB, Bugie E.1947. Micromonosporin, an antibiotic substance from a little known group of microorganisms. J. Bact. 53 355-357
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC518315/pdf/jbacter00655-0111.pdf

10. Waksman SA, Bugie E. 1943. Action of antibiotic substances upon Ceratostomella ulmi. Proc. Soc. Expert. Biol. & Medicine. 54:79-82.

During the battery operation, the electrode components undergo irreversible changes chemically, structurally and morphologically which are harder to pinpoint with presently available tools. Electrode components are made from microsized particles and often nanoparticles (1 nm = 1000,000 times smaller than the thickness of a human hair). A central mechanism that governs all lithium ion type batteries, including the one that we use everyday is, “shuttling of Li – ions between cathode and anode during charge/discharge cycle.
 
What do you infer from the picture below?

A micrometer-sized particle is swelling and breaking apart. And what If I tell you this particle makes the electrode in your cell phone battery? Shocking? What you see is an agglomerate of Ge nanoparticles that form the cathode in Ge-Li battery imaged by transmission x-ray microscopy (TXM) in tomography mode (3D), “in operando” – meaning imaging while the battery is being charged and discharged. As the particles that make up the electrode pulverize, they lose electrical contact with each other, sabotaging battery capacity and lifetime. Ge based electrodes in a Li-ion rechargeable battery could offer four times higher power than the currently used Li-ion battery types. But this irreversible damage of electrodes prevents us from taking advantage of Ge based Li-ion batteries.
 
What makes the particles crack after charging?
 
Upon charging, lithium is released from the anode and it alloys with germanium at the cathode (GeLi4). Since each Ge atoms takes up four lithium ions, volume of the agglomerates increase enormously, fracturing at thinner regions, which the arrows indicate.
 
Look at the colorful picture below showing a series of images, during charging and discharging, of an electrode in a Li-ion battery that we all currently carry in our smart phones.

What you see are agglomerates of LiFePO4 nanoparticles that form the cathode in Lithium phosphate batteries. The images are obtained by (2D) imaging with transmission x-ray microscopy (TXM) and are color coded to distinguish between iron in two chemical states. Fe2+ (as LiFePO4) is green and Fe3+ (as FePO4) is red. Fe3+ (red hue) upon charging, gradually turn into Fe2+ (green hue); the reverse happens upon discharging the battery.
 
What does this mean?
 
In lithium phosphate batteries, while we charge our devices at the power outlet, the cathode, lithium iron phosphate, (shown in the picture) releases Li –ions and electrons that then find their way to the anode (Li –metal) through the electrolyte. While we use the device, Li-ions and electrons revert to LFP electrode – discharging. According to the mechanism, complete discharge of the battery should result in complete red hue and a fully charged battery should be all green. But this is not the case. We see some regions not releasing lithium and regions not receiving lithium back indicating inhomogeneous charging and discharging.
 
Why is the charging/discharging not homogenous? The study hints at the importance of pore structure within the agglomerate.
 
Mechanical cracking and inhomogeneous charging/discharging reduce the capacity as well as lifetime of a battery. This compels battery scientists to find sophisticated tools that can look at the electrode at work with nanoscale resolution. This will help them to understand what happens to the individual nanoparticles and identify suitable electrode pore structures that support uniform charging.
 
Zooming into the region of interest to look at individual nanoparticles is not possible with TXM. This is because the size of the x-ray spot coming out of object is much too large to be focused by the objective lens; x-rays are diffracted around the objective lens aperture edges, making the image blurred.  Extremely complicated lens designs are required to rectify the simple objective lens and it is a big challenge. If we reduce the lens aperture, the image will not receive much light and thus will not have enough contrast. The figure below provides a clear illustration of the diffraction limit that we are talking about. What we need is a nanoprobe with a likely spot size of 100 nm to look at individual nanoparticles (high spatial resolution) and that can reveal structural, morphological and chemical changes during battery charging/discharging.

Spatial resolution depends on the wavelength of the light, angle and aperture.
D= λ/2n sinθ
 
If we look at our currently available options, scanning electron microscopy provides smaller spot size, but is limited to the surface level; as electrons interact strongly with materials and lose their energy during interaction, they never penetrate more than a few nm below the material surface. Deeper probing of micrometer sized agglomerates requires strongly penetrating x-rays, especially at the higher energy end of the spectrum. The good news is that our modern synchrotrons are capable of producing intense tunable x-rays over a wide range of both soft (upto 10 KeV) and hard x-rays (10 KeV and above).
 
X-ray diffraction (crystallography) could in principle provide the material structure at atomic precisions. But again we have a hurdle - related to our ability to extract the information on the precise position of atoms. This is a famous phase problem that has yet to be solved. In simple terms, when x-rays encounter an obstacle like an atom in a material, the photons get scattered. While the intensity of the scattering photons can be measured, the angle at which the x-ray photons are scattered is lost. Subsequently the information on the precise positions of atoms is lost. The structure of the object is only obtained by a trial and error method using approximations and refinement procedures.
 
An emerging technique called x-ray ptychography is able to tackle the issue of optical elements and phase problem with a few tricks of the trade. Stanford Researcher Dr. Johanna Weker, at the SLAC National Accelerator Center, investigates degradation of battery materials using x-ray ptychography. The technique has proven its potential to reveal bulk material structure at nanoscale resolution.

What is Ptychography anyway? Heard of photography, holography, tomography and a moment ago crystallography. How does ptychography work? In fact, ptychography is in a way related to all of them. “Ptycho” from Greek means, “fold”. Invented by Walter Hoppe, a German Physicist. The name derives from the optical configuration used n the experiment and in x-ray ptychogrphy, it means - interference between two Bragg reflections from coherently illuminated overlapping spots.
 
Ptychography combines the strengths of two different techniques – coherent x-ray diffraction and scanning x-ray microscopy. What do we need to perform ptychography experiment? - Coherent x-rays and suitable algorithms for data refinement.

Ptychography addresses the two challenges – suitable objective lens and phase problem, in obtaining x-ray vision of materials in a very smart way.
 
Solve challenge 1: Probe on nanoscale
 
It is hard to manufacture complex objective lens for nanometer resolution. Okay, let’s eliminate the objective lens. The reward is almost 50% gain in the image brightness or contrast. Since no objective lens is used, the resolution is limited only by the wavelength of the x-ray. To compensate for the objective lens, the x-rays must be coherent – both temporally and spatially. We need monochromatic (temporally coherent) x-rays confined by pinholes or slits (spatially coherent). This is already achieved. X-rays produced at the synchrotron beam lines in bending magnet configuration are coherent (to certain extent). We can look into the material in detail to distinguish structures that are even 2nm (soft x-ray ptychography) and 10 nm (hard x-ray ptychography) apart. We have coherent x-rays and diffraction limit is not an issue anymore. Recently developed scanning transmission x-ray microscope operates also without objective lens (but the resolution is limited due to microscopy mode).
 
 
Solve challenge 2: Detection
 
Help from scanning x-ray microscopy solves the second challenge, the phase problem - indirectly. Obtaining absolute phases that is, the angle at which the x-rays are diffracted, is lost. There is no way to obtain the information that is lost.  Then what is the Ptychographic trick? It is to measure diffraction patterns from two individual points (A and B for example) with the illumination overlapping  (“fold”) by 50%. With the help of Iterative algorithms, absolute phase of the overlapping region, C can be guessed from diffraction pattern at A and diffraction pattern at B, individually. Here spot B serves as a feedback center while guessing the structure from diffraction pattern at A and vice versa. This way errors occurred while assuming the structure at the spot A can be eliminated. Of course, more spots will improve accuracy. We should note that the region C contains crucial information. Structure of the material at the spot A and B is thus imaged. By scanning the material spot by spot the entire material can be imaged with nm accuracy (theoretically 10 nm – 0.1nm, depending on the x-ray energy).

Essentially, x-ray ptychography is nothing but STXM operating in ptychography mode.

What are the demonstrated capabilities of x-ray ptychography? What does an x-ray ptychography image look like?
 
With x-ray ptychography, chemical and structural information can be extracted even for thick samples (micrometer) with unprecedented spatial resolution. X-ray ptychography is most desirable in detecting elements with lower atomic mass such as carbon, nitrogen and oxygen where conventional fluorescence techniques fail due to low fluorescence yields.
 
In ptychography, one can obtain something called optical density image that reveal morphology of the nanoparticle such as cracks. Look at the power of ptychography (a) in revealing cracks in a sample of lithium iron phosphate sample compared to STXM (b), around 700 eV x-ray energy.

Here are optical density images of lithium iron phosphate nanoparticles obtained from STXM (a) and ptychography (b). Clearly ptychography image indicates multiple particles (outlines) and cracks (red arrows) while STXM could show only a blurred image. Combining chemical imaging with optical density map is extremely revealing. Color-coded optical density map below distinguishes regions containing LiFePO4 (red) and FePO4 (blue) in lithium iron phosphate battery.

Since ptychography set-up is very similar to that of STXM, modifying already existing STXM layout at the beam lines with new hardware is sufficient. Effort is required to create suitable software to collect diffraction data and reconstruct the diffraction patterns so the material structure can be evaluated, but can be achieved. Hard x-ray ptychography is now well established while soft x-ray ptychography is still under development.
 
An interesting application of x-ray ptychography is in biological sciences. Recently, (low atomic mass) elemental distribution in frozen algae was obtained using x-ray ptychography. 3D structure determination is another attractive feature of x-ray ptychography that is emerging. Apart from biologists, additive manufacturing research can greatly benefit from this method. X-ray ptychography is a boon to nanoscience.

About the Author
Dr. Vijayalakshmi (Viji) Kalyanaraman is a part-time chemistry instructor and a freelance editor. She received her PhD from the University of Hamburg, Germany for investigating interfacial electron dynamics using synchrotron x-rays. She also enjoys communicating scientific research to the general audience through blogs.