Why Do Girls Like Pink? (Neuroscience)

Recent research on gender development is reviewed.

In a recent article, published in the November 2020 issue of Neuroscience and Biobehavioral Reviews, Melissa Hines of the University of Cambridge reviews the latest findings on the development of gender, such as the role of testosterone and socialization and how the two interact (e.g., why girls tend to like the color pink). The present post is a selective summary of this review.

Girl in a pink dress ©Freedesignfile

Testosterone and gender development

Let us begin with hormones. Hormones can have a temporary effect on development—an effect that rises and falls depending on the hormone concentration. For instance, estrogen has feminizing effects (e.g., breast development) at puberty.

Hormones can also have organizational influences, causing changes that persist even when the hormone is no longer present.

Testosterone is one hormone with such organizational influences.

Consider the effects of testosterone early in life. The concentration of testosterone is much higher in males than females, particularly from week 8 to week 16 or 24 of pregnancy, and from the first to the third month of infancy.

These are probably the critical periods during which testosterone causes sex-related organizational influences, ultimately reducing female-typical and increasing male-typical behaviors.

Since testosterone influences attributes that show sex differences, it may be helpful to know which behaviors show the largest average sex differences. Those would be gender role behaviors (e.g., preferred toys, sex of playmates), sexual orientation, and gender identity (one’s sense of self as female or male or both). Other characteristics often showing large sex differences include cognitive spatial abilities, empathy, dominance, and physical aggression.

Most of the findings on the effects of testosterone come from animal research or the study of genetic variations in humans. One such genetic variant is congenital adrenal hyperplasia (CAH).

CAH is associated with high levels of testosterone exposure. Compared to unaffected females, females with CAH show more male-typical gender role behaviors and are more likely to be bisexual or homosexual. It has been estimated that about 2 percent ultimately identify as men, which is a much larger percentage than the overall population estimate.

Socialization and gender development

Early testosterone exposure is not the only factor influencing gender behavior. Both self-socialization and external socialization are important too.

External socialization refers to the effects of encouragement of particular kinds of activities by other people (e.g., parents, friends, classmates, teachers).

For example, parents often buy their children toys perceived as gender-appropriate. A recent study of the room contents of 2- to 6-year-old American children found “boys’ rooms contained more play guns, tools, and machines for pretend play; spatial-temporal objects; sports equipment; and vehicles,” while “girls’ rooms contained more dolls, costume jewelry and dress-up clothes, ruffles, and floral furnishings.”

Once they know their sex, children also self-socialize, meaning they imitate the choices of people of their own sex in order to behave in ways expected of them. For instance, they prefer activities and objects favored by those of their sex and show a liking of objects they are told are for their sex (e.g., “dolls are for girls, not boys”).

Interactions of testosterone and socialization: Pink vs. blue

Gender development is also shaped by the interaction between socialization and testosterone. A good illustration concerns color preference (i.e., pink for girls and blue for boys).

Color preference appears to be mostly absent in children younger than 2, even though they seem to show a preference for gender-typical objects (e.g., toys vs. dolls).

The gender difference in color preference seems to emerge between ages 2 and 3. During the next couple of years, this difference becomes larger as children become more deeply aware of themselves as boys or girls, “learning that this will not change over time or if they engage in other-gender activities.”

By adulthood, the pink/blue color preference shows less of a sex difference. Though women, compared to men, still show a marginally greater preference for pink, both male and female adults prefer blue to pink.

This suggests a female preference for pink is not hardwired or sculpted by evolution. So how does this interest for pink develop?

One theory suggests color preference results from the association between colors and emotionally pleasant experiences. And this is partly due to socialization.

Specifically, as Hines notes, “children may learn to like the colors of the toys that are typed for their own sex, pink for girls, and anything but pink for boys, contributing to the stronger preference for pink in girls than in boys.”

In addition, “Girls also may identify strongly with their assigned sex during early childhood, and so may show particularly strong preferences for pink compared to older ages.”

The female preference for pink declines over time as girls have more opportunities to engage with objects not color-coded for their use and as they develop a deeper understanding of their gender.

Concluding thoughts on gender development

Some people believe gender-related behaviors are mainly caused by biological factors (nature), while others believe they are mainly caused by social and environmental factors (nurture).

However, if we were to think of gender-related behaviors in developmental terms, we could see how gender development is affected by numerous influences that interact. An early change in one part of the system, especially during critical periods in development, might significantly reduce or increase the effect of another factor later on.

These changes might concern seemingly trivial differences, like color preference (pink vs. blue), or more significant ones, like empathy, spatial ability, and aggression.

This article is originally written by Arash Emamzadeh and is republished here from psychology today under common creative licenses. To read original click here.

Low Blood Pressure During Hemodialysis May Indicate Peripheral Vascular Disease (Medicine)

Using a large nationwide registry of patients receiving maintenance hemodialysis, this study published in the American Journal of Kidney Diseases found that higher frequency of low blood pressure episodes during hemodialysis was associated with a higher incidence of diagnosed peripheral arterial disease.

Peripheral artery disease (PAD) is a condition characterized by progressive atherosclerotic narrowing or occlusion of the arteries, particularly to the lower extremities. PAD often goes undiagnosed in patients with kidney failure who may not experience traditional symptoms of claudication. It is plausible that sudden reductions in blood pressure as occurs during intradialytic hypotension (IDH) could reduce limb perfusion and lead to more PAD events or exacerbate PAD symptoms. Using a large nationwide registry of hemodialysis patients and the electronic health records of a large dialysis provider, researchers found that more frequent IDH was associated with a higher incidence of recognized PAD.

These results suggest that patients with more frequent IDH warrant careful examination for PAD such as foot examinations or other diagnostic evaluations.

Reference: Eun Young Seong, Sai Liu, Sang Heon Song, Wolfgang C. Winkelmayer, Maria E. Montez-Rath, Tara I. Chang, “Intradialytic Hypotension and Newly Recognized Peripheral Artery Disease in Patients Receiving Hemodialysis”, AJKD, 2020. https://www.ajkd.org/article/S0272-6386(20)31138-0/fulltext https://doi.org/10.1053/j.ajkd.2020.10.012

Provided by National Kidney Foundation

Why Are We Reluctant to Ask Why? (Psychology)

How can you ask the question “Why?” without shutting down the conversation?

We stop asking the question “Why?” about the time we begin to think we understand it all. This usually occurs in adolescence. Once the adolescent attitudes begin to mature into adulthood, it should be time to begin asking why again. Once the realization occurs that no one has all knowledge, it should become easier to ask questions — including why questions. Yet, we are told that the question “why” will shut down the person being asked and so you should avoid it. What else might it shut down? 

Waves Unspoken. Source: Madelyn Blair

In my work, I’ve always been told that I should avoid asking the question “why.” I was told it makes people uncomfortable. Yet, we all begin our lives as young children by asking why about anything, such as, “Why are there so many people who don’t know me?” “What does ‘kind’ mean?” or “Why do trees just stand there?” Other questions are a daily occurrence. And as one author put it, “One day the flow of questions will stop, but of course even as adults, we’re still searching for the answers.”

Children like to know why things are as they are. What am I saying? All of us like to know why things are as they are. Yet, for some reason, we stop asking why. Fortunately, scientists are always asking this question, which is why we understand so much about the universe. Deep down, the question of why comes from our curious nature to know more about something.

The effect is that people stop asking questions. If you have to edit your question so as not to ask “why,” does it also edit your thinking so that you eventually stop thinking?

When I teach graduate students, I use their questions as a measure of their thinking. Eventually, they have to write or do something, but up to then, the best measure is their questions. Even a comment in class can reflect reading from somewhere else. I am interested in what the student is thinking for themselves. So, I listen to their questions the first signal of how they are thinking. 

Assuming for the moment that what I am saying has relevance, I have to believe that if my students or audience are not asking questions, it must be that someone or something suggested that asking questions was a dangerous pursuit.

How often have I met a leader who says, “Remember, there are no stupid questions.” When I hear that, I am not inspired to ask anything. Once I recognized this in myself, I began to change the way I asked for questions during class or after a speech. As a result, I say something like, “A question just means you want more information. What more would you like me to explore?” I hope that says I’m really interested in learning what others are looking for. It’s so easy — so why do people still feel reluctant to ask why? 

How can you ask the question “why” without the “why?”

Let’s look at some examples. Maybe the reluctance to ask why questions is because some people use that question as an easy way to put an issue on the table (“Why can’t these politicians solve global warming?”). Or we might use why questions to appear smart (“Why did we choose this product?”). Or they want to derail a meeting by asking a question that has already been answered (“Why have you called this meeting?”). Or they are too lazy to explore in their minds what they are really interested in knowing (“Why?”). Or they don’t want to take any responsibility in the answer (“Why am I spending my time here?”). I suspect you have heard these kinds of questions. No wonder the warning is given. 

Hopefully, as we become more experienced, we learn how to ask the “why” question indirectly. Moreover, we can ask so that we become involved in the answer. This says that while I am asking a question, it is because I am a part of the conversation and part of the answer as well. For example, “What you are saying is [use your favorite word, e.g., exciting, interesting, fascinating] to hear. Please tell me the steps that led you to this conclusion.” By sweetly asking the question “why” while taking away the judgment and putting ourselves in the middle of the answer, we may even bring the question to a deeper level. 

Using the earlier examples, let’s see how they can be shifted as well so that the judgment dimension is diminished or eliminated entirely. 

Reason for asking why is to put an issue on the table  

Original “why”: Why can’t these politicians solve global warming?

Alternative question: I’m curious about the deeper concerns that hold politicians back from addressing global warming. 

Effect: This approach shifts the conversation to one that is not judgmental and might actually be helpful by exploring another dimension.

Reason for asking why is to appear smart  

Original “why”: Why did we choose this product?

Alternative question: This product looked good in the beginning. As I review the original reasons for doing so, they are coming up short. How do others see the decision?

Effect: This approach brings more voices to the concern without judgment.

Reason for asking “why” is to derail a meeting by asking a question that has already been answered 

Original “why”: Why have you called this meeting?

Alternative question: I’m confused; would you please remind me of our purpose for this meeting?

Effect: This approach puts you in a vulnerable posture (I’m confused) which removes judgment from the question and frees the leader to review the purpose and its reasoning.

Reason for asking “why” is to avoid thinking of what they are really interested in knowing 

Original “why”: Why?

Alternative question: Can you tell me more about (fill in the blank)?

Effect: This approach tells the speaker you are not just interrupting but interested in something specific.  

Reason for asking “why” is to remove any responsibility in the answer  

Original “why”: Why am I spending my time here?

Alternative question: I feel I can’t contribute to the objectives of this meeting. Please tell me what you hope I bring to this meeting?

Effect: This approach can actually elicit the real purpose of your presence and may even catch you out as, hopefully, the expected contribution may be reasonable and appropriate.

Is there more to be lost if we don’t ask? 

In not asking why, I wonder if we have also stopped asking questions in general. Are we living on assumptions we made years ago? Are we basing our actions on previous experiences and never questioning that those early experiences no longer exist? Or are we satisfied only to ask who did something, when did that happen, or how can I get that refund? These are all practical questions, but are we losing opportunities to learn more deeply as we carefully avoid asking why and curb and limit the kinds of questions we ask? Ask yourself if you are stunting your thinking as well. 

One of the practices that I recommend to those who wish to enhance their resilience is to ask questions. Asking questions is the first step to nurturing curiosity and pushing our knowledge to a new level — and in-depth knowledge is a trait of resilient people. Curiosity, after all, it’s the engine of learning. 

Is there something you can do right now?

We’ve seen that asking questions — especially the right questions, can lead to a new understanding of an issue that may have been obscured by confusing facts, conflicting opinions, or obsolete assumptions. If there is one lesson I have learned is that I need to be asking more questions; even challenging myself to see if I can ask a better question, a more important question, or a question that will deepen the conversation and challenge even my own thinking. 

Powerful questions are really doorways leading toward the more resilient and vibrant life you want to lead. 

In any event, asking questions, along with enhancing resilience, opens possibilities. And when we are in a moment when we have been pummeled by the unexpected, it’s great to be ready with more possibilities from which to choose our response — resiliently. 

Think of a time when you encountered something that simply piqued your curiosity. You just had to learn more. Perhaps it was when you met a new person over a Zoom call who said something intriguing. Think about how you realized the questions that were bubbling up in your mind. Think about what you did to satisfy the questions — or not! Spend time today looking at the world from the perspective of what more might you like to know about what you are seeing. What assumptions are you making that might have snuffed out your curiosity? Formulate questions that would tell you what you would like to know. At the end of the day, consider how differently you saw the world through curious eyes. 

I’d love to hear about your experiences of asking questions that carry no judgment. Please comment here, and I’ll join the conversation. 

References: [1] Kelly O’Brien (March 22, 2017). How Does Life Live?, NYT Op-Doc https://www.nytimes.com/2017/03/21/opinion/how-does-life-live.html

This article is originally written by Madelyn Blair, and is republished here from psychology today under common creative licenses.

How Inner Crust of Neutron Star Affects Its Radius? (Astronomy)

Lopes and colleagues studied how the small contribution of the inner crust to the total equation of state (EoS) of a neutron star affects its mass-radius relation, focusing on the canonical mass of 1.4 M.

The neutron star can be divided in four distinct regions: outer crust, inner crust, outer core and inner core.

Graphical abstract by nature

The outer crust is the region understood between 10-¹⁴ fm-³ ≲ n ≲ 10-⁴ fm-³, where the ground state of nuclear matter is at which all neutrons are bound in nuclei, and that it forms a perfect crystal with a single nuclear species, (number of neutrons N, number of protons Z), at lattice sites.

The inner crust is the region comprehending around 10-⁴ ≲ fm-³ ≲ n ≲ 10-¹ fm-³. Here, very neutron rich nuclei are immersed in a gas of dripped neutrons.

If the density is high enough (around 0.06 – 0.1 fm-³) the surface and Coulomb contributions can be ignored and the matter can be approximate by an infinite and uniform plasma of interacting protons, neutrons and free electrons (and muons if the electron Fermi energy is high enough) in chemical equilibrium. This is the outer core. Therein exist a very special point: the nuclear saturation density: n0 (0.148 – 0.170 fm-³). From this point, the nuclear forces become repulsive instead of attractive.

The region with n > 2 n0 is called inner core. At such densities new and exotic degrees of freedom can be present.

It is well accepted that the symmetry energy slope at the saturation density – which correspond to the outer core region – is the main responsible to control the neutron stars radii. Although some studies suggest that this cannot be the whole history, it is undeniable that the symmetry energy slope plays more than a significant role.

In the present work, nevertheless, Lopes and colleagues however explore another region of the neutron star: the inner crust. Instead of build a model for it, they study only its behaviour, using an empirical parametrization for the EoS: p(∊) = K.∊^γ + b in the range of 0.003 fm-³ < n < 0.08 fm-³, where they varying the value of γ and determine the value of the constants K and b in order to keep the EoS continuum. Also, in order to gain physical insight, they calculated the speed of sound of the inner crust. They showed that although for all γ values they always have a monotically increasing EoS, they have very distinct behaviour for the speed of sound as well different values of the radius of the canonical mass.

FIG. 1. (Colour online) Square of the speed of sound in the parameterizated inner crust for different values of γ.
FIG. 2. (Colour online) Mass-radius relations for different values of γ. The light blue (yellow) hatched region correspond the credibility interval of 68% (95%).

They see that different behaviours of the speed of sound can affect the radius of the canonical star by more than 1.1 km. They concluded that this result can help us understand extreme results as GW170817, where some studies indicate that the radius of the canonical star cannot exceed 11.9 km.

Reference: Luiz L. Lopes, “The neutron star inner crust: an empirical essay”, ArXiv, pp. 1-5, 2020. https://arxiv.org/abs/2012.05277v1

Copyright of this article totally belongs to our experienced researcher S. Aman. One is allowed to use it only by proper credit either to him or to us.

Pitt Scientists Identify Genetic Risks of Rare Disease (Medicine)

In a paper published today in the American Journal of Human Genetics, a group of international collaborators led by researchers from the University of Pittsburgh School of Medicine identified new genetic associations that can predict individual susceptibility to a rare inflammatory disease called Takayasu arteritis.

Professor of pediatrics and medicine, University of Pittsburgh, and chief, Division of Pediatric Rheumatology, UPMC Children’s Hospital of Pittsburgh. © UPMC

The study, conceived by Amr Sawalha, M.D., professor of pediatrics and medicine at Pitt, and chief, Division of Pediatric Rheumatology, UPMC Children’s Hospital of Pittsburgh, accumulated samples from 1,226 individuals with Takayasu arteritis across five different populations around the globe, making it the largest collection of these samples in the world.

In Takayasu arteritis, inflammation damages the aorta and other large vessels, which can lead to rupture of major blood vessels or decreased blood supply to the limbs, brain and other vital organs and puts patients at risk of a heart attack, stroke or major blood loss and organ damage.

“Many of us who treat patients with Takayasu arteritis are frustrated because we don’t really know how the disease works,” said Sawalha. “We don’t have good tools to predict a disease flare-up. Some patients have very active disease without clear symptoms or an increase in inflammatory markers.”

By performing a genome-wide association study in healthy people and Takayasu arteritis patients, the researchers identified variations in several regions of the genome suggestive of the role of certain immune cells in this disease. They also identified novel molecules and pathways that can be targeted for therapy.

The team went on to compare the genetics of Takayasu arteritis with genetic predisposition to hundreds of other traits, assessing shared genetics between Takayasu arteritis and other immune-mediated diseases.

“We found that, genetically speaking, Takayasu arteritis was closest to Crohn’s disease,” said Sawalha. “This suggests that we can try developing treatments based on what we know works for inflammatory bowel disease, which is a much more common condition.”

Until this report, knowledge about the genetic predisposition to Takayasu arteritis was extremely limited, due to difficulty collecting a large enough number of samples to represent the genetic architecture of ancestrally diverse populations.

This study was made possible only because of international collaborations, said Sawalha. His group gathered samples and data from patients in Turkey, Canada, China, Italy, the United Kingdom and across the U.S., and included patients from populations under-represented in genetic studies.

In the future, scientists hope to use their data to find genetic determinants of how the disease manifests itself–which individuals are more likely to develop severe disease, which arteries might be affected and which patients are more likely to carry the disease silently without presenting easy-to-identify molecular markers.

“This study opens a lot of possibilities,” said Sawalha. “Expanded knowledge of the genetic component of Takayasu arteritis will help us develop more effective therapies moving forward.”

Other authors on the manuscript include Lourdes Ortiz-Fernandez, Ph.D., of Pitt; Haner Direskeneli, M.D., of Marmara University in Turkey; Peter Merkel, M.D., M.P.H., of the University of Pennsylvania; Justin Mason, M.D., Ph.D., of Imperial College London; Lindi Jiang, M.D., Ph.D., of Fudan University in China; and Enrico Tombetti, M.D., of University of Milan, among 71 total authors. 

This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants R01 AR070148, U54 AR057319, U01 AR51874 04), the National Center for Research Resources of the National Institutes of Health (U54 RR019497) and the Office of Rare Diseases Research of the National Center for Advancing Translational Sciences. Additional support was provided by Imperial College London, National Institute for Health ResearchBiomedical Research Centre, the Wellcome Trust (WT107881) and the Medical Research Council (MC_UU_00002/4).

Provided by UPMC

About the University of Pittsburgh School of Medicine

As one of the nation’s leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.

Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region’s economy. For more information about the School of Medicine, see http://www.medschool.pitt.edu.

About UPMC Children’s Hospital of Pittsburgh

Regionally, nationally, and globally, UPMC Children’s Hospital of Pittsburgh is a leader in the treatment of childhood conditions and diseases, a pioneer in the development of new and improved therapies, and a top educator of the next generation of pediatricians and pediatric subspecialists. With generous community support, UPMC Children’s Hospital has fulfilled this mission since its founding in 1890. UPMC Children’s is recognized consistently for its clinical, research, educational, and advocacy-related accomplishments, including ranking in the top 10 on the 2020-2021 U.S. News & World Report Honor Roll of America’s Best Children’s Hospitals. UPMC Children’s also ranks 15th among children’s hospitals and schools of medicine in funding for pediatric research provided by the National Institutes of Health (FY2019).

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New Analysis Method for Predicting The Risks and Effects of Immunotherapy (Medicine)

In a new study, researchers at Uppsala University have been able to show differences in how rituximab, a monoclonal antibody drug, interacts with the blood of healthy individuals compared to patients with chronic lymphatic leukemia. This has awakened hopes that this analysis method could pave the way for important breakthroughs in immunotherapy research and treatment.

Immunotherapy—using the body’s own immune system to combat tumor cells—is an area in which rapid progress is being made. Many new treatments are helping to increase survival rates among cancer patients, but more effective tools are still needed to predict how these drugs will affect an individual’s immune system. In a new study at Uppsala University, researchers compared what happens when Rituximab monoclonal antibodies interact with the blood of healthy individuals and of patients with the disease that the monoclonal antibodies are intended to treat. The results showed that the immunological activation markers differ between the groups—an observation that could enable new scientific breakthroughs.

“Rituximab is used to treat a range of diseases in which B cells are malignant or growing out of control. The monoclonal antibody binds to the CD20 protein expressed on the B cell and draws natural killer (NK) cells, a part of the immune system, to the site which then help to kill the B cell. The action of Rituximab is specific with few side effects, but when it binds to B cells it can also activate proteins in our blood that signal danger. This can cause Cytokine Release Syndrome (CSR)—normally with mild symptoms in the form of nausea and fever, but it can also become life-threatening. This unpredictability is a major challenge, but the results from our study show that our analysis method can provide patient-specific information and thus become an important tool for the whole immunotherapy field if we are able to understand the individual’s specific response to a given antibody-based therapy,” says Sara Mangsbo of the Department of Pharmaceutical Biosciences.

In their study, the researchers used a complete human whole blood model to analyze the immune response, and the efficacy and toxicity of treatment with Rituximab. In healthy individuals, only a reduction in the number of B cells was observed. In patients with chronic lymphatic leukemia, however, a variable reduction in the number of B cells as well as CRS were observed—except in one patient who had no NK cells. The results increase our understanding of what happens when Rituximab encounters blood from patients with chronic lymphoid leukemia.

“Immunotherapy is being used more and more frequently to treat various kinds of cancer, but we need better methods to predict the effect and risk of side effects in individual treatment recipients before the start of treatment. Analysis tools such as this potentially have great value for both the healthcare system and patients,” says Mattias Mattsson, consultant physician at the Uppsala University Hospital Haematology Clinic and co-author of the article.

The use of a human whole blood model means that the analysis takes into account all the immune cells circulating in the blood, as well as the many proteins and metabolites present in the blood serum. The method thus adds a new dimension to the analysis results that to date has not been reliably captured by the available methods, which are based on purified cells or serum components.

“Understanding the mechanisms and resistance associated with monoclonal antibody-based drugs requires physiologically relevant tools and methods. Here, in collaboration with Uppsala University, we have studied how the blood loop can be used for the immuno-profiling of blood and drugs. The results show that there is a disease-specific immune response when blood and drugs interact. This indicates that the blood loop can be used for individual treatment and preclinical studies to identify and understand the toxicity risks for monoclonal antibody-based drug candidates,” says Mark Cragg, co-author and Professor of Experimental Cancer Research at the University of Southampton.

The method also involves a further step in being able to study monoclonal antibodies without the need for animal studies. The study is based on the group’s previous work, which was carried out with financial support from the Swedish Research Council’s funding for 3R projects, which aim to replace, reduce and refine animal experiments.

“Our results show a clear way forward. More extensive studies in specific patient groups are needed now to increase our understanding of how individual immune systems will react to both Rituximab and other monoclonal antibodies. In the long term, we hope to take the method all the way to clinical trials as well as to the healthcare system in order to provide a better answer to which patients will respond well to specific immunotherapy treatments,” says Sara Mangsbo.

Reference: Profiling of donor-specific immune effector signatures in response to rituximab in a human whole blood loop assay using blood from CLL patients. International Immunopharmacology. doi.org/10.1016/j.intimp.2020.107226

Provided by Uppsala University

New Insights About Age-related Macular Degeneration Could Spur Better Treatments (Medicine)

“Wet” age-related macular degeneration (AMD) is one of the most common causes of irreversible vision loss in the elderly, and it occurs when abnormal and leaky blood vessels form in the retina, in part due to inflammation. New research by investigators at Massachusetts General Hospital (MGH) reveals insights into potential drivers of the disease—which currently has no cure—that could be targeted through prevention or treatment strategies. The findings are published in eLife.

Two inflammatory pathways involving complement (which is an immune system component) and a protein complex called the inflammasome (which, as its name suggests, triggers inflammation) promote the formation of abnormal blood vessels that are hallmarks of wet AMD, but it’s unclear how these pathways are activated. Previous studies suggest that the inflammasome may be activated by a protein called NLRP3, mainly in the retinal pigment epithelium of the eye (a cell layer that separates the vascular layer of the eye from the retina).

To investigate further, researchers conducted experiments in a mouse model of wet AMD. The team showed that inflammasome activation by NLRP3 occurs mainly in cells called macrophages and microglia, but not in the retinal pigment epithelium. The scientists also discovered that proteins other than NLRP3 can lead to inflammasome activation and worsening of wet AMD.

“This means that rather than targeting only NLRP3 in wet AMD, it may be beneficial to block essential proteins of the inflammasome instead that are required for its activation, independently of whether NLRP3 or other proteins initiate inflammasome activation,” explains senior author Alexander G. Marneros, MD, Ph.D., a principal investigator at MGH’s Cutaneous Biology Research Center and an associate professor of Dermatology at Harvard Medical School. “Our findings provide guidance on how to block inflammasomes in wet AMD.”

Marneros notes that previous studies conducted in cells suggest that complement activation can in turn lead to inflammasome activation, but this study in mice found that this activation occurs largely independently from complement-mediated inflammation. “Our study in a mouse model defines the cell types that contribute to inflammasome-mediated inflammation in wet AMD and uncovers the specific roles and contributions of NLRP3 inflammasomes, non-NLRP3-inflammasomes, and complement for the manifestation of wet AMD,” he says.

In addition to providing new insights into how inflammation is regulated in wet AMD, the study also suggests that novel therapies that block inflammasome-mediated inflammation could be improved when combined with treatments that inhibit complement-mediated inflammation. “A combined therapeutic approach that blocks both these inflammatory pathways is likely going to have synergistic effects in lessening the symptoms of wet AMD. Thus, our findings in this mouse model may have important clinical relevance for novel therapies for this common blinding disease,” says Marneros.

Reference: Jakob Malsy et al, Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization, eLife (2020). DOI: 10.7554/eLife.60194

Provided by Massachusetts General Hospital

Gene Could Help Predict Response to Cervical Cancer Treatment (Medicine)

UCLA researchers have identified a potential diagnostic marker that could help predict how likely someone with cervical cancer is to respond to the standard treatment of chemotherapy and radiation.

©Parkway

The scientists found that PACS-1, a gene that resides on a small segment of the long arm of chromosome 11, is overexpressed in cancer tissues, which can result in cancer growth and spread. Further, they discovered that translocation of the PACS-1 protein from outside to inside the cell nucleus—a function required for normal cell growth—plays a role in the development of cervical cancer that is resistant to chemotherapy and radiation. Higher levels of PACS-1 expression in the nucleus could indicate resistance to the treatment, the researchers say.

Cervical cancer is the second leading cause of cancer-related death among women worldwide. While infection with human papillomaviruses plays a significant role in cervical cancer development, the presence of a virus alone is not enough to cause cancer; genetics and environmental factors such as smoking and poor eating habits also play a role. Therefore, it is important to identify biological markers as targeting agents for diagnosis and treatment.

The researchers performed a western blot, a technique for detecting specific protein molecules from among a mixture of proteins, on cervical tumors and healthy cervical tissue and discovered an overexpression of PACS-1 in the tumor tissues. The team then developed in vitro human cell line models to assess the protein’s role in cell growth. Finally, they used a fluorescence-activated sorter analysis to help determine if the overexpression of PACS-1 protein was associated with cancer chemo resistance.

If confirmed in animal studies, the use of PACS-1 as a diagnostic marker could help lead to the development of therapeutic strategies to overcome treatment resistance in cervical cancer. Alternative methods of treatment, including the inhibition of PACS-1 expression, could be used in combination with chemotherapy or immune system-activating agents.

The study’s senior author is Eri Srivatsan, a professor of surgery at the David Geffen School of Medicine at UCLA and member of UCLA’s Jonsson Comprehensive Cancer Center and Molecular Biology Institute. The first author is Mysore Veena, a scientist at the Geffen School of Medicine.

Reference: Mysore S. Veena et al, Dysregulation of hsa-miR-34a and hsa-miR-449a leads to overexpression of PACS-1 and loss of DNA damage response (DDR) in cervical cancer, Journal of Biological Chemistry (2020). DOI: 10.1074/jbc.RA120.014048

Provided by University of California, Los Angeles

Study Reveals Surprising Variability of Muscle Cells (Medicine)

Usually, each cell has exactly one nucleus. But the cells of our skeletal muscles are different: These long, fibrous cells have a comparatively large cytoplasm that contains hundreds of nuclei. But up to now, we have known very little about the extent to which the nuclei of a single muscle fiber differ from each other in terms of their gene activity, and what effect this has on the function of the muscle.

In this single muscle fiber, a multitude of nuclei can be clearly seen. The researchers used DAPI for staining, it stains the DNA in the nuclei blue. Credit: C. Birchmeier Lab, MDC

A team led by Professor Carmen Birchmeier, head of the research group on Developmental Biology/Signal Transduction at the Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC), has now unlocked some of the secrets contained in these muscle cell nuclei. As the researchers report in the journal Nature Communications, the team investigated the gene expression of cell nuclei using a still quite novel technique called single-nucleus RNA sequencing—and in the process, they came across an unexpectedly high variety of genetic activity.

Muscle fibers resemble entire tissues

“Due to the heterogeneity of its nuclei, a single muscle cell can act almost like a tissue, which consists of a variety of very different cell types,” explains Dr. Minchul Kim, a postdoctoral researcher in Birchmeier’s team and one of the two lead authors of the study. “This enables the cell to fulfill its numerous tasks, like communicating with neurons or producing certain muscle proteins.”

Kim undertook the majority of the experimental work in the study, and his data was also evaluated at the MDC. The bioinformatics analyses were performed by Dr. Altuna Akalin, head of the Bioinformatics and Omics Data Science Platform at the MDC’s Berlin Institute of Medical Systems Biology (BIMSB), and Dr. Vedran Franke, a postdoctoral fellow in Akalin’s team and the study’s co-lead author. “It was only thanks to the constant dialogue between the experiment-based and theory-based teams that we were we able to arrive at our results, which offer important insight for research into muscle diseases,” emphasizes Birchmeier. “New techniques in molecular biology such as single cell sequencing create large amounts of data. It is essential that computational labs are part of the process early on as analysis is as important as data generation,” adds Akalin.

Injured muscles contain activated growth-promoting genes

The researchers began by studying the gene expression of several thousand nuclei from ordinary muscle fibers of mice, as well as nuclei from muscle fibers that were regenerating after an injury. The team genetically labeled the nuclei and isolated them from the cells. “We wanted to find out whether a difference in gene activity could be observed between the resting and the growing muscle,” says Birchmeier.

And they did indeed find such differences. For example, the researchers observed that the regenerating muscle contained more active genes responsible for triggering muscle growth. “What really astonished us, however, was the fact that, in both muscle fiber types, we found a huge variety of different types of nuclei, each with different patterns of gene activity,” explains Birchmeier.

In this part of a muscle fiber, Rian was stained as well. Rian is a long, non-coding RNA (lncRNA) that is highly expressed in a cluster. This indicates that the nuclei have a function in metabolism of the cell. Credit: C. Birchmeier Lab, MDC

Stumbling across unknown nuclei types

Before the study, it was already known that different genes are active in nuclei located in the vicinity of a site of neuronal innervation than in the other nuclei. “However, we have now discovered many new types of specialized nuclei, all of which have very specific gene expression patterns,” says Kim. Some of these nuclei are located in clusters close to other cells adjacent to the muscle fiber: for example, cells of the tendon or perimysium—a connective tissue sheath that surrounds a bundle of muscle fibers.

“Other specialized nuclei seem to control local metabolism or protein synthesis and are distributed throughout the muscle fiber,” Kim explains. However, it is not yet clear what exactly the active genes in the nuclei do: “We have come across hundreds of genes in previously unknown small groups of nuclei in the muscle fiber that appear to be activated,” reports Birchmeier.

Muscle dystrophy seemingly causes many nuclei types to be lost

In a next step, the team studied the muscle fiber nuclei of mice with Duchenne muscular dystrophy. This disease is the most common form of hereditary muscular dystrophy (muscle wasting) in humans. It is caused by a mutation on the X chromosome, which is why it mainly affects boys. Patients with this disease lack the protein dystrophin, which stabilizes the muscle fibers. This results in the cells gradually dying off.

“In this mouse model, we observed the loss of many types of cell nuclei in the muscle fibers,” reports Birchmeier. Other types were no longer organized into clusters, as the team had previously observed, but scattered throughout the cell. “I couldn’t believe this when I first saw it,” she recounts. “I asked my team to repeat the single-nucleus sequencing immediately before we investigated the finding any further.” But the results remained the same.

The mouse nuclei resemble those of human patients

“We also found some disease-specific nuclear subtypes,” reports Birchmeier. Some of these are nuclei that only transcribe genes to a small extent and are in the process of dying off. Others are nuclei that contain genes that actively repair damaged myofibers. “Interestingly, we also observed this increase in gene activity in muscle biopsies of patients with muscle diseases provided by Professor Simone Spuler’s Myology Lab at the MDC,” says Birchmeier. “It seems this is how the muscle tries to counteract the disease-related damage.”

“With our study, we are presenting a powerful method for investigating pathological mechanisms in the muscle and for testing the success of new therapeutic approaches,” concludes Birchmeier. As muscular malfunction is also observed in a variety of other diseases, such as diabetes and age- or cancer-related muscle atrophy, the approach can be used to better research these changes too. “We are already planning further studies with other disease models,” Kim confirms.

Reference: Minchul Kim et al, Single-nucleus transcriptomics reveals functional compartmentalization in syncytial skeletal muscle cells, Nature Communications (2020). DOI: 10.1038/s41467-020-20064-9

Provided by Max Delbrück Center for Molecular Medicine