Culture

Just as people keep their houses clean and clutter under control, a crew of cells in the body is in charge of clearing the waste the body generates, including dying cells. The housekeeping cells remove unwanted material by a process called phagocytosis, which literally means 'eating cells.' The housekeepers engulf and ingest the dying cells and break them down to effectively eliminate them.

"Phagocytosis is very important for the body's health," said Dr. Zheng Zhou, whose lab at Baylor College of Medicine has been studying phagocytosis for many years and provided key new insights into this essential process. "When this cell-eat-cell process fails, the dying cells will lose their integrity, break down and release their content into the surrounding tissues. Dumping the cell content would cause direct tissue damage and trigger inflammatory and autoimmune responses. If the dying cells are infected by a virus, releasing the cellular content would spread the infection."

In the current study, Zhou, professor in the Verna and Marrs McLean Department of Biochemistry and Molecular Biology at Baylor, and her colleagues focused on necrosis, the type of cell death caused by injury or disease. Necrosis is mostly associated with stroke, cancer, neurodegenerative diseases and heart conditions. The team investigated in more detail the signal necrotic cells display that cues the 'eating' or phagocytic cells to engulf and eliminate the dying cell.

"In previous work, the Zhou lab showed that the signal in necrotic cells is phosphatidylserine, which is a type of lipid," said Yoshitaka Furuta, first author of the current study on which he worked while he was an undergraduate student intern in the Zhou lab. Furuta currently is a student in Baylor's Development, Disease Models and Therapeutics Graduate Program.

The team found that necrotic cells, but not living cells, expose phosphatidylserine on their outer surfaces and when phagocytes detect it, they ingest and destroy the dying cells."

Healthy cells keep phosphatidylserine in their inside, but when they are injured, for instance by lack of oxygen during a stroke when neurons are over excited due to constant entry of calcium ions, or during neurodegeneration, a process begins that ultimately flips phosphatidylserine to the outside of the cell. "We wanted to know what activates the flipping of phosphatidylserine," Furuta said.

Following the process of necrosis in the transparent worm C. elegans

The researchers worked with the model organism C. elegans, a worm that is as long as a credit card is thick. C. elegans is transparent, which allows the researchers to visually identify necrotic neurons, which look swelled when compared to living cells, and follow changes in the dynamics of cellular components using a time-lapse recording approach they developed.

Previous work in C. elegans neurons had shown that certain mutations in ion channel proteins, which regulate the flow of ions like calcium2+ in and out of the cell, induced necrosis that was accompanied by an increase of calcium ion levels inside the cell. To investigate whether changes in calcium ion levels were linked to the triggering of the eat-me signal, the team introduced some of the ion channel mutant genes in neurons of their C. elegans model and monitored both calcium levels and phosphatidylserine over time.

"We discovered in our model of necrosis that a robust and transient increase in calcium ions inside the cell preceded phosphatidylserine exposure in necrotic neurons," said Zhou, a member of Baylor's Dan L Duncan Comprehensive Cancer Center. "Further experiments showed that necrotic neurons first had a small increase of calcium ions, which prompted the release of more calcium ions from an intracellular structure called the endoplasmic reticulum (ER), a larger source of calcium. Having larger than normal calcium levels inside the cell triggered phosphatidylserine exposure."

Supporting the role of calcium ions as a trigger of the 'eat-cell' signal, the researchers found that artificially increasing the level of calcium ions inside living cells also resulted in phosphatidylserine exposure and that suppressing calcium release from the ER prevented exposure of the signal.

The team also zoomed in into the process leading to the flipping of phosphatidylserine and found another piece of the puzzle. They discovered that a calcium increase inside the cells activates ANOH-1, an enzyme known to promote phosphatidylserine exposure.

"It was interesting to me that calcium can be good and bad for living cells," Furuta said. "Too much calcium is toxic to cells and induces necrosis, but at the same time calcium is necessary for dying cells to expose phosphatidylserine, the eat-me signal that promotes their clearance."

"Necrosis is a universal phenomenon that is present in many types of diseases and the clearance of necrotic cells is very important for keeping our bodies healthy," Zhou said.

Our findings provide new insight into the process of necrosis that can potentially lead to the development of therapeutic strategies, maybe along the lines of promoting clearance of necrotic cells by modulating phosphatidylserine exposure, which may help reduce the toxic effects of necrosis and improve cellular housekeeping."

Retinoblastoma starts in the retina, the thin membrane at the back of the eye. Most patients are infants or toddlers when their cancer is found. Without treatment, the cancer spreads. Thanks to chemotherapy, surgery and other treatments, 96% of patients survive.

St. Jude researchers studied how survivors fared years later at home and at school. A previous St. Jude study of 98 retinoblastoma survivors found that their early learning and life skills declined from diagnosis to age 5.

Researchers tested 78 of the same survivors five years later. The results were more upbeat. By age 10, almost all the children functioned within the normal range in those areas. That included children who had one eye removed, although they did not make up quite as much ground in the areas of learning, thinking and memory.

"The good news is that as a group the children did improve over time, but not everyone is recovering at the same rate," said Victoria Willard, PhD, of St. Jude Psychology. "The findings show we all need to be aware of factors that put children at risk for difficulties later. It highlights that all young children with retinoblastoma may benefit from early intervention to promote growth and development."

The Journal of Clinical Oncology published a report on this work.

Recently published research from the University of Arizona Health Sciences shows that advanced-stage kidney cancer is more common in Hispanic Americans and Native Americans than in non-Hispanic whites, and that both Hispanic Americans and Native Americans in Arizona have an increased risk of mortality from the disease.

"We knew from our past research that Hispanic Americans and Native Americans have a heavier burden of kidney cancer than non-Hispanic whites," said Ken Batai, PhD, a Cancer Prevention and Control Program research member at the UArizona Cancer Center and research assistant professor of urology in the College of Medicine - Tucson. "But we also know that around 90% of the Hispanic population in Arizona is Mexican American - either U.S.-born or Mexican-born - and we do not think this subgroup is well-represented in the national data."

With funding from the National Cancer Institute, Dr. Batai led a team of UArizona Cancer Center researchers that examined data from the National Cancer Database and the Arizona Cancer Registry to look for disparities in surgical treatment of kidney cancer. They also investigated the possibility that delayed treatments may result in advanced-stage kidney cancer, which has been associated with high mortality rates in Hispanic Americans and Native Americans.

The paper, "Renal Cell Carcinoma Health Disparities in Stage and Mortality among American Indians/Alaska Natives and Hispanic Americans: Comparison of National Cancer Database and Arizona Cancer Registry Data," was published in the journal Cancers.

The study found that Arizona's Hispanic Americans are about two times more likely than non-Hispanic white people to have advanced-stage kidney cancer and have nearly a two times higher risk of mortality from early-stage kidney cancer. Similarly, Native Americans are about 30% more likely to have advanced-stage kidney cancer and face a 30% increased risk of mortality from early-stage kidney cancer.

These findings suggest that observed disparities in kidney cancer mortality risk cannot be explained by delays in treatment.

The researchers utilized state data to organize Hispanic Americans into various subgroups, including U.S.-born Mexican Americans. They determined this group to have a three times higher risk of mortality compared with non-Hispanic white Americans. National cancer statistics do not break down subgroups within the general Hispanic population, thus risks to U.S.-born Mexican Americans living in Arizona may be understated in national reporting.

Dr. Batai attributes the discrepancy in national versus state data to the data-collection process. The National Cancer Database relies on hospital-based reporting, whereas the state registry is population-based. Many small hospitals and clinics in rural settings may not report to the National Cancer Database, which could explain the misrepresentation of Hispanic Americans in Arizona.

"To this point, there has been no research documenting this disparity in Hispanic Americans," Dr. Batai said. "This can be very useful information to share with primary care providers and urologists who may not yet be aware."

"Carefully documenting these disparities is something that distinguishes us as a comprehensive cancer center," said Joann Sweasy, PhD, Cancer Center director and inaugural holder of the Nancy C. and Craig M. Berge Endowed Chair. "Dr. Batai is embedded in our center not only in prevention, but he is also a part of our genitourinary clinical research team. This research benefits both perspectives, which are critical for us to meet the needs of our patients."

The research could drive further investigation into why Arizona's Hispanic and Native American populations face increased risks from kidney cancer.

"We know these populations also have higher prevalence of diabetes and blood pressure, both of which are risk factors for kidney cancer," Dr. Batai said. "While we continue to explore differences in kidney cancer surgical treatment across these groups, we are investigating if there are biologic bases in kidney cancer disparities."

New research from Simon Fraser University suggests that students learning remotely become night owls but do not sleep more despite the time saved commuting, working or attending social events.

The study, led by psychology professor Ralph Mistlberger, Andrea Smit and Myriam Juda, at SFU's Circadian Rhythms and Sleep Lab, compared self-reported data on sleep habits from 80 students enrolled in a 2020 summer session course at SFU with data collected from 450 students enrolled in the same course during previous summer semesters. The study results were recently published in the journal PLOS ONE.

"There is a widespread belief among sleep researchers that many people, especially young adults, regularly obtain insufficient sleep due to work, school, and social activities," says Mistlberger. "The move toward remote work and school during COVID-19 has provided a novel opportunity to test this belief."

The student participants kept daily sleep diaries over a period of two-to-eight weeks, completed questionnaires and provided written reports. Fitbit sleep tracker data was collected from a subsample of participants.

The team found that students learning remotely in the summer 2020 session went to bed an average of 30 minutes later than pre-pandemic students. They slept less efficiently, less at night and more during the day, but did not sleep more overall despite having no early classes and 44 per cent fewer work days compared to students in previous semesters.

"One very consistent finding is a collective delay of sleep timing - people go to bed and wake up later," says Mistlberger. "Not surprisingly, there is also a marked reduction in natural light exposure, especially early in the day. The lack of change in sleep duration was a bit of a surprise, as it goes against the assumption that young adults would sleep more if they had the time."

Self-described night owls were more likely to report a greater positive impact on their sleep, getting to sleep in, instead of waking up early for that morning class, while morning types were more likely to report a negative response to sleeping later than usual.

Sleep plays an important role in immune functioning and mental health, which is why good sleep habits are crucial.

"My advice for students and anybody working from home is to try to get outside and be active early in the day because the morning light helps stabilize your circadian sleep-wake cycle - this should improve your sleep, and allow you to feel more rested and energized during the day," says Mistlberger.

Loneliness and social isolation have been significant problems for the general population during the COVID-19 pandemic, but for cancer patients these issues were particularly acute, likely due to isolation and social distancing, according to a new UCSF study.

The study, which is the first to evaluate loneliness, anxiety, depression, fatigue and other symptoms in a single group of patients, is published in Cancer, a peer-reviewed journal of the American Cancer Society.

"We found that oncology patients were experiencing a deep sense of loneliness," said first author Christine Miaskowski, RN, PhD, a professor in the UCSF School of Nursing.

"For these patients, the burden of their symptoms is extremely high, and oncology clinicians can suggest a number of strategies to help them," she said. "Patients should be encouraged to maintain contact with family and friends, and structure their daily routines when possible, through outdoor activities for example, as well as to maintain a healthy diet and sufficient sleep. These suggestions might mitigate some of the negative effects of loneliness."

The COVID-19 pandemic brought to the forefront a pervasive sense of loneliness in the lay population, but the effects have not been well-studied in oncology patients. The new survey, administered in late May 2020, evaluated the severity of loneliness, social isolation and related symptoms - such as anxiety, depression, fatigue, sleep disturbance, cognitive dysfunction and pain - in a sample of 606 oncology patients.

Altogether, 53 percent were found to be in the lonely group, which was higher than the range reported prior to the pandemic (32 percent - 47 percent). About a third had moderately high degrees of loneliness, and 5.3 percent reported high levels of depression.

The lonely group was significantly more likely to be younger than the non-lonely group and less likely to be married or partnered. They also had a higher number of comorbidities and were more likely to report a diagnosis of depression and back pain.

Older cancer patients reported lower levels of loneliness, while patients 50 to 59 reported higher levels. The researchers believe older adults adapted their need for social contact to available opportunities.

Lower levels of household income were associated with higher levels of loneliness. The authors suggest that people at higher incomes have "more opportunities to engage in social activities and reciprocate in social relationships."

Nearly 83 percent of the patients in the lonely group suffered from breast cancer, a third were currently in cancer treatment and a quarter had metastatic disease. Nearly 92 percent of the participants were female - as a result, no conclusions could be drawn about sex differences, the authors said.

Primarily, the participants were White, well-educated, and had an annual income exceeding $60,000. As such, the authors said, their findings may not fit all patients with cancer, and symptoms could be higher in patients who are socioeconomically disadvantaged.

Researchers at North Carolina State University and the University of North Carolina Greensboro made a surprising finding while examining areas where sand flies rear their young: a new species of bacteria that is highly attractive to pregnant, or gravid, sand flies. The findings could advance the production of ecologically safe baits or traps to reduce sand fly populations.

Sand flies are vectors for important parasitic diseases affecting people in tropical and subtropical regions in Asia, Africa and the Middle East. One of those diseases is Leishmaniasis, which generally causes sores and skin ulcers but in some cases can detrimentally affect internal organs.

"Sand flies live in sheltered places such as animal burrows, caves, and rock or tree crevices, so it's difficult to reach them with insecticides," said Loganathan Ponnusamy, principal research scholar in NC State's Department of Entomology and Plant Pathology and the corresponding author of a paper describing the research. "If you're able to attract sand flies with a chemical that attracts them in nature, you're better able to target and kill them."

The research team, which included researchers from Gideon Wasserberg's lab at the University of North Carolina Greensboro, cultured a number of different bacterial species from the sand fly larval rearing area and found one that hadn't yet been identified: Sphingobacterium phlebotomi, a new member of the family of bacteria known as Sphingobacteriaceae.

To prove that the bacterium hadn't already been identified, Madhavi Kakumanu, an NC State research scholar, performed a number of tests - including scanning electron microscopy, chemical analysis and whole genome sequencing - and showed the bacterium's novelty.

"We were culturing and isolating a lot of different bacteria and found this new one almost by accident," Kakumanu, the paper's first author, said.

Bahjat Fadi Marayati, a graduate student in Wasserberg's lab, conducted attraction tests and demonstrated that this new bacteria species produces volatile chemicals that were attractive to pregnant sand flies.

Pregnant sand flies preferred the smell of the new bacterium over other chemical compounds presented during testing, Ponnusamy said, showing that the bacterium acted as a beacon for an appropriate place for females to lay eggs.

Ponnusamy says further testing will be done to narrow down even further the chemical compounds that attract sand flies.

HOUSTON - (May 6, 2021) - A Rice University laboratory has adapted its laser-induced graphene technique to make high-resolution, micron-scale patterns of the conductive material for consumer electronics and other applications.

Laser-induced graphene (LIG), introduced in 2014 by Rice chemist James Tour, involves burning away everything that isn't carbon from polymers or other materials, leaving the carbon atoms to reconfigure themselves into films of characteristic hexagonal graphene.

The process employs a commercial laser that "writes" graphene patterns into surfaces that to date have included wood, paper and even food.

The new iteration writes fine patterns of graphene into photoresist polymers, light-sensitive materials used in photolithography and photoengraving.

Baking the film increases its carbon content, and subsequent lasing solidifies the robust graphene pattern, after which unlased photoresist is washed away.

Details of the PR-LIG process appear in the American Chemical Society journal ACS Nano.

"This process permits the use of graphene wires and devices in a more conventional silicon-like process technology," Tour said. "It should allow a transition into mainline electronics platforms."

The Rice lab produced lines of LIG about 10 microns wide and hundreds of nanometers thick, comparable to that now achieved by more cumbersome processes that involve lasers attached to scanning electron microscopes, according to the researchers.

Achieving lines of LIG small enough for circuitry prompted the lab to optimize its process, according to graduate student Jacob Beckham, lead author of the paper.

"The breakthrough was a careful control of the process parameters," Beckham said. "Small lines of photoresist absorb laser light depending on their geometry and thickness, so optimizing the laser power and other parameters allowed us to get good conversion at very high resolution."

Because the positive photoresist is a liquid before being spun onto a substrate for lasing, it's a simple matter to dope the raw material with metals or other additives to customize it for applications, Tour said.

Potential applications include on-chip microsupercapacitors, functional nanocomposites and microfluidic arrays.

As the human body's largest organ, the skin is responsible for protecting against a wide range of possible infections on all fleshy surfaces, from head to toe. So how exactly does the skin organize its defenses against such an array of threats?

A new Yale study shows that the epidermis, the outermost layer of skin, is comprised of an army of immune cells that station themselves at regular intervals across the skin's vast expanse to resist infection. When necessary, the researchers found, these immune system soldiers are able to reposition themselves to protect vulnerable areas.

The study, published in the journal Nature Cell Biology, was conducted by the lab of Valentina Greco, the Carolyn Walch Slayman Professor of Genetics, at Yale School of Medicine.

"It's a surveillance system with two separate roles," said Catherine Matte-Martone, manager of the Greco lab manager and co-first author of the study. "The skin controls the sentinels by mediating their numbers based on its own density, while they in turn provide dynamic coverage to prevent cracks in the skin's defenses."

The epidermis contains two main types of immune system cells, Langerhans cells (LCs) and dendritic epidermal T cells (DETCs). In the study, the research team led by Matte-Martone and Sangbum Park, a researcher from Michigan State University (MSU), captured images of these immune system cells interacting with epithelial cells, the closely packed skin cells that comprise most of the epidermis.

They found that the immune system cells are distributed in a distinct pattern, maintaining a minimum distance between the individual cells. According to the researchers, these immune cells seem to have the ability to avoid each other, preventing clusters in any locations and maintaining a consistent distribution.

The phenomenon is similar to a property observed in neurons, in which scientists have observed a tendency of neurons from a single branch to avoid each other.

"Our study suggests that LCs and DETCs appear to have a mechanism of 'self-avoidance,', similar to neuronal cells," said Park, an assistant professor at MSU and former postdoctoral fellow in the Greco lab at Yale.

When the team removed some immune cells in one area, they observed that the remaining cells were able to reposition across the skin tissue to defend the gaps in coverage. They also found that they could disrupt the normal distribution of those cells by knocking out a gene known as Rac1 (Ras-related C3 botulinum toxin substrate 1), which regulates projections on immune cells called dendrites. This process, they hypothesize, helps maintain the distance between immune cells.

The findings illustrate how specialized cell types can cooperate to carry out a larger role within the body.

"It is fascinating to observe how these different cell types co-exist and interact together in a developmental context rather than an immunological one," Martone said.

Early on in the COVID-19 pandemic, health officials seized on contact tracing as the most effective way to anticipate the virus's migration from the initial, densely populated hot spots and try to curb its spread. Months later, infections were nonetheless recorded in similar patterns in nearly every region of the country, both urban and rural.

A team of environmental engineers, alerted by the unusual wealth of data published regularly by county health agencies throughout the pandemic, began researching new methods to describe what was happening on the ground in a way that does not require obtaining information on individuals' movements or contacts. Funding for their effort came through a National Research Foundation RAPID research grant (CBET 2028271).

In a paper published May 6 in the Proceedings of the National Academy of Sciences, they presented their results: a model that predicts where the disease will spread from an outbreak, in what patterns and how quickly.

"Our model should be helpful to policymakers because it predicts disease spread without getting into granular details, such as personal travel information, which can be tricky to obtain from a privacy standpoint and difficult to gather in terms of resources," explained Xiaolong Geng, a research assistant professor of environmental engineering at NJIT who built the model and is one of the paper's authors.

"We did not think a high level of intrusion would work in the United States so we sought an alternative way to map the spread," noted Gabriel Katul, the Theodore S. Coile Distinguished Professor of Hydrology and Micrometeorology at Duke University and a co-author.

Their numerical scheme mapped the classic SIR epidemic model (computations based on a division of the population into groups of susceptible, infectious and recovered people) onto the population agglomeration template. Their calculations closely approximated the multiphase COVID-19 epidemics recorded in each U.S. state.

"Ultimately, we'd like to come up with a predictive model that would let us determine what the likely outcome would be if a state took a (particular) action," Katul added.

By plotting on a map all of the data published weekly by county health agencies, the researchers also discovered that the disease spread out across the country in similar patterns, from the largest cities to the tiniest hamlets.

"High infection 'hotspots' interspersed within regions where infections remained sporadic were ubiquitous early in the outbreak, but the spatial signature of the infection evolved to affect most regions equally, albeit with distinct temporal patterns," the authors wrote.

"We wondered whether the spread - in space and time - was predetermined, or if there were spatial variability related to local policy," said Elie Bou-Zeid, a professor of Civil and Environmental Engineering at Princeton University and a co-author. "We found that the distribution tended to be proportional to the population."

When the alarm went out in March of last year, it was already too late, the authors noted.

"The virus could not be isolated. While the superhighways of contagion - air flights - were curtailed, the disease spread at the local level from city to city," said Michel Boufadel, professor of environmental engineering, director of the Center for Natural Resources at NJIT, and the corresponding author of the study. "Using the standard precautions of masking and distancing is not enough if there are a lot of people out there. There will still be superspreader events, resulting from 5-10 people gathering."

Their model, he said, allows them to separately examine the two key driving mechanisms of the pandemic: individuals taking preventive measures such as social distancing and wearing masks and local and state policies on shutting down or reopening public spaces.

"In this case, states did not much learn from each other and that made it difficult to have a different trend," Bou-Zeid noted.

How do environmental engineers become pandemic experts?

"There are a lot of similarities between the spikes in the number cases and the bursts of energy found in turbulent mixing," said Boufadel.

SAN FRANCISCO, CA--May 6, 2021--In the brain of a person with Alzheimer's disease, neurons degenerate and die, slowly eliminating memories and cognitive skills. However, not all neurons are impacted equally. Some types of neurons in certain brain regions are more susceptible, and even among those subtypes--mysteriously--some perish and some do not.

Researchers at Gladstone Institutes have uncovered molecular clues that help explain what makes some neurons more susceptible than others in Alzheimer's disease. In a study published in the journal Nature Neuroscience, the scientists present evidence that neurons with high levels of the protein apolipoprotein E (apoE) are more sensitive to degeneration, and that this susceptibility is linked to apoE's regulation of immune-response molecules within neurons.

"This is the first time such a link has been established, which is quite exciting and could open new paths to developing treatments for Alzheimer's disease," says Gladstone Senior Investigator Yadong Huang, MD, PhD, senior author of the study.

Finding Clues by Comparing Individual Neurons

ApoE has long been a focus of Alzheimer's disease research because people carrying a gene that produces a particular form of apoE (called apoE4) have a higher risk of developing the disease. For this study, Huang and his team harnessed recent advancements in single-cell analysis to study the potential role of apoE in the variable susceptibility of neurons in Alzheimer's disease.

Specifically, they applied a technique known as single-nucleus RNA sequencing, which reveals the extent to which the different genes in any given cell are expressed and converted into RNA, the intermediate between genes and proteins. This approach allowed them to compare individual cells within a cell type, as well as across different cell types.

The researchers used this technique to study brain tissue from both healthy mice and mouse models of Alzheimer's disease. They also analyzed publicly available data for human brain tissue--some from healthy brains and some with varying degrees of Alzheimer's disease or mild cognitive impairment.

In both mice and humans, the analysis showed that neurons varied greatly in their extent of apoE expression, even within the same subtype. In addition, the amount of apoE expression was strongly linked to the expression of immune-response genes, which also varied significantly among neurons.

Digging deeper, the researchers examined the connection between apoE and the immune response genes. They found that, in both mouse and human neurons, high levels of apoE turned on genes in the major histocompatibility complex class-I (MHC-I). MHC-I is part of a pathway involved in eliminating excess synapses (connections between neurons) during brain development, and may also alert the immune system to damaged neurons and synapses in the adult brain.

"This was an intriguing clue that by controlling the expression of MHC-I in neurons, apoE might help determine which neuron should be recognized and cleared by the immune system," says Kelly Zalocusky, PhD, first author of the study and a scientist in Huang's lab at Gladstone.

A Process Gone Awry Leads to the Progressive Destruction of Neurons

The team found that, in brain tissue, the proportion of neurons expressing high levels of apoE and MHC-I genes fluctuates in a way that closely matches neurodegeneration and the progression of Alzheimer's disease.

They observed this relationship both in mouse models of Alzheimer's disease and in human brain tissue at different stages of neurodegeneration. Their work also revealed a causal link between the expression of MHC-I induced by apoE and the increase in tangled aggregates of a protein called tau, which is a hallmark of Alzheimer's disease and is a good predictor of neurodegeneration.

So, taken together, what do all these findings mean?

"We think that, normally, apoE turns on the expression of MHC-I in a small number of damaged neurons to produce 'eat me' signals that mark the neurons for destruction by the immune cells," says Huang, who is also director of the Center for Translational Advancement at Gladstone, as well as professor of neurology and pathology at UC San Francisco. "You don't want to keep damaged neurons around because they could malfunction and cause problems."

But in Alzheimer's disease, the scientists think this normal process for clearing out damaged neurons may become overactivated in a larger number of cells, leading to the progressive loss of neurons.

In other words, aging brains may face stressors that boost the amount of apoE in some neurons past healthy levels. The study shows that neurons carrying the form of apoE associated with increased risk of Alzheimer's disease, apoE4, are particularly susceptible to these stressors. This excess apoE turns on the expression of MHC-I, marking these neurons for destruction. Meanwhile, neurons with lower levels of apoE remain unharmed. Consequently, this process results in selective neurodegeneration within a given neuron type in Alzheimer's disease, guided by the level of apoE.

Further research could help clarify how apoE and MHC-1 determine which neurons die and which survive in Alzheimer's disease.

"Additional studies could reveal potential new targets for treatments that may be able to disrupt this destructive process in Alzheimer's disease and potentially in other neurodegenerative disorders as well," says Huang.

LOS ANGELES (May 6, 2021) -- A team of researchers from UCLA, Cedars-Sinai and the Cystic Fibrosis Foundation has developed a first-of-its-kind molecular catalog of cells in healthy lungs and the lungs of people with cystic fibrosis.

The catalog, described today in the journal Nature Medicine, reveals new subtypes of cells and illustrates how the disease changes the cellular makeup of the airways. The findings could help scientists in their search for specific cell types that represent prime targets for genetic and cell therapies for cystic fibrosis.

"This new research has provided us with valuable insights into the cellular makeup of both healthy and diseased airways," said Dr. Brigitte Gomperts, a co-senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "If you can understand how things work in a state of health, it becomes easier to see what cellular and molecular changes occur in a disease state."

A progressive genetic disorder that affects more than 70,000 people worldwide, cystic fibrosis results from mutations to the CFTR gene. Cells that contain the defective protein encoded by the gene produce unusually thick and sticky mucus that builds up in the lungs and other organs. This mucus clogs the airways, trapping germs and bacteria that can cause life-threatening infections and irreversible lung damage.

While several new therapies can partially restore the function of these damaged proteins, easing symptoms of the disease, slowing its progression and improving quality of life, these treatments only work in people with some of the many CFTR mutations that can cause cystic fibrosis.

"We have made tremendous progress in the development of treatments for the underlying cause of cystic fibrosis, but many people cannot benefit from these medicines," said John (Jed) Mahoney, a senior co-author of the paper and head of the stem cell biology team at the Cystic Fibrosis Foundation Therapeutics Lab. "This research provides critical insight into how the disease alters the cellular makeup of the airways, which will enable scientists to better target the next generation of transformative therapies for all people with cystic fibrosis."

The research team was assembled through the Cystic Fibrosis Foundation's Epithelial Stem Cell Consortium, which brings together scientists from across the U.S. in an ongoing effort to identify different subtypes of stem cells in the lungs and study their function. Because these cells can self-renew and produce a continuous supply of specialized cells that maintain, repair and regenerate the airways, therapies aimed at correcting CFTR mutations in stem cells hold the best hope for a one-time, universal treatment for the disease.

"This catalog represents an important step toward identifying those rare stem cells that regenerate the airways over a person's lifetime," said Gomperts, who is also a professor of pediatrics and pulmonary medicine at the David Geffen School of Medicine at UCLA. "We suspect these cells could be targets for future therapies that may provide a long-term correction to the mutation that causes this disease."

'Un-blending' a smoothie: How the catalog was created

For the study, Gomperts, Mahoney and their co-senior authors, Barry Stripp of Cedars-Sinai and Kathrin Plath of UCLA, compared tissue samples taken from lungs removed from 19 people with cystic fibrosis, all of whom had received lung transplants, with samples taken from healthy lungs donated by 19 individuals who had died from other causes.

Researchers at the three institutions employed similar but distinct methods to break these tissues down and examine them using a technology called single-cell RNA sequencing, which allowed them to analyze thousands of cells in tandem and classify them into subtypes based on their gene expression patterns - this is, which genes are turned on and off.

"The process is analogous to taking a smoothie and 'un-blending' it to discover all the ingredients it contains and measure how much of each ingredient was used," said Plath, a professor of biological chemistry and a member of the UCLA Broad Stem Cell Research Center.

Using a novel computer-based bioinformatics approach to compare the gene expressions patterns of the various cells, the team was able to create a catalog of the cell types and subtypes present in healthy airways and those affected by cystic fibrosis, including some previously unknown subtypes that illuminate how the disease alters the cellular landscape of the airways.

"We were surprised to find that the airways of people with cystic fibrosis showed differences in the types and proportions of basal cells, a cell category that includes stem cells responsible for repairing and regenerating upper airway tissue, compared with airways of people without this disease," said Stripp, a professor of medicine and director of the lung stem cell program at the Cedars-Sinai Board of Governors Regenerative Medicine Institute.

Specifically, the researchers discovered that among the basal cell populations, there was a relative overabundance of cells that appear to be transitioning from basal stem cells into specialized ciliated cells, which use their finger-like projections to clear mucus out of the lungs.

"We suspect that changes the basal cells undergo to replenish ciliated cells represent an unsuccessful attempt to clear mucus that typically accumulates in airways of patients with cystic fibrosis," Stripp said.

The increase in transitioning cells provides further evidence suggesting that expression of the mutated CFTR gene disrupts normal function of the airways, leading to changes in the way that basal stem cells produce specialized cells.

Moving forward, the researchers will continue to study the new data for insights into how cystic fibrosis alters the cellular landscape of the airways - including why this unsuccessful transition occurs- and to identify the long-lived basal stem cells that would be the ideal target for a CFTR gene correction.

PHILADELPHIA-- When evaluating the opioid crisis, research reveals that external factors - such as the volume of pre-filled syringes, or a default number of opioid tablets that could easily be ordered at discharge for the patient - can shift prescribing and compel emergency department (ED) physicians to administer or prescribe greater quantities of opioids. A new study published in the Journal of Medical Toxicology reveals that opioid prescribing behavior can also be decreased by external factors, such as a supply shortage.

Led by the Perelman School of Medicine at the University of Pennsylvania, researchers evaluated pharmacy data from the electronic medical records (EMR) collected before, during, and after a period of parenteral opioid shortage across two large urban academic emergency departments - the Hospital of the University of Pennsylvania and University Hospital in Newark, New Jersey. In this case, the shortage was of parenteral morphine and hydromorphone, as a result of supply chain disruptions caused by Hurricane Maria in 2018.

Researchers found that the percentage of patients who received an opioid among all ED visits during the 2018 shortage fell significantly from 11.5% pre-shortage to 8.5% during, and did not return to baseline once the shortage abated. Further, the total number of oral or IV opioid doses administered during the shortage also decreased and remained lower than pre-shortage levels once supply chains were restored. However, the study also found that while fewer opioid doses were administered to fewer patients, there was no change in net Morphine Milligram Equivalent (MME) per patient receiving opioids.

"Although the percentage of patients who received non-opioid analgesics did not rise during the shortage, it was significantly higher in the post-shortage period," said lead investigator Amanda Deutsch, MD, an Emergency Medicine resident at Penn. "This suggests that a subset of patients were transitioned to non-opioids, and this prescribing practice was a sustained change after the resolution of the shortage."

The study also found that because the shortages were specifically of parenteral morphine and hydromorphone, those were replaced by parenteral fentanyl, but the overall total use in MME of opioids administered remained the same. The use of oral morphine also appeared to increase during the shortage period. These findings may suggest that the shortage may have led to a shift from IV opioid use to oral opioid formulations.

However, researchers felt that the shift in prescribing patterns during the shortage can offer an opportunity for more research into how external factors can influence ED prescribing practices. "Changing clinician prescribing behavior is challenging," said author Jeanmarie Perrone, MD, a professor of Emergency Medicine at Penn. "This study shows encouraging data to support that there are environmental modifications that can nudge providers toward more judicious opioid use."

How did people living in the Bronze Age manage their finances before money became widespread? Researchers from the Universities of Göttingen and Rome have discovered that bronze scrap found in hoards in Europe circulated as a currency. These pieces of scrap - which might include swords, axes, and jewellery broken into pieces - were used as cash in the late Bronze Age (1350-800 BC), and in fact complied with a weight system used across Europe. This research suggests that something very similar to our 'global market' evolved across Western Eurasia from the everyday use of scrap for cash by ordinary people some 1000 years before the beginning of classical civilizations. The results were published in Journal of Archaeological Science.

This study analysed around 2,500 metal objects and fragments from among the thousands of hoards of fragments from the late Bronze Age that, over time, have been unearthed in Central Europe and Italy. The researchers used a statistical technique that can determine if a sample of measurements is due to an underlying system. This technique can detect, for instance, if the analysed objects are multiples of a weight unit. The researchers' analysis provides very significant results for fragments and scraps, which means that these metal objects were intentionally fragmented in order to meet predetermined weights. The analyses confirm that the weight unit that regulated the mass of metals was the same unit represented in European balance weights of the same period. The researchers conclude that these scraps were being used as money, and that the fragmentation of bronze objects was aimed at obtaining 'small change' or cash.

Trade in prehistory is commonly imagined as a primitive system based on barter and on the exchange of gifts, with money appearing as some kind of evolutionary milestone somewhere during the making of Western state-societies. The study challenges this notion by introducing the concept that money was a bottom-up convention rather than a top-down regulation. Bronze Age money in Western Eurasia emerges in a socio-political context in which public institutions either did not exist (as was the case in Europe) or were uninterested in enforcing any kind of monetary policy (as in Mesopotamia). In fact, money was widespread and used on a daily basis at all levels of the population.

The spread of the use of metallic scraps for cash happened against the background of the formation of a global market in Western Eurasia. "There was nothing 'primitive' about pre-coinage money, as money before coins performed exactly the same functions that modern money does now," explains Dr Nicola Ialongo at the University of Göttingen's Institute for Prehistory and Early History. Ialongo adds, "Using these metallic scraps was not an unexpected development, as it is likely that perishable goods were used as currency long before the discovery of metallurgy, but the real turning point was the invention of weighing technology in the Near East around 3000 BC. This provided, for the first time in human history, the objective means to quantify the economic value of things and services, or, in other words, to assign them a price."

Scientists from Nanjing University and University of Macau have discovered nano-scaled apoptotic bodies (ABs) as a new brain-targeting drug carrier, bringing new promise for the Parkinson's Disease as well as other brain diseases.

The blood-brain barrier (BBB) is the most restrictive barrier that keeps most biomolecules and drugs from the brain, setting "barriers" for the treatment of cerebrovascular diseases. With the increasingly serious ageing problem, the treatment of brain diseases now faces tough challenges, and therefore efficient brain drug delivery strategies are urgently needed.

Apoptotic bodies (ABs), secreted from dying cells, have been discovered for half a century but their roles are underestimated. ABs are rarely considered for drug delivery, due to their uneven size distribution (varying from hundreds to thousands of nanometres) and complex composition (especially large chromosomal DNA fragments and various kinds of cytoplasmic proteins). However, with the natural bioactive lipids and affluent proteins, Abs should be more functional than being just an in vivo recycling unit.

In this paper, the team separated the small apoptotic bodies (sABs) and revealed their potential advantages as a delivery system for brain targeting. First, compared with the micron-sized apoptotic bodies, sABs have a more uniform size, with few DNA fragments and abundant RNAs. Second, sABs are stable in serum and has a long circulating time in vivo, not easily engulfed by the phagocytes. Third, the drug loading efficiency into sABs is high and the process is productive and controllable. Additionally, sABs are vesicles shed from the cell membrane, so the molecules in the cell membrane are preserved on the vesicles, providing a way for incorporating targeting ligands. With these advantages, sABs are likely a new candidate for drug delivery.

This paper 'Delivering Antisense Oligonucleotides across the Blood-Brain Barrier by Tumor Cell-Derived Small Apoptotic Bodies', is recently published in Advanced Science. Professor Lei Dong of Nanjing University, the leading author of this work, believes that sABs would be able to overcome the bottleneck of the exosome-based therapeutics and become a new class of drug delivery careers. They successfully loaded TNF-a antisense oligonucleotide (ASO) into sABs secreted by melanoma cells with high brain metastasis. The drug-loaded sABs could penetrate BBB, delivering the anti-inflammatory ASO to microglia and showing a remarkable efficacy in alleviating the development of Parkinson's disease in mice.

With the outstanding encapsulation and delivery efficiency to the microglia within the brain, the cancer cell-derived sABs might revolutionize the diagnosis, prevention and treatment of many brain diseases.

Scientists are calling for more stringent pesticide bans to lower deaths caused by deliberately ingesting toxic agricultural chemicals, which account for one fifth of global suicides.

A NHMRC funded study, in which the University of South Australia analysed the patient plasma pesticide concentrations, has identified discrepancies in World Health Organization (WHO) classifications of pesticide hazards that are based on animal doses rather than human data.

As a result, up to five potentially lethal pesticides are still being used in developing countries in the Asia Pacific, where self-poisonings account for up to two thirds of suicides.

In a paper published in Lancet Global Health, UniSA Research Chair of Therapeutics and Pharmaceutical Science, Professor Michael Roberts, says while deaths from pesticide poisonings have fallen dramatically in recent years, it is still a common cause of global suicides.

Each year, more than 150,000 people die from deliberately ingesting pesticides, although this number was much higher - averaging 260,000 a year - before specific chemicals were banned.

Prof Roberts was a member of a team of international researchers who used Sri Lanka as a case study, in which they compared the number of deaths from pesticides in a rural area between 2002 and 2019.

Of 35,000 people (mainly men aged in their late 20s) hospitalised for pesticide self-poisoning, 6.6 per cent died.

The three most toxic agents were paraquat, dimethoate and fenthion, which were all banned by 2011, reflected in much lower fatalities after that date. Since then, five other common pesticides still allowed by the WHO were disproportionately responsible for 24 per cent of fatalities, the team found.

"If human data for acute toxicity of pesticides was used for hazard classification and regulation worldwide, it would prevent many deaths and have a substantial impact on global suicide rates," Prof Roberts says. "Australia is fortunate in that its regulations properly balance good pesticide use versus public health concern."

He predicts that fatal poisonings across Asia could fall by more than 50 per cent, and total suicides in the region could fall by at least a third.

"Instead, the WHO classifications are largely based on animal median lethal doses. This method ignores the differences between species and how they respond to treatment, and the formulations used."

Fatalities from pesticide poisonings also differed greatly from that predicted by the WHO classification.

The researchers have called for the WHO to eliminate all pesticides with fatality rates above five per cent.

"Setting a global benchmark and relying on human data is critical to reducing suicides, particularly in countries such as Sri Lanka, South Korea, Bangladesh and China, where agriculture is still a dominant industry."

"We also found evidence that some banned agents were still in circulation due to illegal importation, so there is still a need to tighten existing regulations," Prof Roberts says.