Earth

Bioengineers at the University of California San Diego have redesigned how harmless E. coli bacteria "talk" to each other. The new genetic circuit could become a useful new tool for synthetic biologists who, as a field, are looking for ways to better control the bacteria they engineer to perform all sorts of tasks, including drug delivery, bioproduction of valuable compounds, and environmental sensing.

What's new about the UC San Diego control strategy of the E. coli that serve as workhorses of synthetic biology? The bacterial cells within a population are engineered to be unable to communicate with each other through chemical signals unless one particular external molecule is present.

This work is published in the March 4, 2020 issue of the journal Nature Communications.

"We hope that this system can increase control and safety of synthetic genetic circuits, and therefore facilitate their transition to real life applications," said Arianna Miano, a UC San Diego bioengineering PhD student and the first author on the Nature Communications paper.

This work is from the UC San Diego lab led by Jeff Hasty, who is a professor of bioengineering at the Jacobs School of Engineering, and of biology in the Division of Biological Sciences.

Traditionally, synthetic biologists use native bacterial communication systems, known as quorum sensing, to control the bacterial communities they use for tasks such as targeted drug delivery.

Quorum sensing in bacteria is based on the production, diffusion and reception of small signaling molecules between bacterial cells within a population. The majority of these systems rely on the internal resources of each cell for the production of the signaling molecule.

One of the challenges of quorum sensing systems is that they are hard to externally regulate. To address this issue, the UC San Diego researchers created an "inducible quorum sensing system." It is designed to give synthetic biologists better control of bacterial communication systems -- and thus better control of the useful tasks these bacterial communities are performing.

Inspired by a genetic circuit found in the photosynthetic bacterium Rhodopseudomonas palustris and first described in the academic literature in 2008, the UC San Diego researchers created a quorum sensing system that only functions when the bacterial are provided with a plant-derived compound called p-coumaric acid. This compound is found in most fruits and vegetables.

"The bacteria coordinate differently according to how much of the p-coumaric acid we provide in the media," said Miano. "If we give no p-coumaric acid, the bacteria can't communicate with each other, but when we provide them with medium concentrations they are able to signal and share information on the size of their colony."

"If we give them too much, they over-produce signaling molecules which tricks them into behaving as if they were always part of a large population," said Miano.

The UC San Diego bioengineers demonstrated their inducible quorum sensing circuit, which can control bacterial cell coordination in time and space, by co-expressing it with a lysis gene.

The choice to demonstrate via a lysis gene builds on previous projects from the Hasty lab at UC San Diego, including research demonstrating how bacteria lysis could be used to deliver cancer-killing drugs around a tumor.

In the new work, the UC San Diego researchers demonstrated how the inducible quorum sensing could greatly expand control over this cargo delivery platform, compared to currently available native quorum sensing systems.

In particular, the researchers used low and medium concentrations of p-coumaric acid to cause populations of bacteria with both the new inducible quorum sensing circuit and the lysis gene to switch between no delivery and steady oscillations of cargo delivery.

Using a lysis gene and traditional quorum sensing system, the cargo would only be delivered when the bacteria reached a high enough concentration.

"We have just scratched the surface of the potential of this communication system. We are excited to see the applications that will follow by coupling it to the expression of different genes," said Miano.

The researchers also demonstrated that subjecting bacteria to high concentrations of p-coumaric acid wiped out all the cells by forcing them to constantly produce the lysis proteins, independent of population size. (See video)

According to popular theory, men live shorter lives than women because they take bigger risks, have more dangerous jobs, drink and smoke more, and are poor at seeking advice from doctors.

But research by scientists at UNSW Sydney suggests the real reason may be less related to human behaviour and more to do with the type of sex chromosomes we share with most animal species.

In a study published today in Biology Letters, researchers from UNSW Science's School of Biological, Earth and Environmental Sciences analysed all available academic literature on sex chromosomes and lifespan - and they tried to establish whether there was a pattern of one sex outliving the other that was repeated across the animal kingdom.

Specifically, they wanted to test the 'unguarded X hypothesis' which suggests that the Y chromosome in heterogametic sexes - those with XY (male) sex chromosomes rather than XX (female) sex chromosomes - is less able to protect an individual from harmful genes expressed on the X chromosome. The hypothesis suggests that, as the Y chromosome is smaller than the X chromosome, and in some cases absent, it is unable to 'hide' an X chromosome that carries harmful mutations, which may later expose the individual to health threats.

Conversely, there is no such problem in a pair of homogametic chromosomes (XX), where a healthy X chromosome can stand in for another X that has deleterious genes to ensure those harmful genes aren't expressed, thus maximising the length of life for the organism.

First author on the paper and PhD student Zoe Xirocostas says that after examining the lifespan data available on a wide range of animal species, it appears that the unguarded X hypothesis stacks up. This is the first time that scientists have tested the hypothesis across the board in animal taxonomy; previously it was tested only within a few groups of animals.

"We looked at lifespan data in not just primates, other mammals and birds, but also reptiles, fish, amphibians, arachnids, cockroaches, grasshoppers, beetles, butterflies and moths among others," she says.

"And we found that across that broad range of species, the heterogametic sex does tend to die earlier than the homogametic sex, and it's 17.6 per cent earlier on average."

Interestingly, the researchers observed this same pattern in the classes of animals possessing their own unique pair of sex chromosomes that are the reverse of all other animals. In birds, butterflies and moths, it is the male of the species that has the homogametic sex chromosomes (denoted by ZZ) while the female has the heterogametic chromosomes (ZW). Female birds, butterflies and moths were usually found to die earlier than their male counterparts, giving credence to the unguarded X hypothesis - although strictly speaking, it's an unguarded Z in this case.

But while this study confirms that the unguarded X hypothesis is a reasonable explanation for why one sex outlives the other on average, there was one statistic that emerged from the data that took Ms Xirocostas by surprise.

"We found a smaller difference in lifespan between the males and females in the female heterogametic species compared to males and females in the male heterogametic species," she says. "In species where males are heterogametic (XY), females live almost 21 per cent longer than males. But in the species of birds, butterflies and moths, where females are heterogametic (ZW), males only outlive females by 7 per cent."

Simply put, heterogametic males (XY) die sooner than heterogametic females (ZW) when compared to the opposite sex in their species. Does this mean there is something still fundamentally life-shortening about being a male member of any species?

Ms Xirocostas thinks this could be the case, and lists side effects of sexual selection, the degree of Y chromosome degradation and telomere dynamics as possible explanations for this surprising trend.

"I was only expecting to see a pattern of the homogametic sex (XX or ZZ) living longer, so it came as an interesting surprise to see that the type of sex determination system (XX/XY or ZZ/ZW) could also play a role in an organism's longevity."

Ms Xirocostas says future studies of this phenomenon should test a hypothesis raised in the paper that the difference in lifespan between sexes is proportional to the difference in chromosome length between sexes, which could help us further understand the factors affecting ageing. But for now, she believes, the unguarded X hypothesis stands.

March 3, 2020, Alexandria, Va.--The American Association for Dental Research (AADR) released findings of a new research study, "Survey of Dental Researchers' Perceptions of Sexual Harassment at AADR Conferences: 2015-2018" in the Journal of Dental Research (JDR).

The research assessed perceptions and experiences related to sexual, gender-based and nongender-based harassment among registrants at AADR annual meetings from 2015 to 2018 (n=10,495); examined demographic factors associated with reported experiences; and identified facilitators and potential solutions concerning these types of harassment. The survey received 824 responses, or 7.85%.

"In 2018, AADR introduced a Professional Conduct at Meetings Policy delineating unacceptable behaviors, including intimidating or harassing speech and actions," said Timothy Wright, AADR President. "Results of this survey form a baseline for us to monitor our events to ensure that future AADR meetings are respectful, supportive, welcoming and safe environments for all."

Quantitative data was collected across 8 types of perceived harassment. Qualitative data analysis was conducted on open-ended responses to questions.

Results

The quantitative analysis revealed that the majority of the 824 respondents did not report perceived experiences with harassment of any type (79%).

Women, AADR and Canadian Association of Dental Research (CADR) members, and frequent attendees were most likely to report instances of perceived harassment.

Harassment of a nonsexual nature (i.e., put-downs/condescension) was most commonly reported (14.7%), while harassment of a sexual nature was less frequent (0.9% to 7.9% depending on type of harassment).

The qualitative analysis of the 229 respondents who provided input on open-ended questions revealed perceived facilitators of unwelcome behaviors as well as proposed solutions.

Reports of sexual harassment at a scientific workplace, graduate program, or other career-related venue did not appear to be more frequent than perceived experiences of any type of harassment at an AADR meeting (22.4% vs. 20.9%) but may be more common in terms of harassment types of a more sexual nature.

Conclusion

The landmark National Academies of Science, Engineering, and Medicine 2018 report on "Sexual harassment of women: Climate, culture, and consequences in academic sciences, and medicine" clearly articulated the problem of sexual harassment in the biomedical sciences and specifically highlighted the role of professional organizations in addressing sexual harassment. AADR conducted this survey with researchers from Boston University to assess the climate at our own meetings and address any shortcomings. While the majority of survey respondents had no personal experience with harassment at AADR meetings, the fact that 1 in 5 did is cause for concern and warrants steps for improvement. Therefore, AADR will continue promoting the AADR's Professional Conduct at Meetings Policy and continue involvement in the Societies Consortium on Sexual Harassment in STEMM in order to offer a collegial, safe and welcoming environment for all.

"The survey's findings underscore the importance of the AADR's efforts in addressing the issue of sexual harassment," said Boston University Assistant Professor Brenda Heaton, lead author of the survey report.

Top-down projects for improving the lives of poor farmers were often unsuccessful because they didn't systematically consider the diverse rural households survive and thrive. To tap this local knowledge, scientists and development agencies began surveying households to assure that research and development schemes were on target. But the surveys were not designed to be compared with one another, lacking what scientists call "interoperability" - meaning one organization's household surveys could not be compared with another's. For big-picture analysis, much of the data was of little use.

A team of CGIAR researchers began tackling the household survey interoperability problem in 2015. More than 13,000 standardized surveys and 21 countries later, they published their findings, methods and analysis of their massive dataset in February in Scientific Data, a Nature publication.

Moreover, they invited the global research-for-development community to contribute to the open-access dataset, which today includes more than 30,000 interviews conducted in 33 countries. (The publication only analyzed interviews through mid-2018.) Data is collected on tablets or smartphones, which can be solar powered for use in remote regions.

Broad adoption of this standardized survey tool may help guide international efforts to address smallholder challenges related to climate change, food security, nutrition, farm productivity, and social inclusion.

"The lack of standardization of agricultural household surveys, especially in international 'agriculture for development' research, has resulted in a proliferation of survey tools and indicators leading to datasets which are often badly documented, incoherent, and with limited interoperability," the authors wrote. "The current state of affairs limits our ability to compare outcomes across studies and to draw general conclusions on the effectiveness of interventions and the trade-offs between outcomes."

Researchers at the International Livestock Research Institute (ILRI) developed the tool, which they dubbed the Rural Household Multi-Indicator Survey, or RHoMIS. Other CGIAR co-authors included researchers at the Alliance of Bioversity International and CIAT, the International Institute for Tropical Agriculture, the International Maize and Wheat Improvement Center, and World Agroforestry.

"With this tool, we gain a consistent level of detail over a wide range of topics," said Mark van Wijk, the lead author. "This allows us to look for system interactions that are observable in a wide diversity of locations, projects, cultures or climate zones."

"Used to take months"

RHoMIS was built to collect raw data on 758 variables and create 41 indicators based on the data. Variables include household demographics and diets, farming practices related to livestock and crops, subsistence farming vis-à-vis farming for markets, fertilizer and pesticide use and yields, among many others. Key indicators produced span agricultural production and off-farm activities, including market integration, nutrition, food security, poverty and greenhouse gas emissions.

Along with being standardized, RHoMIS is flexible to include questions modules tailored to specific research projects. Surveys are taken on smartphones or tablets and can take as little as 40 minutes, compared with up to 3 hours for other surveys. The tool's digital platform stores, aggregates and visualizes data for additional ease of use.

Development organizations, researchers and NGOs are already using the tool. RHoMIS has been used in climate-smart agriculture research in East Africa and Central America, changes in livelihoods and food security in Tanzania, mobile phone use for climate information in East Africa, and food security research in Central America's dry corridor, among others. The NGO Tree Aid, which plants trees to help rural communities, uses RHoMIS as an essential part of its monitoring work.

"RHoMIS has allowed us to revolutionize the way we work with surveys," said Jacob van Etten, a co-author and research director for digital inclusion at the Alliance. "A big benefit of standardization is that we don't need laborious data management. We can jump from data collection to insights in a very short time, a process that used to take months. These insights can then directly feed into decision-making and start to improve our projects right away."

Potential: biggest smallholder database

Understanding the diversity and dynamics of rural households is crucial, given the diverse effects of global changes in climate, population growth, urbanization, and food demand. Moreover, achieving the United Nations' sustainable development goals - notably zero hunger - requires more intensified, sustainable food production and development of rural economies.

Reliable indicators at the farm-household level of both farm performance and household welfare are therefore needed to better understand and model these dynamics, and to inform the design and implementation of interventions by governments, donors, and international agencies, across a wide range of different geographies and socio-economic dimensions.

"Our goal is that in five years the RHoMIS-based dataset is the go-to place for information on smallholder farming," said Wijk, adding that the tool will likely be useful to more NGOs and national statistics agencies. "By then, it will probably be the biggest single database on subsistence farming, with reliable information on productivity, management, poverty, food security, gender relationships and so much more."

A woman's mental health during pregnancy has a direct influence on the development of her child's immune system, according to a new study from pediatric researchers at the University of Alberta.

Previous research indicated a link between a woman's mental state and the development of asthma and allergies in children, but this is the first study in humans to identify the mechanism at work.

"Our study shows that what happens to the mother during pregnancy could affect the levels and function of the cells that produce immunoglobulin in children," said Anita Kozyrskyj, a pediatric epidemiologist and a leading researcher on gut microbes.

The researchers examined health records of 1,043 mother-infant pairs who are participating in the CHILD Cohort Study, which is following the health of thousands of Canadian children into their teens.

The mothers filled out regular questionnaires about their mood during and after their pregnancies, asking, for example, whether they felt sad or overwhelmed. Stool samples from the babies were examined for the presence of intestinal secretory immunoglobulin A (sIgA), an antibody that plays a crucial role in immunity.

"This immunoglobulin is really important in the microbiome for developing oral tolerance to environmental antigens," said lead author Liane Kang, who carried out the research for her MSc and is now studying medicine at the U of A.

Mothers who reported symptoms of depression during their third trimester, or persistently before and after the birth, were twice as likely to have babies with the lowest levels of immunoglobulin A in their gut. The mothers' symptoms did not have to be severe enough for a clinical diagnosis of depression. No link was found with postpartum depression.

The results held true even when variable factors such as breastfeeding and antibiotic use by the mothers and babies were taken into account.

"We know that women who have psychological distress are less likely to breastfeed and interact with their children," said Kang. "Antibiotic use could also impact how the infant gut microbiome is developing."

"Despite all these factors there was still a link between depression and lower immunoglobulin A in the infant."

Kozyrskyj noted that the lowest levels of immunoglobulin A were found in infants between four and eight months old, when they would normally begin to produce their own immunoglobulin.

"The largest impact of depression in the mothers was seen in this startup phase of the child's own immune system," she said.

The researchers said lowered immunity places the babies at risk for respiratory or gastrointestinal infections, as well as asthma and allergies, and may also lead to elevated risk for depression, obesity and autoimmune diseases such as diabetes.

Kozyrskyj posited that higher levels of the stress hormone cortisol may be transferred from depressed mothers to their fetuses and interfere with the production of cells that will make immunoglobulin after birth. She suggested more research is needed to understand this link between the maternal microbiome and infant immune development.

Both researchers said their study indicates that more mental health supports are needed for pregnant women.

"New mothers are going through a very different stage in their life where they have to take care of another human being, and there are a lot of stressors that come with that," said Kang.

"These findings should not be used to blame mothers," said Kozyrskyj. "Maternal mental health does not occur in isolation."

It is estimated that as many as 80% of advanced-stage cancer patients may develop cachexia, a potentially fatal metabolic syndrome characterized by extreme weight loss and muscle wasting, but scientists do not yet fully understand why it is more frequently associated with certain kinds of tumor than others, or why not all cancer patients develop it.

Tumor genetics could provide an answer. Researchers at São Paulo State University (UNESP) in Brazil analyzed 12 types of cancer and identified patterns of tumor protein secretion that correlated with the prevalence of cachexia and average weight loss for each type.

The study was supported by São Paulo Research Foundation - FAPESP. The principal investigator was Robson Francisco Carvalho, a professor at UNESP's Botucatu Institute of Biosciences (IBB). Researchers from the University of Southern Denmark and the University of Antioquia's Medical School in Colombia also contributed to the study. The results were published in the Journal of Cachexia, Sarcopenia and Muscle.

According to Carvalho, cachexia is most frequent in patients with pancreatic, esophageal, colorectal, stomach and head-and-neck cancer, and least frequent in patients with breast and prostate cancer.

"Cachexia-inducing factors, mainly deriving from cancer, had already been associated with development of the syndrome but it was not yet possible to link them to this variation in its prevalence and severity," he said. "In the case of cancer of the pancreas, for example, which correlates closely with cachexia, we found alterations in the expression of 14 out of 25 genes that encode cachexia-inducing factors. In prostate cancer, which does not, we found no change in the expression of any of these 25 genes."

Tumor databases

The findings of the study were based on an analysis of clinical and molecular data from two public tumor databases, The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project. To delineate a specific tumor profile, the researchers used 4,651 samples of 12 types of cancer and compared them with 2,737 samples of normal tissue from the same organs.

Every cell or tissue produces a transcriptome, a set of RNA molecules responsible for "transmitting" the information encoded by the genes, and for guiding protein synthesis. "Based on transcriptome analysis we compared the gene expression profiles of the proteins secreted by tumors and normal tissue," Carvalho explained.

This initial analysis identified new factors that were specific to each type of tumor and could potentially explain variations in the prevalence and severity of cachexia in cancer. Data on all cellular protein-encoding genes came from the Human Protein Atlas. A total of 2,933 human genes associated with proteostasis have been described to date.

After analyzing the genes for their list of proteins, the researchers focused on investigating the genes that encode the 25 growth factors and cytokines known to be cachexia-inducing factors. These include CXCL8, IL1B, LIF, TGFA and IL6, analyzed in a previous study based on blood samples from cachectic patients with pancreatic cancer.

"In this manner we identified major correlations between the expression profiles of cachexia-inducing factors specific to each tumor type and the prevalence of the syndrome and average weight loss in patients with these cancers," Carvalho said.

In pancreatic cancer, for which the patient survival rate is low, average weight loss is 13.7 kilograms (kg). In prostate cancer, which has a high survival rate, average weight loss is less than 2 kg.

"We also identified major correlations between the expression profiles of cachexia-inducing factors for each type of tumor and a worse patient prognosis [lower survival rate]," he noted.

Patients with end-stage (refractory) cachexia are expected to survive for less than three months.

Biomarkers

The genes described in the article have the potential to serve as biomarkers of the risk of developing cachexia, a complex condition whose treatment continues to defy science. "This suggests each type of tumor requires specific treatment against cachexia," Carvalho said. "Knowledge of this profile can help physicians identify patients with an unfavorable prognosis, which influences important decisions about their treatment."

The researchers at IBB-UNESP had previously made a key discovery in this connection. "Last year, while analyzing cachexia in cases of lung cancer, we found that the protein IL8 secreted by the tumor can induce muscle cell atrophy," Carvalho said.

Conducted in collaboration with the Danish research group and with FAPESP's support, the previous study was published in the journal Cancers. "Our analysis of secreted protein gene expression in the tumors of patients with lung cancer and low muscularity as assessed by computed tomography also identified a set of molecules that can be used for prognosis prediction," he explained.

Practical application of this knowledge remains a challenge. "Having identified this set of biomarkers of cachexia with significant prognostic value, we may be able in future to develop a panel for assessment of the expression of these genes in tumor tissue," said Paula Paccielli Freire, who conducted the investigation while researching for a PhD at IBB-UNESP.

The researchers are now analyzing the transcriptomes of individual cells in tumors with a high prevalence of cachexia, using a technique known as single-cell RNA sequencing. Transcriptome analysis was possible hitherto only with samples of tumor mass, which contains a complex mixture of various cell types.

"With the advance of single-cell RNA sequencing, we're now able to identify exactly which cell secretes which cachexia-inducing factor," Carvalho said.

An international team of scientists and engineers, led by University of Minnesota Associate Professor K. Andre Mkhoyan and Professor Emeritus Michael Tsapatsis (currently, a Bloomberg Distinguished Professor at Johns Hopkins University), have made a discovery that could further advance the use of ultra-thin zeolite nanosheets, which are used as specialized molecular filters. The discovery could improve efficiency in the production of gasoline, plastics, and biofuels.

The breakthrough discovery of one-dimensional defects in a two-dimensional structure of porous material (a zeolite called MFI) was achieved using a powerful high-resolution transmission electron microscopy (TEM) on the University of Minnesota Twin Cities campus. By imaging the atomic structure of the MFI nanosheets at unprecedented detail, the researchers found that these one-dimensional defects resulted in a unique reinforced nanosheet structure that changed the filtration properties of the nanosheet dramatically.

The findings are published in Nature Materials, a peer-reviewed scientific journal.

"TEM imaging of thin zeolite crystal at the atomic-scale has been a long-standing challenge as these crystals are readily damaged under the high-energy electrons, which are needed for atomic-scale imaging," said Mkhoyan, an expert in advanced TEM and the Ray D. and Mary T. Johnson/Mayon Plastics Chair in the Department of Chemical Engineering and Materials Science at the University of Minnesota's College of Science and Engineering. "It requires a deep understanding of the mechanisms of beam damage for zeolite crystals and the doses of electron beam that the zeolite can take. This work pushed the limits of our electron microscopes, where we can reliably produce atomic-resolution images of such extremely thin (just 3-nanometers-thick) zeolite nanosheets with identifiable one-dimensional intergrowths."

The minute differences between the two materials (see enclosed image) was detected by Prashant Kumar, a graduate in the University of Minnesota Twin Cities College of Science and Engineering, after nearly five years of research.

"I have been fascinated by the beautiful symmetrical patterns in MFI crystal throughout my Ph.D. work," said Kumar, a lead author of the study. "After staring at noisy images in the TEM for countless hours, I finally saw the symmetry breaking in the TEM images of MFI nanosheets--I knew this was unusual."

Despite the subtle differences, this knitting of lines of one zeolite within another have pronounced consequences in the ability of nanosheets to recognize and selectively transport molecules enabling selective separations and catalysis. University of Minnesota Professors Traian Dumitrica (mechanical engineering) and Ilja Siepmann (chemistry) led the simulations to test this pattern and performance. Their findings revealed that the knitted materials are less responsive to stress and more selective in separating molecules based on size and shape.

Membranes made from these enhanced nanosheets for the lab simulations were fabricated by a research group led by Tsapatsis, and they were tested under industrial conditions as well by Benjamin McCool, head of separations and process chemistry at ExxonMobil. The latter resulted in record filtration performance--p-xylene and o-xylene separated at five times higher efficiency than the Tsapatsis' group has reported to date.

MFI zeolite is a porous structure of silicon and oxygen atoms and is previously known to grow with one-dimensional structures, or a zeolite called MEL, in bulk form. However, these defects have never been specifically fabricated or intergrown in two-dimensional nanosheets.

"Making ultra-selective thin film membranes and hierarchical catalysts by fine tuning the frequency and distribution of intergrowths of porous frameworks is a concept introduced by our research group a decade ago," said Tsapatsis. "The discovery by TEM of one-dimensional intergrowths in two-dimensional nanosheets and the practical implications suggested by modeling bring the potential of this concept to a new level and suggest new opportunities for targeted synthesis that we have not imagined possible."

His team now hopes to create heterostructures of MFI-MEL nanosheets that can maximize the MEL content and push the filtration performance of the thin films to even higher efficiency, as predicted by the lab simulations. For Mkhoyan--who runs the U's analytical electron microscopy lab, where research at the atomic scale is daily routine--the breakthrough finding is an opportunity to further improve the way microscopes are used to study nanomaterials in atomic-level detail.

Irvine, Calif., March 3, 2020 -- With drug resistance a major challenge in the fight against cancer, a discovery by University of California, Irvine biologists could offer new approaches to overcoming the obstacle. Their research reveals that a mechanism enabling the diseased cells to scavenge dead cell debris for nourishment holds a pivotal role. The study by Aimee Edinger, professor of developmental & cell biology, and researcher Vaishali Jayashankar appears in Nature Communications.

(Link to open access study: https://www.nature.com/articles/s41467-020-14928-3)

"Cancer cells require a tremendous amount of nutrients," Edinger said. "Chemotherapy and other treatments that damage DNA force tumor cells to rev up their metabolism to make the repairs necessary to survive and grow. Targeting DNA metabolism in this way often works for a while, but in virtually all patients, tumor cells become resistant and the treatment becomes ineffective."

In probing the problem, the two scientists examined a process called macropinocytosis. It enables a cancer cell desperate for nourishment to scoop up dead cell material within a tumor and feed on it.

"Tumors contain a lot of dead cells because the blood supply is abnormal, causing many cancer cells to starve to death," Edinger said. "Using this method of scavenging, cancer cells can obtain the amino acids, sugars, fatty acids and nucleotides they require to keep growing."

This new research revealed that macropinocytosis makes a previously unappreciated contribution to breast cancer drug-resistance. Edinger and Jayashankar also demonstrated that the same process could thwart treatments for pancreas and prostate cancer.

"What we see is that blocking macropinocytosis can help us to treat many different cancers more effectively," Edinger said. "This knowledge could enable better biomarker selection in clinical drug trials currently underway, leading to improved response to pharmaceutical combinations. It also provides a strong rationale for developing drugs that target and block macropinocytosis."

The number of treatments for rare diseases affecting children has increased, a new study suggests. But federal incentives intended to encourage drug development for rare conditions are being used more often to expand the use of existing drugs rather than for creating new ones.

Children are estimated to make up half of patients with rare diseases, which includes conditions that affect less than 200,000 Americans. Developing drugs for children with rare diseases is crucial to ensuring new treatment options, but it's not always profitable for drug manufacturers.

To motivate manufacturers to develop drugs to treat rare diseases, or "orphan drugs," federal policy provides incentives such as tax credits, grants for testing, and a seven-year period of exclusivity during which competitors can't market an alternative version of the drug for the same disease.

Of the 402 orphan drug indications approved through the U.S. Food and Drug Administration between 2010 and 2018, a third were specifically for children or for diseases that predominantly affected children, according to the findings published in Pediatrics.

But most of these pediatric orphan drug approvals were new uses of existing drugs, some of which are decades old and had already been approved to treat common diseases. Twenty received breakthrough designation, which is granted to drugs that hold particular promise for improving upon existing treatments.

"Our study reveals reason for optimism and reason for concern," says senior author Kao-Ping Chua, M.D., Ph.D., a pediatrician and researcher at Michigan Medicine C.S. Mott Children's Hospital and the Susan B. Meister Child Health Evaluation and Research Center.

"Many pediatric orphan indications may have represented breakthroughs for children with rare diseases. At the same time, most indications were not for new drugs, and some represented relatively minor expansions of use. Orphan drugs are costly to society, and it's important to make sure that these costs are justified by the amount of benefit to patients."

The researchers found that the 136 pediatric orphan drug approvals targeted 87 unique diseases, most commonly cystic fibrosis, acute lymphoblastic leukemia and immune disorder hereditary angioedema.

"Although the Orphan Drug Act has been effective in incentivizing drug development, our findings suggest that not all pediatric orphan indications hold the same value," says lead author Lauren Kimmel, a research assistant at the University of Michigan Medical School and CHEAR.

"Policymakers should ensure that resources are being used efficiently and effectively to stimulate development of new therapies for rare diseases that don't have any treatment options."

Telomerase allows cancer cells to live forever

Researchers develop small molecule that irreversibly inhibits telomerase

Promising new molecular tool is inspired by nature

EVANSTON, Ill. --- One of the hallmarks of cancer is cell immortality. A Northwestern University organic chemist and his team now have developed a promising molecular tool that targets and inhibits one of cell immortality's underlying gears: the enzyme telomerase.

This enzyme is found overexpressed in approximately 90% of human cancer cells and has become an important subject of study for cancer researchers. Normal cells have the gene for telomerase, but it typically is not expressed.

"Telomerase is the primary enzyme that allows cancer cells to live forever," said Karl A. Scheidt, who led the research. "We want to short-circuit this immortality. Now we have designed a first-of-its-kind small molecule that irreversibly binds to telomerase, shutting down its activity. This mechanism offers a new pathway for treating cancer and understanding cellular aging."

Scheidt is a professor of chemistry in the Weinberg College of Arts and Sciences and a professor of pharmacology at Northwestern University Feinberg School of Medicine.

The big idea for the small molecule design came from nature. A decade ago, Scheidt was intrigued by the biological activity of chrolactomycin, which is produced by bacteria and has been shown to inhibit telomerase.

Scheidt and his team used chrolactomycin as a starting point in the design of their small molecules. They produced more than 200 compounds over the years, and the compound they call NU-1 was the most effective of those tested. Its synthesis is very efficient, taking fewer than five steps.

"NU-1 inhibits telomerase unlike anything that came before it," Scheidt said. "It does this by forming a covalent bond. Another advantage of NU-1 is that its molecular structure should enable scientists to add cargo, such as a therapeutic."

The study was published last week by the journal ACS Chemical Biology.

All human cells have telomeres, short DNA sequences that cap the ends of each strand of DNA. Their job is to protect our chromosomes and DNA. When a cell divides, the telomeres get shorter until they can no longer do their job. Natural cell death follows.

In contrast, cancer cells, with their heightened telomerase activity, become immortal by reversing the normal telomere shortening process. The enzyme telomerase copies telomeres over and over again, lengthening the telomeres. The result is unlimited cell division and immortality. The famous HeLa cells, isolated from the cervical cancer tissue of Henrietta Lacks in the 1950s, are still dividing.

Telomerase has been a target for cancer therapeutics research for decades. In 2009, three scientists received the Nobel Prize in Physiology or Medicine for their earlier research into telomeres and telomerase.

After developing their new compounds, Scheidt and his team initiated collaborations with Professor Stephen Kron at the University of Chicago and Scott Cohen at the Children's Medical Research Institute in Sydney to investigate the extra-telomeric role of telomerase inhibition.

The studies focused on how the new compounds interact with telomerase on a molecular level and how telomerase inhibition sensitizes cells to chemotherapies and irradiation. From this work, NU-1 rose to the top.

"By publishing this study, we are test driving this exquisite tool to see what it can do and to learn more about telomerase," Scheidt said. "We also are continuing to make it better."

The research was done in human cells. The next steps, Scheidt said, are to make more potent compounds and investigate them in animal models.

CRISPR-Cas9 has revolutionized the field of genetics by its ability to cut DNA at defined target sites. Researchers are using the Cas9 enzyme to specifically switch off genes, or insert new DNA fragments into the genome. But no matter how specific the Cas9 enzyme is - sometimes it cuts where it shouldn't. Scientists at the Max Planck Unit for the Science of Pathogens in Berlin and the Faculty of Medicine of the Martin Luther University Halle-Wittenberg now report a Cas9 variant that increases the specificity of genome editing.

In order for Cas9 to cut a DNA target, it needs to be directed to the target site by what is called a guide RNA. The guide RNA contains the complementary sequence to the DNA target site, working like a ZIP Code to guide Cas9 to its target. "Sometimes, however, Cas9 can also cut DNA sequences that are very similar to the actual target, known as off-targets," explains Emmanuelle Charpentier, director of the Max Planck Unit for the Science of Pathogens.

This undesired activity of CRISPR-Cas9 can lead to inaccuracies in genome editing. "An unintended cut at the wrong place in the human genome can have profound consequences. That is why we need a more specific system," says Michael Böttcher, Assistant Professor at the Medical Faculty of the Martin Luther University.

Scientists are therefore trying to optimize Cas9 specificity using different approaches. In the current study, the team of researchers from Berlin and Halle focused on an evolutionarily conserved domain of Cas9, known as bridge helix.

Amino acids form stable loop

The researchers found that the bridge helix plays a critical role in the mechanism by which Cas9 interacts with its guide RNA and DNA target site. They identified a group of amino acid residues that make contact with the phosphate backbone of the guide RNA, thereby facilitating the formation of a stable loop, which is essential for the activity of Cas9. In such a loop, the Cas9-bound guide RNA pairs with the complementary strand of the DNA target sequence while displacing the second DNA strand, thereby enabling Cas9 to cut both DNA strands.

The researchers generated new Cas9 variants by changing these amino acid residues and found that several variants cut much less frequently at off-target sites than the original Cas9 enzyme. They further show that one of the identified variants, called R63A/Q768A, increased the gene editing specificity of Cas9 also in human cells. "Our results provide a new basis for further optimization of CRISPR-Cas9. They demonstrate the need to gain more knowledge about the biochemistry of CRISPR-Cas systems to further improve them", says Charpentier.

Researchers at Washington University School of Medicine in St. Louis appear to have discovered a way to make radiation therapy for colorectal cancer more effective by inhibiting a protein found in cancer cells in the gut. The approach also helps protect healthy tissue from the negative effects of radiation.

Studying cells, mice and tumor samples from patients with cancer, the scientists targeted an enzyme known as indoleamine 2,3 dioxygenase 1 (IDO1). Treating tumor cells with a drug that inhibits that enzyme didn't eliminate colorectal cancer completely. Nor did radiation therapy alone. But when the researchers combined the drug with radiation, cancer cells grew more slowly and, in some cases, stopped multiplying altogether.

The findings are published online March 3 in the journal Cancer Immunology Research.

Radiation therapy is a mainstay of colorectal cancer treatment. Depending on the radiation dose, the therapy can have side effects, such as fatigue, skin issues, and bowel and bladder problems. But the therapy also can slow tumor growth or even destroy tumor cells.

"In every model we studied, the combination therapy showed great promise," said senior author Matthew A. Ciorba, MD, an associate professor of medicine and director of the Inflammatory Bowel Disease Center at Washington University. "Neither strategy was wholly effective by itself, but the combination was very effective, leading to more cell death within tumors, higher activation of the immune system and better protection of healthy tissue."

Excluding certain skin cancers, colorectal cancer is the third most common type of cancer in the United States and the second-leading cause of cancer death. About 145,000 new cases were diagnosed in 2019, with an estimated 51,000 deaths. Death rates from colorectal cancer have been dropping, probably because screening can detect polyps before they become cancerous, and doctors can remove such polyps before they become a problem. But when cancer is more advanced at detection, effective treatments remain elusive.

Ciorba, a gastroenterologist, had been studying the IDO1 protein in research aimed at treating inflammatory bowel diseases such as Crohn's disease and colitis. The IDO1 gene is very active in those disorders, as it is in colorectal cancer.

In this study, the researchers treated colon cancer cell lines with radiation and found that the cells made more IDO1 protein after a single dose. They also looked at tumor samples from patients with colorectal cancer and found that radiation caused those cells to make more of the protein. Further experiments suggested the protein might be protecting cancer cells from the effects of radiation.

"In earlier studies, we had found that the absence of the protein made mice less likely to develop colorectal cancer when the animals were exposed to carcinogens," said the paper's first author, Baosheng Chen, PhD, a research instructor in medicine in the gastroenterology division. "However, blocking the protein using the inhibitor was not as effective as expected in animal models of colorectal cancer. So the focus of our investigation was to see whether we could combine this drug inhibitor with another agent we already use, such as radiation, to treat cancer more effectively."

Using techniques to block the IDO1 gene, as well as the drug epacadostat to block the protein's activity, made radiation more effective in slowing tumor growth. Combining the strategies contributed to tumor shrinkage in 40% of the tumors the researchers studied. In mice, combining radiation with inhibition of the protein also resulted in tumors located away from the primary cancer shrinking or growing more slowly. And in other experiments, the combination therapy prevented recurrence of the cancers.

"It acted almost like a vaccine," Ciorba said. "Mice that received the combined therapies were less likely to develop other cancers of the same type."

The researchers now are testing the approach in people with colorectal cancer.

"Our patients with rectal cancers receive radiation first, and then they have chemotherapy," said study investigator Haeseong Park, MD, an assistant professor of medicine and a medical oncologist. "After radiation and chemotherapy, patients are re-evaluated, and if they still have evidence of cancer, they get surgery. Currently, more than half of our patients eventually need surgery, but our ongoing clinical trial is designed to combine radiation with inhibition of IDO1 to lower the percentage of patients who eventually need surgery, while also protecting them from radiation's toxicities."

Because the protein also is overexpressed in other abdominal and pelvic cancers, Ciorba explained that blocking its activity may be helpful in other types of cancer, too.

"It may be possible to expand this strategy and use it in treating esophageal, cervical and ovarian cancer," he said.

Imagine a wire with a thickness roughly one-hundred thousand times smaller than a human hair and only visible with the world’s most powerful microscopes. They can come in many varieties, including semiconductors, insulators and superconductors.

Scientists at the U.S. Department of Energy’s (DOE’s) Argonne National Laboratory report fabricating and testing a superconducting nanowire device applicable to high-speed photon counting for nuclear physics experiments that were previously thought impossible. This device operates at temperatures near to absolute zero in magnetic fields forty times stronger than previous such devices and is able to detect low-energy photons as well as other fundamental particles.

“The development of these fast, robust superconducting nanowire devices is an important step toward the implementation of broadband single-photon detection for quantum communication applications.” — physicist Joseph Heremans

“This changes the game for the type of particle detector one can design and build,” said Zein-Eddine Meziani, senior physicist in the Physics division. “Think of this as the first unit of something for which we can ultimately connect many of them together in different configurations for use in various nuclear physics experiments.”

The key property of this technology is superconductivity. At the beginning of the twentieth century, Dutch physicist Heike Kamerlingh Onnes discovered the remarkable property of superconductivity in metals. These superconducting materials lose all resistance to the movement of electricity at a temperature of near absolute zero and have found many different applications over the past century. 

“We chose as our material one of the first superconducting alloys ever discovered, niobium nitride,” said lead author Tomas Polakovic, graduate student in the Physics division. “Having been first identified as a superconductor in 1941, this alloy is extremely well understood, is easy to work with, and functions in an environment with high magnetic field and intense radiation bombardment.”

About 15 years ago, scientists found they could fabricate niobium nitride in nanowire form. Over the years, this material has undergone many improvements by various research groups around the world for possible applications in quantum communication and sensing.

The Argonne team combined a nitrogen ion plasma with sputtering of niobium to form thin films of niobium nitride on a silicon substrate. The resulting film is only 10 nanometers thick, roughly 100,000 smaller than a human hair. They then shaped the nanowire into an integrated circuit-like pattern.

When a nanowire detector carrying a large current absorbs a photon, superconductivity is disrupted, creating a local hot spot. This produces a brief signal, which is electrically counted and measured, then the detector rapidly recovers its lost superconductivity and continues counting. Testing demonstrated that the device can detect individual low-energy photons in the demanding conditions of nuclear physics experiments.

While other detectors must operate at around room temperature outside the enclosed space where particles are streaming, scientists will be able to position the Argonne nanowire detector within that space because it can withstand the harsh conditions therein: temperatures near absolute zero, a strong magnetic field, and high particle rate.

“Rather than replacing existing detector technology, our technology opens many new possibilities for nuclear physics experiments,” co-author and Argonne physicist Whitney Armstrong said.

Looking to the future, Polakovic added, “Although we have not tested this hypothesis yet, our device should be able to detect and analyze the signals from not only low-energy photons, but also individual electrons, protons and nuclei like helium-4, which consists of two protons and two neutrons.”

One possible nuclear physics experiment would involve using the Argonne device in experiments with helium-4 to test the reigning theory of the atomic nucleus, quantum chromodynamics.

Joseph Heremans, a physicist in Argonne’s Materials Science division and Center for Molecular Engineering, is already working to incorporate this technology into his quantum research: “The development of these fast, robust superconducting nanowire devices is an important step toward the implementation of broadband single-photon detection for quantum communication applications.”

“Inventors seldom initially understand all possible uses of their inventions,” Meziani added. “I’m sure there will be all kinds of ideas for cutting-edge science experiments using our superconducting nanowire device in the future.”

A paper based on this study, “Superconducting nanowires as high-rate photon detectors in strong magnetic fields,” appeared in Nuclear Instruments and Methods in Physics Research. In addition to Polakovic, Armstrong, and Meziani, authors are V. Yefremenko, J.E. Pearson, K. Hafidi, G. Karapetrov and V. Novosad.

NASA-NOAA's Suomi NPP satellite provided forecasters with a visible image ex-tropical cyclone Esther's remnant clouds that have now moved over Australia's Northern Territory. The remnants have generated a flood watch including in the Tanami and Central Deserts.

Visible imagery from satellites help forecasters understand if a storm is organizing or weakening and the extent and movement of the storm. The Visible Infrared Imaging Radiometer Suite (VIIRS) instrument aboard Suomi NPP provided an image on Mar. 3 that showed the remnant clouds and storms associated with the ex-tropical cyclone have blanketed the Northern Territory. The center of ex-tropical cyclone Esther is located over the northern Tanami District.

On March 3, the Australian Bureau of Meteorology (ABM), Northern Territory issued a Flood Watch for the Tanami Desert, Central Desert, MacDonnell Ranges, Barkly, Georgina River and Simpson Desert. A flood warning was in effect for Sturt Creek District in Western Australia.

ABM noted widespread rainfall totals of 50 to 100 mm (~2 to 4 inches) have been recorded throughout the northern Tanami Desert. Some isolated areas received as much as 190 mm (7.5 inches).

ABM said, "Rainfall is expected to increase in the Central Desert and southeastern Tanami Desert from today with widespread falls of 70 to120 mm (2.8 to 4.7 inches) expected. Isolated falls of 180 mm (7 inches) could also be possible in places. Rainfall is also expected to increase in the MacDonnell Ranges and southern Barkly during today with 40 to 100 mm (1.6 to 4 inches) daily totals expected into tomorrow. Rainfall extends to the upper Georgina River and Simpson Desert during tomorrow with daily rainfall totals 20 to 80 mm (0.8 to 3.1 inches) expected in many areas."

Esther is forecast to move southeast across the southern Barkly area to the Simpson District by Mar. 4.

Many roads including major transport routes in the flood watch area will continue to be affected and become or remain impassable with some communities and homesteads becoming isolated.

Tropical cyclones/hurricanes are the most powerful weather events on Earth. NASA's expertise in space and scientific exploration contributes to essential services provided to the American people by other federal agencies, such as hurricane weather forecasting.

For updated forecasts from ABM, visit: http://www.bom.gov.au/ 

A new species of quail-sized fossil bird from 44 million year old sediments in Utah fills in a gap in the fossil record of the early extinct relatives of chickens and turkeys, and it shows strong links with other extinct species from Namibia in Southern Africa and Uzbekistan in Central Asia.

In their paper in the online scientific journal Diversity, the authors Dr. Thomas Stidham (Institute of Vertebrate Paleontology and Paleoanthropology, Chinese Academy of Sciences), Dr. Beth Townsend (Midwestern University, Arizona), and Dr. Patricia Holroyd (University of California Museum of Paleontology, Berkeley) describe the fossil of a distinct tiny bone from the shoulder girdle of an extinct quail-like bird from 44 million year old rocks in eastern Utah. While it is a unique fossil, the authors have not given it a formal scientific name, waiting until they find more bones of the skeleton. This new Utah bird appears to be the oldest fossil of the extinct group called Paraortygidae, a relative of the living Galliformes (the group that includes the living chicken, turkey, guineafowl, and quail). This fossil fits in a nearly 15 million-year gap in the fossil record of the galliform lineage in North America.

This extinct species is similar in size to the smallest living Galliformes like quail and hill partridges. It likely lived before the evolution of the large crop and gizzard that we see in living chickens and turkeys, and therefore the Utah species likely had a diet different from its living relatives. The earliest fossils of this paraortygid group are from arid habitats, the seashore, and inland forests demonstrating that they had flexibility in their ecology and diet.

Another interesting aspect of this new fossil is that it closely resembles the small size and unique shape of other early paraortygid fossils from sediments with a similar geological age from Namibia in southern Africa and Uzbekistan in Central Asia which were all separated from each other by oceans.

Dr. Stidham comments, "I didn't think much of the little fossil at first. It wasn't until I saw a recent paper by a Russian colleague describing a very similar fossil from Uzbekistan that I realized that we were looking at the same group of birds on different continents." The paraortygid fossils from Europe, Asia, Africa, and North America show that the group was very widely dispersed early in their evolution and crossed oceans in order to be so widely spread.

By contrast, Holroyd knew the find was something special the moment she turned it over with her pick. "I have worked with Beth Townsend in the Uinta Basin since 2011, and it was the first bird bone I had found there. They are incredibly rare, especially ones this small. I didn't think there was anything like it found there before and so snapped a picture to send to Tom even before we had left the field."

Dr. Townsend, the project leader, notes: "The new Uinta bird fills not only a time gap, but also helps us better understand the animal community at this time. The Uinta Basin is important for understanding ecosystems during times of global warm temperatures, when forests, primates, and early horses were spread across an area that is now desert. The discovery of this new paraortygid shows us that small ground-dwelling birds were part of these ancient forests and may have competed with early mammals for resources."

In summary, Dr. Stidham says, "Even tiny incomplete fossils can provide the data to link global scientific questions together." All of the scientists involved in this project are eager to search for more fossil discoveries in the eastern Utah during the next field season.