Culture

The relapse of brain tumors after therapy is driven by cancer stem cells that were not affected by the treatment. In mouse models of glioblastoma, scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) were now looking for molecular markers that specifically characterize brain tumor stem cells. They identified an enzyme that is responsible for the threatening stem cell properties of glioblastoma and at the same time represents a possible "Achilles heel" where cancer stem cells could be vulnerable.

Many cancer therapies destroy normal, rapid dividing cancer cells that make up the bulk of the tumor. The cancer stem cells, however, hardly divide and are resistant to chemotherapy and radiation. Even worse, they are activated by the treatments and are then responsible for the tumor's relapse. This is particularly the case with glioblastoma, the most aggressive of all brain tumors.

"The only way to prevent a relapse after the treatment of a glioblastoma would be a therapy that is effectively targets the brain tumor stem cells," says Haikun Liu from the German Cancer Research Centre (DKFZ). "However, this would require us to know molecular target structures that are specific to these cancer stem cells so that the therapy does not damage healthy cells. However, the problem is that brain tumor stem cells hijack many pathways of healthy brain stem cells and share many molecular characteristics."

Liu and his colleagues therefore undertook to identify specific marker molecules of brain tumor stem cells. They started their investigation on glioblastomas of mice in order to check in a second step whether the discovered structures play a role in human brain tumors as well. Using modern ribosomal RNA sequencing techniques, which allows the scientist to quantify protein translation, they compared the protein equipment of brain tumor stem cells with that of normal brain stem cells.

Among the proteins produced in cancer stem cells, but not in brain stem cells, an enzyme of energy metabolism appeared to be of particular interest: Glycerol-3-phosphate dehydrogenase 1 (GPD1)-producing cancer cells did not divide and occurred mainly in the tumor borders, where the cancer grows into healthy brain tissue. Very early on, about two weeks after the onset of tumor development, the researchers were able to detect GPD1 production in the growing tumor.

GPD1 is known to be a stress responsive gene in yeast, the expression is induced when cells face stress conditions. The specific expression of GPD1 in dormant cancer stem cells but not in neural stem cells suggests that the cancer stem cells use this enzyme to fight against stress signals in the tumor environment. It also indicates that the GPD1 cells are possibly resistant to chemotherapy.

The researchers treated mice with the standard chemotherapeutic agent temozolomide and analyzed the tumors at different points in time after the end of the therapy: During the treatment, the GPD1-producing cells did not divide and remained in a dormancy state characteristic of stem cells. However, with the onset of the relapse, they woke up from their slumber - a strong indication that they are responsible for the recurrence of the tumor. If GPD1 was genetically eliminated from the tumor stem cells of mice, the animals survived longer.

High GPD-1 levels - unfavorable prognosis

Is GPD1 also responsible for the dangerous stem cell properties in human glioblastomas? A database analysis of tumor genomes showed that a high GPD1 production correlates with an unfavorable prognosis in glioblastoma patients. High GPD1 levels are also associated with progression in other types of cancer, such as renal cell carcinoma.

As in the tumors of mice, GPD1-producing cells were found predominantly on the invasion front in tissue sections of human brain tumors. Cell lines cultivated from glioblastomas lost their ability to form tumorspheres, a feature of brain tumor stem cells, after the researchers genetically switched off GPD-1.

"All our results suggest that GPD1 is responsible for the "stemness" of brain tumor stem cells. In normal brain stem cells, the enzyme does not seem to play a special role," summarizes Haikun Liu. From scientific literature, Liu and his colleagues know that mice can live without GPD1 without any problems. Even people whose GPD1 gene is damaged by mutations do not have severe health problems. This is an important indication that it is possible to block the enzyme with active substances without triggering severe side effects.

"This work was a first step towards identifying protein markers that characterize the dormant brain tumor stem cells and investigating their role in tumor biology," said Liu. "We discovered so many interesting properties of GPD1 that we are now going to further investigate the enzyme as a target structure for possible new therapies."

Mitosis is the process by which the genetic information encoded on chromosomes is equally distributed to two daughter cells, a fundamental feature of all life on earth. Scientists led by Alexander Dammermann at the Max Perutz Labs, a joint venture of the University of Vienna and the Medical University of Vienna, now examine how centrioles contribute to this process. The findings, published in "Developmental Cell", help to elucidate the function of these tiny cellular structures in mitosis.

Correct mitosis requires the formation of a filamentous spindle that ensures that chromosomes are separated to opposite ends of the cell. Similar to ropes pulling a heavy weight, the spindle needs an anchor point from where it can develop. This point is provided by centrioles that accumulate a protein meshwork called the pericentriolar material or PCM around them to form centrosomes, which serve as both the origin and attachment site for the filaments of the mitotic spindle.

Centrioles promote mitotic spindle assembly

While it was known that centrioles are essential for the initial formation of the centrosome, their role in further mitotic growth and maintenance of the PCM throughout cell division was previously unclear. The scientists were able to answer these questions with the help of C. elegans, a model organism that has exceptionally large centrosomes. Using laser microsurgery, they were able to remove the centrioles from within the centrosome at different stages of mitosis without destroying the entire structure. "What we found was that centriole ablation did not lead to an immediate collapse of the PCM as we had expected. However, further growth was strongly impaired, revealing a critical role for centrioles in PCM accumulation, and therefore mitotic spindle assembly", first authors Triin Laos and Gabriela Cabral explain.

Centrioles promote centrosome structural integrity

Beyond their role in PCM assembly, centrioles were also essential for structural integrity, with acentriolar centrosomes liable to being pulled apart as cells proceeded through mitosis. This finding was particularly remarkable given the small size of centrioles relative to the surrounding PCM. How centrioles could confer structural integrity to a structure >30x larger is not immediately clear. The authors envision that centrioles provide anchor sites for proteins that impart tensile strength to the PCM by acting similar to steel bars in reinforced concrete. By controlling PCM assembly and structural integrity, centrioles then have critical roles throughout cell division. How centrioles perform these apparently disparate functions remains the biggest open question, the authors agree.

Scientists at DESY have achieved a new world record for an experimental type of miniature particle accelerator: For the first time, a terahertz powered accelerator more than doubled the energy of the injected electrons. At the same time, the setup significantly improved the electron beam quality compared to earlier experiments with the technique, as Dongfang Zhang and his colleagues from the Center for Free-Electron Laser Science (CFEL) at DESY report in the journal Optica. "We have achieved the best beam parameters yet for terahertz accelerators," said Zhang.

"This result represents a critical step forward for the practical implementation of terahertz-powered accelerators," emphasized Franz Kärtner, who heads the ultrafast optics and X-rays group at DESY. Terahertz radiation lies between infrared and microwave frequencies in the electromagnetic spectrum and promises a new generation of compact particle accelerators. "The wavelength of terahertz radiation is about a hundred times shorter than the radio waves currently used to accelerate particles," explained Kärtner. "This means that the components of the accelerator can also be built to be around a hundred times smaller." The terahertz approach promises lab-sized accelerators that will enable completely new applications for instance as compact X-ray sources for materials science and maybe even for medical imaging. The technology is currently under development.

Since terahertz waves oscillate so fast, every component and every step has to be precisely synchronized. "For instance, to achieve the best energy gain, the electrons have to hit the terahertz field exactly during its accelerating half cycle," explained Zhang. In accelerators, particles usually do not fly in a continuous beam, but are packed in bunches. Because of the fast-changing field, in terahertz accelerators these bunches have to be very short to ensure even acceleration conditions along the bunch.

"In previous experiments the electron bunches were too long", said Zhang. "Since the terahertz field oscillates so quickly, some of the electrons in the bunch were accelerated, while others were even slowed down. So, in total there was just a moderate average energy gain, and, what is more important, a wide energy spread, resulting in what we call poor beam quality." To make things worse, this effect strongly increased the emittance, a measure for how well a particle beam is bundled transversally. The tighter, the better - the smaller the emittance.

To improve the beam quality, Zhang and his colleagues built a two-step accelerator from a multi-purpose device they had developed earlier: The Segmented Terahertz Electron Accelerator and Manipulator (STEAM) can compress, focus, accelerate and analyze electron bunches with terahertz radiation. The researchers combined two STEAM devices in line. They first compressed the incoming electron bunches from about 0.3 millimetres in length to just 0.1 millimetres. With the second STEAM device, they accelerated the compressed bunches. "This scheme requires control on the level of quadrillionths of a second, which we achieved," said Zhang "This led to a fourfold reduction of the energy spread and improved the emittance sixfold, yielding the best beam parameters of a terahertz accelerator so far."

The net energy gain of the electrons that were injected with an energy of 55 kiloelectron volts (keV) was 70 keV. "This is the first energy boost greater than 100 percent in a terahertz powered accelerator," emphasised Zhang. The coupled device produced an accelerating field with a peak strength of 200 million Volts per metre (MV/m) - close to state-of-the-art strongest conventional accelerators. For practical applications this still has to be significantly improved. "Our work shows that even a more than three times stronger compression of the electron bunches is possible. Together with a higher terahertz energy, acceleration gradients in the regime of gigavolts per metre seem feasible," summarized Zhang. "The terahertz concept thus appears increasingly promising as a realistic option for the design of compact electron accelerators."

What The Study Did: Photographs of 24 men before and after facial cosmetic surgery were part of this survey study to examine whether surgery was associated with perceived changes in attractiveness, masculinity and a variety of personality traits.

The study was carried out in the Dulbecco Telethon Laboratory of Prions & Amyloids at CIBIO, lead by Emiliano Biasini, University of Trento and involved the team led by Prof. Pietro Faccioli, a physicist from the same university and affiliated to the Italian National Institute of Nuclear Physics.

Prions are unusual infectious agents made by aberrantly folded forms of a physiological protein called the cellular prion protein, or PrPC. These pathogens are known to replicate in absence of genetic material by recruiting normal PrPC molecules at the surface of cells and forcing them to change conformation and become infectious themselves. The resulting accumulation of prion particles in the nervous system lies at the root of neurodegenerative conditions known as transmissible spongiform encephalopathies, including Creutzfeldt-Jakob disease, fatal familial insomnia and Gerstmann-Sträussler-Scheinker in human, but also a variety of other pathologies in mammals such as the famous mad cow disease, which in the nineties caused a large epidemics in UK and Europe and several cases of cross-species transmission to human caused by the ingestion of infected meat.

Even though we know the existence of prions since 1982, thanks to the work of Nobel Laureate Stanley Prusiner, direct information regarding the structure of these non-canonical infectious agents is still lacking» - says Emiliano Biasini, Assistant Telethon Scientist and Associate Professor at the Department CIBIO, University of Trento. &laquoIn fact, their insoluble and aggregated nature hampers the use of classical high resolution techniques for studying protein structures such as X-ray crystallography or nuclear magnetic resonance. However, such information is instrumental to rationally design drugs against these agents. In an attempt to fill this gap, we found unexpected help from a discipline usually considered far away from biology or chemistry, that is particles physics.

Telethon researchers revised previous models of prion structure and proposed a novel architecture consistent with recent experimental data. This new model allowed Pietro Faccioli's group to apply their innovative algorithms for the reliable prediction of protein conformational transitions to the prion replication mechanism &laquoCross-disciplinarity has been the key» - explains Giovanni Spagnolli, Ph.D. student at the Department CIBIO, University of Trento and first author of the paper. &laquoWithout the contribution of the colleagues from physics we would have never been able to afford the kind of calculation required to simulate such complex systems. For the first time we reconstructed a physically-plausible mechanism of prion replication, which now allow us to formulate new hypotheses and design new drug discovery schemes to tackle the neurodegenerative processes unleashed by these infectious agents.

The calculation algorithms that allowed the reconstruction of prion replication are derived from mathematical methods of theoretical physics, originally formulated to study phenomena of the subatomic world, such as the quantum tunneling effect. These mathematical methods have been adapted here to allow the simulation of complex biomolecular processes such as the folding and aggregation of proteins - says Pietro Faccioli, Associate Professor at the Department of Physics, University of Trento and affiliated to the Italian National Institute for Nuclear Physics.

Stem cells self-renew and give rise to cells that are differentiated during development. These differentiated cells can change into stem cells under appropriate conditions in most plants, in which this process is more readily apparent, and some animals. Researchers have previously succeeded in forming new shoots from intact leaves by inducing single transcription factors in Arabidopsis. However, it has not been clear whether these transcription factors induce meristematic tissue that subsequently induces stem cells or directly induces them. To this end, Assistant Professor Masaki Ishikawa and Professor Mitsuyasu Hasebe at the National Institute of Basic Biology in Japan, Designated Associate Professor Yoshikatsu Sato of the Institute of Transformative Bio-Molecules (WPI-ITbM) at Nagoya University in Japan and their collaborators found that induction of the transcription factor STEM CELL INDUCING FACTOR1 (STEMIN1) in leaves directly changes leaf cells into stem cells in the moss Physcomitrella patens. This discovery of a direct stem cell inducing factor will facilitate the further elucidation of the molecular mechanisms underlying stem cell formation in land plants.

In most plants and some animals, differentiated cells can revert to stem cells during or even after development under appropriate conditions. While stem cells do not appear to initiate after embryogenesis in mammalians, induction of some transcription factors induces conversion of somatic cells to induced pluripotent stem (iPS) cells. However, plant cells are more plastic than animal cells. In particular, stem cell formation is widely observed in the process of making new organs during development and regeneration in land plants. However, Professor Mitsuyasu Hasebe said, "Although some regulators involved in stem cell formation have been identified in angiosperms, understanding the molecular mechanisms of reprogramming and stem cell formation in land plants in general as well as their evolution is still challenging."

Prof. Hasebe and his colleagues aimed to understand molecular mechanisms underlying stem cell formation by using the moss Physcomitrella patens and started a research project named "ERATO Hasebe Reprogramming Evolution project" supported by the Japan Science and Technology Agency in 2005. This moss is a good model to study stem cell formation from differentiated cells. The leafy shoot (gametophore) is formed after a hypha-like branching growth of a filamentous tissue (protonema) has arisen from a spore. When a leaf is excised from a gametophore and cultivated on a culture medium, leaf cells facing the cut convert into stem cells that can undergo tip growth and cell division to produce protonema. In screening for factors involved in stem cell formation, Dr. Yohei Higuchi and Dr. Yoshikatsu Sato, a group leader of the project, succeeded in identifying a gene encoding a transcription factor that changes leaf cells into stem cells without wounding signals, thus leading to formation of protonemata. Dr. Sato said, "This gene was named STEMIN1 (STEM CELL-INDUCING FACTOR 1)".

After the project, Dr. Masaki Ishikawa succeeded in revealing the molecular mechanisms of STEMIN1 during stem cell formation. He said, "We found that STEMIN1 gene was activated in leaf cells that underwent stem cell formation in excised leaves. Furthermore, the deletion of STEMIN1 and its two homolog genes delayed the stem cell formation after leaf excision. These results indicate that STEMIN1 functions in an inherent mechanism to initiate formation of stem cells in Physcomitrella." To further understand this molecular mechanism, Ms. Mio Morishita, a graduate student from SOKENDAI (The Graduate University for Advanced Studies) focused on the STEMIN1-direct target genes. She found that the genes were marked by trimethylation of histone H3 at lysine-27 (H3K27me3), a so-called repressive histone modification, and were transcriptionally repressed in leaf cells. In contrast to this, she also said, "STEMIN1 induction in leaf cells specifically decreased the repressive histone modification levels in the STEMIN1-direct target genes before cell division and activated their gene expression, leading to the formation of stem cells."

Thus, this research group has demonstrated that STEMIN1 functions in an intrinsic mechanism underlying local histone modification changes to initiate stem cell formation. Prof. Hasebe said, "Our new findings will enhance studies on mechanistic insights regarding how a single transcription factor induces stem cell formation in land plants. In addition, since other land plants including angiosperms have orthologs of the STEMIN genes, further studies of this gene family should provide insight into whether this is a general mechanism for stem cell formation in land plants."

A QUT observational study of electric scooter riding in central Brisbane has found nearly half of shared e-scooters were being ridden illegally.

The research has identified the need to ensure that helmets were available for shared e-scooter riders, and called for further research into whether bicycle helmet standards are adequate for e-scooters.

Professor Narelle Haworth, from QUT's Centre for Accident Research and Road Safety - Queensland (CARRS-Q), has published the results of the study in The Medical Journal of Australia.

In the study, the researchers counted passing scooters and bicycles at six locations around central Brisbane for four days and for six hours a day.

The researchers recorded 785 e-scooters, 90 per cent of which were Lime shared scooters and 10 percent were private scooters.

Of the e-scooters observed during the four days, 45 per cent were being ridden illegally because either the rider was not wearing a helmet properly, riding on the road or carrying a passenger.

The most common illegal behaviour by people riding shared e-scooters related to the use of helmets, with 39 per cent either having no helmet or wearing a helmet that was not properly fastened.

The researchers noted a clear difference in safety practices between people who rode private e-scooters and those who rode scooters from a sharing scheme.

The study found about 60 per cent of riders of shared scheme e-scooters wore a helmet correctly during their ride, compared with more than 95 per cent of riders of private e-scooters.

That trend was echoed by the study's observation of bike riders, with 98 percent of private bike riders wearing their helmet correctly compared with 81 per cent of shared-scheme bike riders.

Professor Haworth said dockless e-scooter sharing schemes had emerged in the United States in the past two years, and there were more than 10 e-scooter companies now operating in more than 100 cities across 26 states.

Lime, one of the biggest e-scooter companies, received a permit from the Brisbane City Council to operate in November last year, and there were more than 500,000 trips in the first three months.

"While the e-scooter share schemes are popular, there are concerning reports of escalating emergency presentations due to e-scooter injuries to both riders and pedestrians," Professor Haworth said.

"It is unclear whether the rules appropriately address the safety risks for riders and pedestrians.

"In their submission to a national working party investigating the safety of innovative vehicles, the Royal Australian College of Surgeons and the Australian Injury Prevention Network identified 134 Lime scooter riders attending Brisbane hospitals in the first two months of this year.

"Among the 109 people where injury information was available, 27 per cent had limb fractures, and 14 per cent had some sort of head injury."

The significant factors identified in the injuries were non-use of helmets, speeds exceeding 30km/h and alcohol use.

Professor Haworth said while Lime issued helmets with all of its e-scooters when the scheme started, media reports indicated that many shared e-scooters in Brisbane had no helmets with them when the study was conducted.

"The low helmet wearing rates found for shared e-scooters demonstrates the need to ensure that helmets remain available, and that adequate levels of police enforcement of helmet wearing rules occur," Professor Haworth said.

"Further research is needed to investigate whether the current bicycle helmet standards are adequate for e-scooters."

The study found that more than 89 per cent of shared e-scooter rides in Brisbane were carried out by adults, with nearly nine percent by teenagers and the remaining one per cent by children. About three quarters of shared e-scooters riders were male.

The observational study was conducted between Monday 18 February and Thursday 21 February, about four months after Lime received a permit to operate a dockless e-scooter sharing scheme in Brisbane. The researchers observed the riders from locations on Ann St, Adelaide St, Eagle St, William St, George St and Albert St.

When multidisciplinary health care teams were engaged in caring for patients suffering from refractory cardiogenic shock, a severe condition that can occur after a heart attack, the likelihood of survival increased significantly, by approximately 50 percent. The proof of concept study by investigators at University of Utah Health was published online in the July issue of Circulation.

Patients seen by a multidisciplinary team had a 75 percent chance of survival at 30 days compared to a 50 percent survival rate for those treated before the new approach was implemented. The study, carried out at University Hospital in Salt Lake City, included 123 patients admitted between April 2015 and August 2018 and compared their data with the immediately preceding 121 patients.

"These patients are the sickest of the sick," says Iosif Taleb, M.D., first author of the study and a postdoctoral fellow in cardiology at U of U Health. "Taking a multidisciplinary approach provided a strong survival benefit compared to standard of care treatment."

Refractory cardiogenic shock happens after the heart and circulatory system fail despite optimal medical management, resulting in a lack of blood to adequately fuel organs in the body. To remedy the life-threatening situation, increasingly these patients are connected to a device that mechanically circulates the blood. Despite intervention, 40 to 50 percent die within 30 days. These grim statistics have remained steady worldwide for the past 30 years.

Because of differences in the cause of cardiogenic shock between patients and complexities associated with treating their condition, no published medical guidelines exist for this population. Stavros Drakos, M.D., Ph.D., senior author of the study and medical director of the heart failure and mechanical circulatory support program at U of U Health, wondered whether tapping into existing collaborations within the cardiovascular team could improve the situation for this subset of heart failure patients whose outcomes are amongst the worst.

To test the idea, Drakos and colleagues assembled providers into a single Shock Team. Comprised of a heart failure cardiologist, a cardiothoracic surgeon, an interventional cardiologist and an intensive care unit physician, together they combine their expertise to make decisions regarding each patient's treatment and care. That includes the best type of mechanical circulatory support, how adverse events that arise should be treated and other clinical and follow-up care decisions.

The approach improved survival rate at 30 days for both patients that were discharged and those that remained in the hospital regardless of whether they were originally admitted to University hospital or transferred from referring hospitals. Team decision-making did not appreciably impact the speed of care, as measured by the amount of time between presentation of refractory cardiogenic shock and placement on mechanical support.

Antigone Koliopoulou, M.D., co-author and U of U Health cardiothoracic surgeon, reasons that their success emanates from the collective wisdom of the team. "We think that having a consensus medical decision while carefully discerning positives and negatives of each patient case from the point of view of all involved medical specialties is more likely to be appropriate compared to an individual physician's decision," she says.

At University Hospital, where the study was carried out, the Shock Team remains standard of care practice, demonstrating that the approach is sustainable. Larger clinical trials will need to be carried out to gauge effectiveness in different populations and hospitals.

"This work demonstrates that outcomes can improve when research and academic aspects of such clinical programs are developed in close connection," Drakos says. "Parallel development is mutually beneficial and comes full circle, increasing both the potential of the research and of clinical and patient care."

Heritable Genome Editing in a Global Context: National and International Policy Challenges

Achim Rosemann, Adam Balen, Brigette Nerlich, Christine Hauskeller, Margaret Sleeboom-Faulkner, Sarah Hartley, Xinqing Zhang, and Nick Lee

Ever since the birth of the first human babies from gene edited embryos last year, calls for governance of heritable human genome editing have intensified. But such regulations pose challenges: there are legal differences across jurisdictions, which could lead to germline therapy tourism and rogue research, among other issues. The authors present findings from a multistakeholder study conducted in the United Kingdom on the challenges of governing heritable genome editing. They propose six policy options for enabling safe and ethical clinical applications, including proactive regulation, broad public engagement, and restrictions on advertising. Achim Rosemann is a research fellow at the Department of Sociology at the University of Exeter; Adam Balen is a professor of reproductive medicine and surgery at the University of Leeds; Christine Hauskeller is a professor in the sociology of science at the University of Exeter; Margaret Sleeboom-Faulkner is professor of social and medical anthropology at the University of Sussex; Sarah Hartley is a senior lecturer at the University of Exeter Business School; Xinqing Zhang is professor of social science and bioethics at Peking Union Medical College; Nick Lee is an associate professor at the Centre for Education Studies of the University of Warwick .

Another Voice: "The Experts Are Not Enough": Benjamin Hurlbut of Arizona State University argues that the findings offered by Rosemann and colleagues may ignore the deeper questions about the acceptability of heritable genome editing, focusing instead on limited questions about "how to police outlaws at the margins." The problem, he argues, is that the participants in the study may not be representative of the broad public. He argues that how the stakeholders--and the stakes--of global governance of heritable genome editing are identified should be disclosed and discussed.

A Reluctant Critic: Why Gynecologic Surgery Needs Reform

Louise P. King

Most obstetrician-gynecologists operate so infrequently that their skills may deteriorate, putting their patients at risk. And yet OB-GYNs rarely disclose their lack of experience to their patients. "From an ethical perspective, this status quo cannot be allowed to persist," writes Louise P. King, an assistant professor of obstetrics, gynecology and reproductive biology at Harvard Medical School and a surgeon within the Division of Minimally Invasive Gynecologic Surgery at Beth Israel Deaconess Medical Center. She calls for OB/GYNs to disclose their surgical experience to patients during the informed consent process and for doctors with low volume for the surgery in question to offer referrals to more experienced providers.

Also in this issue:

The Relational Poptential Standard: Rethinking the Ethical Justification for Life-Sustaining Treatment for Children with Profound Cognitive Disabilities

Controlling Measles Through Politics and Policy

Perspective: Beecher Reconsidered

Book Review: The Social Science Blues

URBANA, Ill. - A corn gene identified from a 118-year-old experiment at the University of Illinois could boost yields of today's elite hybrids with no added inputs. The gene, identified in a recent Plant Biotechnology Journal study, controls a critical piece of senescence, or seasonal die-back, in corn. When the gene is turned off, field-grown elite hybrids yielded 4.6 bushels more per acre on average than standard plants.

Dating back to 1896, the Illinois experiment was designed to test whether corn grain composition could be changed through artificial selection, a relatively new concept introduced by Charles Darwin just 37 years earlier. Repeated selection of high- and low-protein corn lines had the intended effect within about 10 generations. As selection for the traits continued, however, additional changes were noticeable.

"One of the things that was noted as early as the 1930s was that the low-protein line stays greener longer than the high-protein line. It's really obvious," says Stephen Moose, professor in the Department of Crop Sciences at Illinois and co-author of the study.

Staying green longer into the season can mean more yield. The plant continues photosynthesizing and putting energy toward developing grain. But, until now, no one knew the specific gene responsible for the stay-green trait in corn.

"The stay-green trait is like a 'fountain of youth' for plants because it prolongs photosynthesis and improves yield," says Anne Sylvester, a program director at the National Science Foundation, which funded this research. "This is a great basic discovery with practical impact."

The discovery of the gene was made possible through a decade-long public-private partnership between Illinois and Corteva Agriscience. Moose and Illinois collaborators initially gave Corteva scientists access to a population derived from the long-term corn protein experiment with differences in the stay-green trait. Corteva scientists mapped the stay-green trait to a particular gene, NAC7, and developed corn plants with low expression for the trait. Like the low-protein parent, these plants stayed green longer. They tested these plants in greenhouses and fields across the country over two field seasons.

Not only did corn grow just fine without NAC7, yield increased by almost 5 bushels per acre compared to conventional hybrids. Notably, the field results came without added nitrogen fertilizer beyond what farmers typically use.

"Collaborating with the University of Illinois gives us the opportunity to apply leading-edge technology to one of the longest running studies in plant genetics," says Jun Zhang, research scientist at Corteva Agriscience and co-author of the study. "The insights we derive from this relationship can result in more bushels without an increase in input costs, potentially increasing both profitability and productivity for farmers."

Moose's team then sequenced the NAC7 gene in the high- and low-protein corn lines and were able to figure out just how the gene facilitates senescence and why it stopped working in the low-protein corn.

"We could see exactly what the mutation was. It seems to have happened sometime in the last 100 years of this experiment, and fortunately has been preserved so that we can benefit from it now," Moose says.

He can't say for sure when the mutation occurred, because in the 1920s crop sciences faculty threw out the original seed from 1896.

"They had no way of knowing then that we could one day identify genes controlling these unique traits. But we have looked in other corn and we don't find this mutation," Moose says.

Future potential for this innovation could include commercialized seed with no or reduced expression of NAC7, giving farmers the option for more yield without additional fertilizer inputs.

Moose emphasizes the advancement couldn't have happened without both partners coming to the table.

"There's value to the seed industry and society in doing these long-term experiments. People ask me why university scientists bother doing corn research when companies are doing it," he says. "Well, yeah they are, and they can do things on a larger and faster scale, but they don't often invest in studies where the payoffs may take decades."

Pelvic pain associated with endometriosis often becomes chronic and can persist (or recur) following surgical and hormonal interventions. According to results published in Regional Anesthesia & Pain Medicine, treating pelvic floor muscle spasm with botulinum toxin may relieve pain and improve quality of life. The study was conducted by scientists at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

"The botulinum toxin injections were incredibly effective in decreasing pain levels, as well as patients' use of pain medications, including opioids," said Pamela Stratton, M.D., a gynecologist and scientist at NINDS, who co-led the study with Barbara Karp, M.D., a neurologist and program director at NINDS. "Many of the women in our study reported that the pain had a profound effect on their quality of life, and this treatment may be able to help them get their lives back."

Endometriosis occurs when the uterine tissue lining grows outside of the uterus and is estimated to affect up to 176 million women worldwide. It is an inflammatory condition that can lead to infertility and cause chronic pain. The usual gynecologic treatments include hormonal therapy and surgery to remove the growths. However, in many cases, pain returns after the interventions.

In the study, women with surgically treated endometriosis who were generally taking hormones to suppress menses, but who continued to experience pain and had pelvic floor muscle spasm, initially received injections of botulinum toxin or saline as part of a placebo-controlled clinical trial, targeting areas of spasm. At least one month after the masked study injection, 13 participants chose to receive open-label botulinum toxin injections in areas that remained in spasm and were then followed for at least four months. These patients were described in the current study at the NIH Clinical Center.

In all participants, during follow-up, pelvic floor muscle spasm was not detected or occurred in fewer muscles. Within two months of receiving the injections, pain decreased in all of the participants, with 11 out of 13 subjects reporting that their pain was mild or had disappeared. Additionally, usage of pain medication was reduced in more than half of the participants. Prior to receiving toxin injections, eight participants reported moderate or severe disability and after treatment, six of those patients noted an improvement.

The participants experienced a decrease in muscle spasm and had pain relief that resulted in less disability and less use of pain medication. These findings suggest that pelvic floor muscle spasm may be experienced by women with endometriosis and contribute to pain persisting after standard treatment. Importantly, the beneficial effects were long-lasting, with many patients reporting pain relief lasting at least six months.

Botulinum toxins, such as Botox, work by blocking the nerve signals for muscles to contract and have been used to treat migraines and certain movement disorders. Previous research has suggested that botulinum toxin may help women experiencing other types of chronic pelvic pain, but this treatment had not been studied in women with endometriosis.

"We know that many doctors are using botulinum toxin to help their patients, but everyone uses slightly different techniques and methods, including different brands of toxin and various doses. This study will begin to provide rigor to help ensure standardized protocols and treatment in pelvic pain," said Dr. Karp.

Larger clinical studies will need to confirm the current findings. In addition, future research will focus on the mechanisms underlying chronic pelvic pain and better understanding of ways in which botulinum toxin may help treat those disorders.

Yersinia have spread fear and terror, especially in the past, but today the plague pathogens have still not been completely eradicated. The bacteria inject various enzymes, including the enzyme YopO, into the macrophages of the immune system. There it is activated and prevents the defense cells from enclosing and digesting the plague bacteria. Using the latest methods, scientists from the Institute of Physical and Theoretical Chemistry at the University of Bonn have now deciphered how YopO changes its shape and thus contributes to confusing the immune system. The results have now been published in the journal "Structure".

Yersinia also includes the plague pathogen, which caused fear and terror worldwide until the discovery of antibiotics. The major epidemics are over, but the World Health Organization (WHO) reported a total of 1451 deaths in 21 countries between 1978 and 1992. Plague bacteria are also found in wild rodents. The transmission occurs mainly via fleas, but also via droplet infection. "Yersinia trick the macrophages of the immune system," says Dr. Gregor Hagelüken from the Institute of Physical and Theoretical Chemistry at the University of Bonn.

The structural biologist has already done research in Yersinia as a PhD student at the Helmholtz Centre for Infection Research in Braunschweig. The special feature of the plague pathogens is a kind of syringe with which they inject the YopO and some other enzymes into the macrophages of the immune system. However, YopO only becomes active when it binds to the actin of the scavenger cell. Normally, the structural protein actin helps the phagocyte to form protrusions with which it flows around the pathogens and then disolves them into small pieces. During this process, the macrophage calls for help from other defense cells.

YopO disrupts the communication of the immune system

"As soon as YopO has bound to the actin, however, it helps to disrupt communication within the macrophage - it can no longer attack," reports Hagelüken. "The Yersinia remain ultimately undisturbed." Researchers have been wondering for quite some time how YopO is activated by binding to actin, thus turning on the switch for the dramatic progression. "Scientists at Oxford University and the National University of Singapore deciphered the structure of the actin-bound YopO as early as 2015," reports Hagelükens colleague and lead author Martin F. Peter. However, the structure was a kind of "still image": it was not recognizable how the YopO changes its shape when it binds to the actin.

"Enzymes are not stiff structures but have several mobile `hinges´ with which they can change their shape," explains Hagelüken. The researchers wanted to take two "snapshots": One of YopO alone and in a second pass one of the YopO/actin complex. These "before and after images" should show how the two partners change their shape as a result of the complex formation. "This idea was a challenge because the normal method of crystal structure analysis did not work with the free YopO. As it turns out, it is too flexible to form ordered crystals," says Peter.

Latest tools for structure elucidation

The scientists at the University of Bonn therefore used several instruments from the structural elucidation toolbox. Together with Dr. Dmitri Svergun from the European Molecular Biology Laboratory in Hamburg, they used the PETRA III electron accelerator of the German Electron Synchrotron DESY. "The extremely intense and focused X-rays can be used to study the overall structure and structural changes of enzymes dissolved in water with the aid of small-angle X-ray scattering," said Svergun.

In addition, the researchers attached spin markers to certain positions of YopO and actin. These function like survey points in the landscape at which, for example, the exact location of a property can be determined. "Using the spin markers, we can use a molecular ruler - the PELDOR method - to measure the nanometer distances between these positions and thus determine how YopO and actin change shape," reports Hagelüken. So far it has been presumed that YopO performs a folding movement like scissors as soon as it binds to actin. "Our results strongly indicate, however, that it is not a larger movement, but many small ones, with which YopO enters the active state," says Peter.

Towards tailor-made substances

If detected in time, the plague can be cured well with antibiotics. "However, bacteria can become resistant if antibiotics are used frequently, which means that the drugs no longer work properly," says Hagelüken. If the basic processes of pathogens with which they outwit the immune system are better understood, it might also be possible to develop more targeted, tailor-made substances to inhibit them.

This clear, gooey substance, which is naturally produced by the human body, has been popularized by cosmetic and skin care products that promote healthier, plumper and more supple skin. Also recognized for its abilities to speed up wound healing, reduce joint pain from osteoarthritis, and relieve dry eye and discomfort, a neuroscientist at Florida Atlantic University's Brain Institute (I-BRAIN) and Schmidt College of Medicine, has discovered a novel mechanism and role in the brain for hyaluronic acid.

In a study published in the journal Brain, Behavior and Immunity, Ning Quan, Ph.D., lead author, a professor of biomedical science in FAU's Schmidt College of Medicine and a member of I-BRAIN, and collaborators, have discovered that hyaluronic acid may be the key in how an immune signal moves from the blood stream to the brain, activating the brain's resident immune cells, the microglia.

This unsuspected molecule may be the main signal passed between these cells, and this new discovery could lead to novel opportunities to shut down brain inflammatory responses. Findings from this study have important implications for better treatments for stroke, neurodegenerative diseases, as well as head injuries.

"We normally think of hyaluronic acid with respect to cartilage formation and also for its role in many processes including cancer progression and metastasis," said Quan. "However, what we have uncovered in our study is a completely unique role for this molecule. We have been able to document a connection between the blood cells and the brain cells, showing that the activating signal passed between these cells is hyaluronic acid."

Quan and collaborators from the Sichuan University, The Ohio State University, and the University of Illinois Urbana-Champaign, demonstrate that inflammation in the central nervous system is oftentimes quenched or restricted, as neurons are extremely vulnerable to inflammation-caused damages. However, this inflammation can be aberrantly amplified through endothelial cell-microglia crosstalk when the brain constantly receives inflammatory signals. Quan's work identified hyaluronic acid as the key signal released by endothelial cells to stimulate microglia and promote oxidative damage.

"To prevent the inflammation from being intensified in the brain, you have to stop the communication between the two cell types," said Xiaoyu Liu, Ph.D., another corresponding author of the study in FAU's Schmidt College of Medicine and I-BRAIN. "We found ascorbyl palmitate, also known as 'Vitamin C Ester,' to be quite effective in inhibiting microglia and reducing the production of inflammatory hyaluronic acid."

In the past, Vitamin C Ester has been widely used as a source of vitamin C and an antioxidant food additive. Now, this latest discovery suggests a novel function of Vitamin C Ester: treating central nervous system inflammation.

"As the newest addition to our Department of Biomedical Science, Dr. Quan's work already is making an important impact on our mission to advance understanding of human health and disease," said Janet Robishaw, Ph.D., senior associate dean for research and chair of the Department of Biomedical Science in FAU's Schmidt College of Medicine. "Long known as a popular skin and joint supplement, this discovery identifies a novel role for hyaluronic acid to potentially treat conditions caused by inflammation in the central nervous system."

Inflammation can occur in the central nervous system as a result of head trauma or stroke, or as part of a systemic immune response. Inflammation within the central nervous system has been associated with chronic neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and multiple sclerosis.

"Neurological disorders such as Parkinson's disease and Alzheimer's disease impact all races, genders, and geographical backgrounds," said Randy Blakely, Ph.D., executive director of FAU's I-BRAIN. "Findings from this study may thus have global implications for how we treat neurodegeneration arising from traumatic brain injuries and brain changes associated with aging and dementia. This exceptional research by Dr. Quan and his colleagues is a testament to the cutting-edge work that is being conducted by our Brain Institute members and the research faculty in FAU's Schmidt College of Medicine."

A new genome-wide analysis by Marta Pereira Verdugo and colleagues uncovers the complex origins of domestic cattle (Bos taurus), demonstrating why it has been difficult to untangle these origins from studies of modern breeds. Cattle were first domesticated around 10,500 years ago from the extinct Eurasian auroch, Bos primigenius, in northern Mesopotamia. By comparing the auroch genome to the genomes of 67 ancient Bos taurus specimens from archaeological sites in the Near East, Verdugo et al. conclude that the first domesticated cattle populations had diverse origins among aurochs, with multiple strains of wild auroch contributing to a growing population of domesticated cows. Around 4,000 years ago, Bos taurus populations across the region received a rapid and widespread influx of primarily male genetic material from the zebu (Bos indicus) from the Indus Valley. This genomic shift occurred during a multi-century drought, and the drought-adapted zebu may have been brought into the domesticated cattle populations as a way to keep herds thriving under arid conditions, the researchers say.

Most mammalian new mums are fiercely protective of their precious offspring; even 5-8 m long southern right whale calves are vulnerable to attack by voracious killer whales. Mia Nielsen from Aarhus University, Denmark, explains that whale mothers and calves often try to hide from predators by gravitating to cloudy water. But the loss of visual contact could force mothers and their young to call to each other more, increasing the risk of attracting the wrong attention. Knowing that humpback whale mothers resort to whispering to their young to protect them from harm, Nielsen and her colleagues, Lars Bejder from the University of Hawaii at Manoa and Peter Madsen, also from Aarhus University, decided to listen in on the conversations between southern right whale (Eubalaena australis) mothers and their calves, to find out how they go unnoticed. The team publishes its discovery that the mothers and their calves shelter in the noisy surf, stay in close proximity and effectively whisper - calling softly less than once per dive - to avoid attracting any unwanted attention in Journal of Experimental Biology at http://jeb.biologists.com.

'One of the initial challenges was getting to know the whales in our study area', says Nielsen, who travelled to Flinders Bay - off the southern tip of Western Australia where the whales breed - with Madsen, Bejder and Fredrik Christiansen to track the graceful creatures. 'The number of whales that frequent the bay is low', says Nielsen, who admits that she was surprised when they eventually located the females with their calves in the surf zone close to shore; which puzzled the researchers. Why were the mothers taking refuge in the most turbulent water? Were the crashing waves providing acoustic cover? And would the mothers and their offspring call to each other more frequently in the stirred-up water to keep in touch?

Stealthily approaching the whales while they rested at the surface, the team attached sound recording tags to the youngsters and their mums in the hope of recording the pair's interactions. 'The tags stayed on the mothers for about 7 hours on average', says Nielsen; however, the calves' tags detached within 40 mins. 'Southern right whales are very physical with each other, the calves spend a lot of time rubbing against the mother and rolling over her back, tail and rostrum', says Nielsen, which explained why the tags wouldn't stay in place. However, after successfully tagging nine whale mums the team recorded almost 63 h of conversation as the mothers and calves sheltered in the surf.

Back in Denmark, Nielsen, Madsen and Simone Videsen scrutinised the recordings. 'It was difficult to assign the calls to either the calf or the mom, because they are so close to each other', says Nielsen; instead she assigned the calls to the calf-mother group. Although it was clear that the animals were producing two types of call - a grunt and a mooing sound - the team was surprised when they realised that instead of communicating continually the mother and calf called less than once per dive. And when the researchers analysed the sound volume of the animals' calls, they were surprised by how quiet the moos and grunts were. The pounding waves drowned out the calls within a few hundred metres, making it difficult for killer whales to eavesdrop on the soft conversations.

Nielsen suspects that it is unnecessary for southern right whale calves and their mothers to raise their voices in their cloudy coastal breeding grounds as the calves remain in close physical proximity to their mothers, swimming in mum's slipstream. And Nielsen and her colleagues suspect that the whales' unconventional choice of location in the crashing surf could conceal and protect them from unwanted attention.