Culture

MINNEAPOLIS - While movement problems are the main symptoms of Parkinson's disease, people with the disease often have non-motor symptoms such as constipation, daytime sleepiness and depression 10 or more years before the movement problems start. A new study suggests that eating a healthy diet in middle age may be linked to having fewer of these preceding symptoms. The study is published in the August 19, 2020, online issue of Neurology®, the medical journal of the American Academy of Neurology.

"While this study does not show cause and effect, it certainly provides yet another reason for getting more vegetables, nuts and legumes in your diet," said study author Samantha Molsberry, Ph.D., of Harvard University in Boston, Mass. "More research is needed to determine whether eating a healthy diet could delay or even prevent the development of Parkinson's disease among people who have these preceding symptoms already."

The study involved 47,679 people who were asked about their diet every four years starting in the 1980s when they were middle-aged. Then in 2012, people were asked whether they had two conditions that are common in people who are later diagnosed with Parkinson's disease: constipation and a sleep disorder called rapid eye movement sleep behavior disorder, which includes acting out dreams during sleep by movement such as flailing arms or shouting or screaming. In 2014-2015, 17,400 of the participants were asked about five more symptoms that can precede Parkinson's disease: loss of sense of smell, impaired color vision, excessive daytime sleepiness, body pain and depression.

The researchers looked at how closely people's diets followed either the alternate Mediterranean diet, which is similar to the Mediterranean diet but includes only whole grains and does not consider dairy, or the Alternative Healthy Eating Index. Both diets encourage eating fruit, vegetables, whole grains, nuts and legumes and discourage eating red meat. They divided the participants into five groups based on how closely they followed the diets.

The study found that the people with the highest adherence to the diets were less likely to have three or more symptoms that precede Parkinson's disease than the people with the lowest adherence. Those in the high group for adherence to the Mediterranean diet were 33% less likely to have three or more symptoms than those in the low adherence group. These results were found after researchers adjusted for other factors that could affect the risk of developing these preceding symptoms, such as physical activity, smoking and body mass index (BMI). The researchers found a similarly strong relationship between following the Alternative Healthy Eating Index diet pattern and having three or more of these non-motor symptoms.

Among the 29,899 women in the study, 37% of the low adherence group had constipation, compared to 32% of the high adherence group. Among the 11,493 women with all of the non-motor symptoms measured, 15% of the low group had body pain, compared to 13% of the high group. In the same 11,493 women, 17% of the low group had symptoms of depression, compared to 14% of the high group. Among the 17,770 men in the study, 22% in the low adherence group had constipation, compared to 12% of the high adherence group. Among the 5,907 men with data on all of the non-motor symptoms, 14% of the low group and 16% had body pain and 13% of the low group and 12% of the high group had symptoms of depression. Molsberry noted that body pain and depression may have occurred at a higher rate in the study than in the general population due to the study design, but that this was also accounted for in the statistical analysis.

Looking at individual food groups, the researchers found that eating more vegetables, nuts, legumes and consuming a moderate amount of alcohol were all associated with a lower risk of having three or more of the preceding symptoms. Moderate alcohol consumption was considered no more than one drink per day for women and no more than two drinks per day for men.

"We need to emphasize that, while these symptoms are associated with an increased risk of Parkinson's disease, especially in combination, experiencing any or several of these symptoms does not necessarily mean that a person will eventually develop Parkinson's disease," Molsberry said.

A limitation of the study was that participants were not asked about preceding symptoms at the start of the study, so some people may have already had these symptoms, which could have influenced their diet.

Like biological fat reserves store energy in animals, a new rechargeable zinc battery integrates into the structure of a robot to provide much more energy, a team led by the University of Michigan has shown.

This approach to increasing capacity will be particularly important as robots shrink to the microscale and below--scales at which current stand-alone batteries are too big and inefficient.

"Robot designs are restricted by the need for batteries that often occupy 20% or more of the available space inside a robot, or account for a similar proportion of the robot's weight," said Nicholas Kotov, the Joseph B. and Florence V. Cejka Professor of Engineering, who led the research.

Applications for mobile robots are exploding, from delivery drones and bike-lane take-out bots to robotic nurses and warehouse robots. On the micro side, researchers are exploring swarm robots that can self-assemble into larger devices. Multifunctional structural batteries can potentially free up space and reduce weight, but until now they could only supplement the main battery.

"No other structural battery reported is comparable, in terms of energy density, to today's state-of-the-art advanced lithium batteries. We improved our prior version of structural zinc batteries on 10 different measures, some of which are 100 times better, to make it happen," Kotov said.

The combination of energy density and inexpensive materials means that the battery may already double the range of delivery robots, he said.

"This is not the limit, however. We estimate that robots could have 72 times more power capacity if their exteriors were replaced with zinc batteries, compared to having a single lithium ion battery," said Mingqiang Wang, first author and recently a visiting researcher to Kotov's lab.

The new battery works by passing hydroxide ions between a zinc electrode and the air side through an electrolyte membrane. That membrane is partly a network of aramid nanofibers--the carbon-based fibers found in Kevlar vests--and a new water-based polymer gel. The gel helps shuttle the hydroxide ions between the electrodes.

Made with cheap, abundant and largely nontoxic materials, the battery is more environmentally friendly than those currently in use. The gel and aramid nanofibers will not catch fire if the battery is damaged, unlike the flammable electrolyte in lithium ion batteries. The aramid nanofibers could be upcycled from retired body armor.

To demonstrate their batteries, the researchers experimented with regular-sized and miniaturized toy robots in the shape of a worm and a scorpion. The team replaced their original batteries with zinc-air cells. They wired the cells into the motors and wrapped them around the outsides of the creepy crawlers.

"Batteries that can do double duty--to store charge and protect the robot's 'organs'--replicate the multifunctionality of fat tissues serving to store energy in living creatures," said Ahmet Emre, a doctoral student in biomedical engineering in Kotov's lab.

The downside of zinc batteries is that they maintain high capacity for about 100 cycles, rather than the 500 or more that we expect from the lithium ion batteries in our smartphones. This is because the zinc metal forms spikes that eventually pierce the membrane between the electrodes. The strong aramid nanofiber network between the electrodes is the key to the relatively long cycle life for a zinc battery. And the inexpensive and recyclable materials make the batteries easy to replace.

Beyond the advantages of the battery's chemistry, Kotov says that the design could enable a shift from a single battery to distributed energy storage, using graph theory approach developed at U-M.

"We don't have a single sac of fat, which would be bulky and require a lot of costly energy transfer," Kotov said. "Distributed energy storage, which is the biological way, is the way to go for highly efficient biomorphic devices."

What The Study Did: This observational study examined the association between state participation in Medicaid expansion through the Affordable Care Act and changes in the use of surgical care for common outpatient procedures.

Authors: Saunders Lin, M.D., of New York University in New York, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamasurg.2020.2959)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

An international team of researchers have discovered a dense, cold gas that's been shot out from the centre of the Milky Way "like bullets".

Exactly how the gas has been ejected is still a mystery, but the research team, including Professor Naomi McClure-Griffiths from The Australian National University (ANU), say their findings could have important implications for the future of our galaxy.

"Galaxies can be really good at shooting themselves in the foot," Professor McClure-Griffiths said.

"When you drive out a lot of mass, you're losing some of the material that could be used to form stars, and if you lose enough of it, the galaxy can't form stars at all anymore.

"So, to be able to see hints of the Milky Way losing this star forming gas is kind of exciting - it makes you wonder what's going to happen next!"

The study also raises new questions about what's happening in our galactic centre right now.

"The wind at the centre of the Milky Way has been the topic of plenty of debate since the discovery a decade ago of the so-called Fermi Bubbles - two giant orbs filled with hot gas and cosmic rays," Professor McClure-Griffiths said.

"We've observed there's not only hot gas coming from the centre of our galaxy, but also cold and very dense gas.

"This cold gas is much heavier, so moves around less easily."

The centre of the Milky Way is home to a massive black hole, but it's unclear whether this black hole has expelled the gas, or whether it was blown by the thousands of massive stars at the centre of the galaxy.

"We don't know how either the black hole or the star formation can produce this phenomenon. We're still looking for the smoking gun, but it gets more complicated the more we learn about it," lead author Dr Enrico Di Teodoro from Johns Hopkins University said.

"This is the first time something like this has been observed in our galaxy. We see these kind of processes happening in other galaxies. But, with external galaxies you get much more massive black holes, star formation activity is higher, it makes it easier for the galaxy to expel material.

"And these other galaxies are obviously a long way away, we can't see them in a lot of detail.

"Our own galaxy is almost like a laboratory that we can actually get into and try to understand how things work by looking at them up close."

Rising temperatures due to our greenhouse gas emissions can cause greater damages to our economies than previous research suggested, a new study shows. Scientists from the Potsdam Institute for Climate Impact Research (PIK) and the Mercator Research Institute for Global Commons and Climate Change (MCC) took a closer look at what climate change does to regions at the sub-national level, such as US states, Chinese provinces or French départments, based on a first-of-its-kind dataset by MCC. If CO2 emissions from burning fossil fuels are not reduced rapidly, a global warming of 4°C until 2100 can make that regions lose almost 10% of economic output on average and more than 20% in the tropics.

"Climate damages hit our businesses and jobs, not just polar bears and coral reefs," says Leonie Wenz from PIK, one of the two authors of the study. "Rising temperatures make us less productive which is relevant in particular for outdoor work in the construction industry or agriculture. They affect our harvests and they mean extra stress and thus costs for our infrastructure as for instance computer centres need to be cooled. By statistically evaluating climate and economic data from the past decades, we found that the aggregated economic damages from rising temperatures are even greater than previously estimated because we looked at the sub-national effects which provide a more comprehensive picture than national averages."

Damages from weather extremes would come on top

Previous research suggested that a 1°C hotter year reduces economic output by about 1%, whereas the new analysis points to output losses of up to three times that much in warm regions. Using these numbers as a benchmark for computing future damages of further greenhouse gas emissions, the researchers find significant economic losses: 10% on a global average and more than 20% in the tropics by 2100. This is still a conservative assessment since the study did not take into account damages from, for example, extreme weather events and sea-level rise, which will also be substantial but are hard to pin down for single regions.

The new insight was made possible by building a novel MCC-dataset of climate and economy for 1500 regions in 77 states around the world that, for some regions, dates back to the 1900s. Data coverage is best for industrialized countries, however, with economic information lacking in particular for large parts of Africa. While the calculations show a substantial impact on economic production, they do less so for permanent economic growth reductions, which might be a reason for hope once emissions are reduced. Importantly, the damages are distributed very unevenly across the world with tropical and already poor regions suffering most from continued warming whereas a few countries in the North might even profit.

The economic cost of each tonne of CO2 emissions: 70-140 US-dollars

The findings have important implications for climate policy, and namely CO2 pricing. "If you update the widely-used climate-economy model DICE developed by Nobel prize winner William Nordhaus with the statistical estimates from our data, the costs of each tonne of carbon emitted to society are two to four times higher," highlights the lead-author of the study, Matthias Kalkuhl from MCC. "According to our study, every tonne of CO2 emitted in 2020 will cause economic damage amounting to a cost between 73 to 142 dollars in 2010 prices, rather than 37 dollars shown by the DICE model. By 2030, the so-called social cost of carbon will already be almost 30 percent higher due to rising temperatures."

By way of comparison: the carbon price in European emissions trading currently fluctuates between 20 and 30 euros per tonne; the national carbon price in Germany rises from 25 euros next year to 55 euros in 2025. These current carbon prices thus reflect only a small part of the actual climate damage. According to the polluter-pays principle, they would need to be adjusted upwards significantly.

New research looking at voters' perception of gender and aspiration suggests that voters do not penalise ambitious women candidates seeking political office, contrary to popular belief.

The study, published in the US journal Political Behavior, challenges the long-held assumption that negative views about ambition are standing in the way of female candidates in politics.

Following Hillary Clinton's unsuccessful bid for the White House in 2016 a notion that 'unbridled ambition' had cost her votes gained traction. Then-President Obama suggested that ambition might be a political liability for women, but not men.

To test this hypothesis the researchers from the universities of Bath and Harvard, developed a four-part framework to evaluate public perceptions towards different aspects of ambition among female candidates.

This looked at ambition as multidimensional: 'progressive' (i.e. aiming for higher office); 'personalistic' (i.e. personality traits, including being determined to succeed and a tough negotiator); 'agenda-based' (i.e. the scope of their proposed policies); 'parental' (i.e. juggling family responsibilities with public life).

The political scientists then tested voters' reactions to these 'ambitious' traits across a sample of nearly 4000 respondents both in the US and UK. In their experiments, people evaluated pairs of hypothetical candidates against information about both their ambition and gender.

Results from their experiments which ran from 2017 to 2020 found that overall female candidates with these traits were not punished - in fact, they were slightly favoured. Yet, there were some differences in acceptance for ambitious women across parties.

In the States, Democrats were more supportive of women with progressive ambition than Republicans (a gap of 7% points). This suggests that ambitious right-wing female candidates in the US might face bias, particularly in the context of non-partisan races (primaries and local elections) when voters are unable to rely on party labels to make decisions. In the UK, they found no differences in attitudes towards female candidates across party affiliation.

They found some evidence that women were more likely to support female candidates with both progressive and agenda-based ambition, compared to men. But they say these differences are not significant across all survey samples. While ambitious political agendas are favoured by voters, they found no significant differences in voters' willingness to support female versus male candidates with ambitious agendas. Parent status was not found to be associated with candidate ambition.

Researcher, Dr Ana Catalano Weeks from the Department of Politics, Languages & International Studies at the University of Bath explains: "For a long time a popular belief has persisted that ambitious women seeking political office get penalised by voters, but our results suggest no evidence to support this assumption. Ambition, including for women, is not a negative trait for voters - if anything it's attractive, especially for Democratic voters.

"Women remain underrepresented in parties and parliaments and one of the reasons might be not the voters, but elites within parties who often play a gatekeeping role. Women might also perceive that they will face additional discrimination if they are perceived as ambitious. This research should act as a rallying cry to women seeking political office not to downplay their aspirations."

Study co-author Dr Sparsha Saha of Harvard University's Department of Government adds: "Our research is part of a line of recent studies which suggest that voter discrimination is not the cause of women's underrepresentation in advanced democracies, and that norms about women with traditionally 'masculine' traits like ambition are changing."

The team now plan to look at perceptions towards ambition in the context of race and ethnicity. They acknowledge that attitudes towards ambitiousness in ethnic minority women may be different in important ways from evaluations of white women.

They also plan to extend their work to see if it holds across other advanced democracies including in Germany, Finland and New Zealand all with prominent female political leaders, and to further explore how history, context, and institutions matter.

A team of researchers at DESY has reached an important milestone on the road to the particle accelerator of the future. For the first time, a so-called laser plasma accelerator has run for more than a day while continuously producing electron beams. The LUX beamline, jointly developed and operated by DESY and the University of Hamburg, achieved a run time of 30 hours. "This brings us a big step closer to the steady operation of this innovative particle accelerator technology," says DESY's Andreas R. Maier, the leader of the group. The scientists are reporting on their record in the journal Physical Review X. "The time is ripe to move laser plasma acceleration from the laboratory to practical applications," adds the director of DESY's Accelerator Division, Wim Leemans.

Physicists hope that the technique of laser plasma acceleration will lead to a new generation of powerful and compact particle accelerators offering unique properties for a wide range of applications. In this technique, a laser or energetic particle beam creates a plasma wave inside a fine capillary. A plasma is a gas in which the gas molecules have been stripped of their electrons. LUX uses hydrogen as the gas.

"The laser pulses plough their way through the gas in the form of narrow discs, stripping the electrons from the hydrogen molecules and sweeping them aside like a snow plough," explains Maier, who works at the Centre for Free-Electron Laser Science (CFEL), a joint enterprise between DESY, the University of Hamburg and the Max Planck Society. "Electrons in the wake of the pulse are accelerated by the positively charged plasma wave in front of them - much like a wakeboarder rides the wave behind the stern of a boat."

This phenomenon allows laser plasma accelerators to achieve acceleration strengths that are up to a thousand times greater than what could be provided by today's most powerful machines. Plasma accelerators will enable more compact and powerful systems for a wide range of applications, from fundamental research to medicine. A number of technical challenges still need to be overcome before these devices can be put to practical use. "Now that we are able to operate our beamline for extended periods of time, we will be in a better position to tackle these challenges," explains Maier.

During the record-breaking nonstop operation, the physicists accelerated more than 100,000 electron bunches, one every second. Thanks to this large dataset, the properties of the accelerator, the laser and the bunches can be correlated and analysed much more precisely. "Unwanted variations in the electron beam can be traced back to specific points in the laser, for example, so that we now know exactly where we need to start in order to produce an even better particle beam," says Maier. "This approach lays the foundations for an active stabilisation of the beams, such as is deployed on every high performance accelerator in the world," explains Leemans.

According to Maier, the key to success was combining expertise from two different fields: plasma acceleration and know-how in stable accelerator operation." Both are available at DESY, which is unparalleled in the world in this respect," Maier emphasises. According to him, numerous factors contributed to the accelerator's stable long-term operation, from vacuum technology and laser expertise to a comprehensive and sophisticated control system. "In principle, the system could have kept running for even longer, but we stopped it after 30 hours," reports Maier. "Since then, we have repeated such runs three more times."

"This work demonstrates that laser plasma accelerators can generate a reproducible and controllable output. This provides a concrete basis for developing this technology further, in order to build future accelerator-based light sources at DESY and elsewhere," Leemans summarises.

PULLMAN, Wash. - Washington State University researchers have made a key first step in economically converting plant materials to fuels: keeping iron from rusting.

The researchers have determined how to keep iron from rusting in important chemical reactions that are needed to convert plant materials to fuels, meaning that the cheap and readily available element could be used for cost-effective biofuels conversion.

Led by Yong Wang, Voiland Distinguished Professor in the Gene and Linda Voiland School of Chemical Engineering and Bioengineering, and Shuai Wang from the State Key Laboratory for Physical Chemistry of Solid Surfaces at Xiamen University, the researchers report on their work on the cover of the July issue of ACS Catalysis.

Researchers have been trying to find more efficient ways to create fuels and chemicals from renewable plant-based resources, such as from algae, crop waste, or forest residuals. But, these bio-based fuels tend to be more expensive with less energy density than fossil fuels.

One big hurdle in using plant-based feedstocks for fuel is that oxygen has to be removed from them before they can be used.

"You want to use the cheapest catalyst to remove the oxygen," said Jean-Sabin McEwen, a co-author on the paper and associate professor in the Gene and Linda Voiland School of Chemical Engineering and Bioengineering.  "Iron is a good choice because it's super abundant."

Iron-based catalysts show great promise for being able to remove oxygen, but because the plant materials also contain oxygen, the iron oxidizes, or rusts, during the reaction, and then the reaction stops working. The trick is to get the iron to remove the oxygen from the plants without taking up so much oxygen that the reaction stops.

In their work, the researchers anchored their iron catalyst with a carbon structure that was modified to incorporate nitrogen. The structure modifies the properties of the iron, so that it interacts less with oxygen while it continues to do the required work of removing oxygen from the plant material. The researchers used the nitrogen as a sort of control dial to tune the iron's interaction with oxygen.

In another recently published paper in Chemical Science led by Yong Wang and Junming Sun, a research assistant professor in the Gene and Linda Voiland School of Chemical Engineering and Bioengineering,  the researchers discovered a durable iron-based catalyst with a thin carbon graphene layer around it. The graphene layer protected the iron while cesium ions allowed the researchers to tailor its electronic properties for the desired reaction.

"We dialed down the oxygen reaction," Sun said. "By protecting iron and tuning its properties, these works provide the scientific basis for using earth abundant and cost-effective iron as catalysts for biomass conversion."

The researchers are now working to better understand the chemistry of the reactions, so they can further increase the reactivity of the iron catalysts. They also will need to try their catalysts with real feedstocks instead of the model compounds used for the study. The feedstocks collected from farm fields will be more complicated in their compositions with a lot of impurities, and the researchers would also have to integrate their catalyst into a series of steps that are used in the conversion process.

"We are trying to make the conversion as economically as possible," Wang said.  "The key is trying to find robust catalysts based on low-cost, earth abundant elements. This is a first step in that direction."

Over the past two decades, a new area at the interface of semiconductor physics, electronics and quantum mechanics has been gaining popularity among theoretical physicists and experimenters. This new field is called spintronics, and one of its main tasks is to learn how to control the spin of charge carriers in well known semiconductor structures. Many theoretical efforts are always required before some idea finds its embodiment in an actual device, and so far theoretical work on spintronics has been outweighing experimental research.

Denis Khomitsky, Associate Professor of Theoretical Physics Department at Lobachevsky University together with postgraduate student Ekaterina Lavrukhina in collaboration with Professor Evgeny Sherman from the University of the Basque Country in Bilbao (Spain) have proposed a new model that describes electron spin behavior in a semiconductor nanowire with a deep quantum dot (an area where electron movement is confined by electrodes), where spin behavior can be controlled by means of a periodic electric field.

It is known that in materials with strong spin-orbital interactions it is possible to control the electron spin without switching the magnetic field. Instead, the control can be achieved by applying a periodic electric field at a specially selected frequency.

This phenomenon, called electric dipole spin resonance, has been known for quite some time, but its practical application is still limited and there is a need for such technology.

"In the proposed model, we have elucidated the role of the continuum states with energies "above" the quantum dot, to which the electron will inevitably "make its way" or tunnel under the action of a sufficiently strong field in the process of resonance. It turns out that to accelerate the spin flip, which is very desirable in electronics and spintronics, there is no need to have very strong electric fields, because in such fields the electron tunnels into the continuum too quickly, and the projection of its spin begins to "fade" with time, taking away valuable information", says Denis Khomitsky who is in charge of this research project at Lobachevsky University.

Hence, a practically important conclusion: it is necessary to choose an optimum interval of control fields in such structures, which will make it possible to flip the electron spin quickly and "carefully" enough not to lose the valuable information.

The team is led by Associate Professor Ayrat Kayumov (Department of Genetics, Kazan Federal University). In this research, the scientists not only performed genome sequencing, but also found a completely new type of PII-Like Protein PotN.

"PII proteins can be called molecular processors," explains Kayumov. "They monitor the ratios of metabolites in a cell which signal the availability of energy, carbon and nitrogen sufficiency, and, depending on this data, they can rearrange the cell functioning. We found a new type of PII-like proteins in this Lactobacillus hilgardii LMG 7934, and it has different functions. We now have to understand which signals trigger the activity of this type of proteins and how cell metabolism is coordinated as a result."

The research is funded by the Presidential Grant Program of Russia for Young Scientists with DSc degrees.

"Our projects aims to characterize molecular mechanisms which allow bacteria to use nitrogen-containing compounds. This can help correct the bacterial metabolism in such a way that it could work in a targeted direction, such as nitrate consumption," continues the interviewee.

For instance, this may come in handy for biological purification and remediation of polluted water sources or to ensilage livestock feed with high nitrate ratios. Excessive nitrates in food can be detrimental to animals.

"Nitrates amass in plants when nitrogen-containing fertilizers are used. These nitrates transform into nitrites during storage or directly in animal gut. Nitrites turn blood hemoglobin into methemoglobin, which leads to oxygen deficiency, including acute forms," says Kayumov. "During ensilaging, gases are produced, and fresh silage is very poisonous. Silage gases contain molecular oxygen, nitrous oxide, nitrous dioxide, and nitric oxide. During ensilaging, nitrates can also be reduced to ammonium. That's why it's important to abide by technological norms to decrease the ratio of nitrates in feed. However, if source plants have over 0.28% of nitrates, ensilaging cannot effectively reduce their ratio."

That's why geneticists aim to produce special ferments for feed ensilaging based on lactobacilli - the latter can help remove nitrates. Targeted genetic modification is a way to achieve exactly that.

The release of massive amounts of proteins called cytokines can lead to some of the most severe symptoms of COVID-19. When large numbers of immune cells release cytokines, this increases inflammation and creates a feedback loop in which more immune cells are activated and this is sometimes called a cytokine storm. An August 19 study in the journal Cell now suggests that high levels of some cytokines may also prevent people who are infected from developing long-term immunity as affected patients were observed to make very few of the type of B cells needed to develop a durable immune response.

"We've seen a lot of studies suggesting that immunity to COVID-19 is not durable because the antibodies decline over time," says co-senior author Shiv Pillai, a professor at Harvard Medical School and member of the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard. "This study provides a mechanism that explains this lower-quality immune response."

The investigators focused on germinal centers--the areas within the lymph nodes and spleens where B cells, the immune cells that produce antibodies, differentiate. Differentiation and changes in antibody genes are required to build immunity to an infectious agent.

"When we looked at the lymph nodes and spleens of patients who died from COVID-19, including some who died very soon after getting the disease, we saw that these germinal center structures had not formed," says co-senior author Robert Padera, a pathology professor at Harvard. "We decided to determine why that's the case."

Because the disease was so new, animal models for studying COVID-19 infection were not yet available at the time they began their study. The researchers instead gained insights from previous studies involving mouse models of other infections that induce cytokine storm syndrome--a malaria model and one of bacterial infection in which germinal centers were lost.

In people with severe COVID-19, one of most abundant cytokines released is called TNF. In the infected mice, TNF appeared to block the formation of germinal centers. In previous cytokine storm models, when the mice were given antibodies to block TNF or had their TNF gene deleted, the germinal centers were able to form. When the researchers studied the lymph nodes of patients who had died of the disease, they found high levels of TNF in these organs. This led them to conclude that TNF may be preventing the germinal centers from forming in people with COVID-19 as well.

"Studies have suggested this lack of germinal centers happens with SARS infections," Pillai says. "We even think this phenomenon occurs in some patients with Ebola, so it was not surprising to us."

The researchers also studied blood and lymphoid tissue from people with active infections who were in different stages of COVID-19. They found that although germinal centers were not formed, B cells were still activated and appeared in the blood, which would allow the patients to produce some neutralizing antibodies. "There is an immune response," Padera says. "It's just not coming from a germinal center."

"Without the germinal centers, there is no long-term memory to the antigens," Pillai adds. He notes that studies of other coronaviruses that cause colds have suggested that someone can get infected with the same coronavirus three or four times in the same year.

The authors say despite their findings, they still believe a successful COVID-19 vaccine can be developed as it should not cause high levels of cytokines to be released.

Covid-19 patients with hypoxia respond positively to icatibant treatment, Radboud university medical center researchers wrote in JAMA Network Open. These findings have led to a follow-up study at ten Dutch hospitals into a drug that may be even more effective. The current study has been funded by ZonMw.

Rapid fluid overload of the lungs - pulmonary edema - is a hallmark of severe infection with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). In a previous article, Nijmegen researchers suggested that this involves the ACE2 receptor. The coronavirus enters the cells via this receptor, after which it can multiply. However, the ACE2 receptor not only provides a gateway for the coronavirus, but it also keeps vasodilatory kinins under control. The infection causes most of the ACE2 receptors of the lung cells to dysfunction. Without ACE2, these kinins have free rein and - by binding to bradykinin receptors - can make the blood vessels leaky. Internist Frank van de Veerdonk, hospital pharmacist Roger Brüggemann and colleagues hypothesized that this process plays an important role in severe Covid-19 infection.

Patient study

After consultation with the Central Committee on Research Involving Human Subjects (CMO) and the Health Care and Youth Inspectorate (IGJ), and with the informed consent of the participating patients, the researchers tested their hypothesis with the drug icatibant. Van de Veerdonk: "This drug is used in patients with the rare condition: hereditary angioedema. These patients sometimes develop acute subcutaneous fluid deposits due to local leakage of blood vessels. Icatibant blocks the bradykinin receptor B2R, which quickly stops the leakage. To determine whether the drug is also suitable for the specific group of Covid-19 patients with fluid in their lungs, earlier this year we administered this drug to nine patients in the Internal Medicine Department and one patient in the Intensive Care Unit."

Hypoxia

The results of this study have now been published in JAMA Network Open. All the patients, which were in need for oxygen treatment due to fluid in their lungs, were given three doses of icatibant by subcutaneous injection at six-hour intervals. The patient in the ICU recovered sufficiently within 24 hours to be moved to the ward and was discharged after 7 days. Eight of the remaining nine patients needed less oxygen supplementation within 24 hours and the ninth after 38 hours. In 18 comparable patients who served as controls, substantially higher levels of oxygen supplementation were needed over time.

Support for the hypothesis

Brüggemann: "Although this was not a randomized trial, the results support our hypothesis. In an early phase of the infection with severe oxygen deficit, we see that icatibant improves the situation. A disadvantage is the short-term effect of the drug. Half of the drug is broken down in two hours, so the effect diminishes quickly. After the treatment, three patients had to be given oxygen again because the drug had worn off."

Different drug

The research published in JAMA Network Open was actually a proof of concept, which the researchers have already built upon. Improved understanding of the role of the kinin-kallikrein system (KKS) in COVID-19 means that the researchers expect even better results from another drug. Brüggemann: "The drug lanadelumab remains active for much longer than icatibant, so you will probably only need to administer it only once or twice". Van de Veerdonk: "Lanadelumab also has a much broader effect. It inhibits the activation of the whole system that causes leakage of the blood vessels. It is therefore not only active for longer but might also be more effective."

Research in hospitals

Based on the initial results published in JAMA Network Open and these more recent insights, Van de Veerdonk and Brüggemann have been awarded a grant from ZonMw for a phase 2 clinical trial with lanadelumab for this specific group of COVID-19 patients. Several Dutch hospitals are participating in the study. If this approach works, Brüggemann and van de Veerdonk expect that the research can immediately be rolled out on a large scale internationally. This is not only important for rapid recovery of patients with hypoxia admitted to the hospital but can also reduce the pressure on IC capacity. Global organizations such as the World Health Organization (WHO) and REMAP-CAP are directly involved in this research, and the strategy is currently being considered by several others. With this strategy Van de Veerdonk and Brüggemann aim to help patients presenting with hypoxia to recover quickly and thus avoid ICU admission.

High blood pressure is often called a silent killer because it is the biggest risk factor for the most death and disability worldwide including heart disease and stroke, but presents no symptoms as a warning indicator. Many elderly people have high blood pressure that is difficult to treat, and good preventative methods and appropriate markers have not been elucidated.

It has been known that high salt intake causes hypertension, but its exact mechanism was not understood until this study which found for the first time that Klotho deficiency, an anti-aging factor produced in the kidneys causes aging-associated hypertension through high salt intake.

Klotho is an anti-aging protein that acts as a hormone and is secreted into the blood from the kidneys. Its presence decreases with age causing the vascular and arterial system to stiffen. A recent study had shown the inverse relationship between the Klotho concentration and BP salt sensitivity. Hypertension is caused by excessive intake of salt, but the sensitivity of blood pressure to salt varies from individual to individual, and highly sensitive people are more likely to have high blood pressure.

In general, young people are less sensitive and are unlikely to develop hypertension, whereas older people are more sensitive to salt and are likely to develop hypertension. However, the mechanism of increased salt sensitivity with aging was unknown. Therefore, the research group first confirmed that salt sensitivity increased in aged mice, and revealed that the cause is that the blood concentration of the anti-aging factor Klotho protein decreases with age. Furthermore, the group clarified the molecular mechanism Wnt5a-RhoA pathway for the first time. The results showed that Klotho supplementation could prevent the development of hypertension, and Klotho levels could be a predictive marker for the development of hypertension.

Corresponding author and Specially Appointed Professor Toshiro Fujita of Shinshu University School of Medicine and Research Center for Social Systems, and Division of Epigenetics, Research Center for Advanced Science and Technology, University of Tokyo states that it took time, "to elucidate the molecular mechanism of salt-sensitive hypertension with aging. Although Klotho deficiency was known to activate Wnt signaling, the detailed mechanism by which Wnt activation causes vasoconstriction was unknown. We found that the Wnt signal has two pathways, the canonical pathway which was understood as significant in oncological research, but it took time to demonstrate that the Wnt-RhoA pathway of the non-canonical pathway causes vasoconstriction in cell experiments and mouse experiments."

In experiments using aged mice and cells, abnormal activation of the above pathway could be reversed by supplementation with Klotho protein. As a result, it was possible to establish that the cause of salt-sensitive hypertension due to aging is Klotho protein decline.

The results of this experiment showed that Klotho supplementation could prevent the development of hypertension in the elderly and that Klotho levels could be a predictive marker for the development of hypertension. Trials for human verification is currently underway. Aging, a universal phenomenon causes not only hypertension but dementia and frailty, and impairs the healthy life expectancy of individuals. The aging-related phenomenon of Klotho protein deficiency may be related to the onset of dementia and sarcopenia, or the loss of muscle-mass and usage associated with aging. Its onset mechanism is currently under investigation.

All current breast cancer drugs were first tested in cell lines. Each cell line began as cancer in a patient. As such, each cell line is a surrogate for that patient's disease. A new database of 40 breast cancer cell lines, developed by Medical University of South Carolina investigators, will help researchers deepen their understanding of these cell lines and speed the development of new gene-targeted therapies.

"Cell lines are the front line for breast cancer research because they are derived from real patients and exhibit the characteristics of the disease that that patient experienced," remarked Stephen P. Ethier, Ph.D., a professor in the Department of Pathology and Laboratory Medicine at MUSC and an MUSC Hollings Cancer Center researcher.

Cell lines represent cancer for what it is, said Ethier -- a multifaceted disease of the genome. The broad picture of cancer as a complex disease, however, is often bypassed in research to laser-focus on only one or two gene changes. Ethier believes this -- the current way of doing research -- is too narrow and that developing better therapies will require evaluation of the entire genomic signature.

In an article recently published in npj Breast Cancer, Ethier and his team describe the implementation of a new resource for cancer researchers. The SUM Breast Cancer Cell Line Knowledge Base, or SLKBase, will push the field forward by providing easily navigable genomic, proteomic and other "omic" information on a total of 40 SUM and other patient-derived cell lines. The database could eventually contribute to the identification, development and implementation of truly personalized gene-targeted therapies for patients with breast cancer.

Dr. Stephen Ethier and his team hope their database will eventually expand to include cancer cell lines from all types of cancer.

Humans have approximately 24,000 genes, collectively called the genome. Written in the language of DNA, the genes act as instructions for how cells are to grow, live and replicate.

Errors in the DNA instructions within a cell can ultimately change how the cell grows, replicates and responds to natural signals that normally act as a brake to these functions. These changes cause the cell to become cancerous.

Personalized or targeted therapies, based on unique gene changes in each patient's cancer, have been a long-term goal in oncology research and medicine, and significant progress has been made. However, implementing truly personalized therapeutic strategies has been slow.

One obstacle has been difficulty identifying and targeting the gene changes that have a function in causing disease.

Several hundred genes might have developed errors in a cancer cell, according to Ethier. "Most of the genes that are changed, however, are playing no role whatsoever in the biology of the disease," he explained.

How can researchers identify which of those gene mutations matter and are worth targeting?

With funding from a South Carolina Clinical & Translational Research Institute pilot grant, Ethier and his team built specialized tools for SLKBase to aid in answering this very question.

"So the way to get from 500 gene changes to two or three that are playing an essential role in the biology of the disease is to do what are called genome-scale knock-out or knock-down experiments," Ethier explained.

In the knock-down experiments, Ethier and his team performed a series of tests in which every gene in the genome was turned off one by one and evaluated for its effects on the growth or survival of the cancer cell. If the cancer cell died or stopped duplicating itself, that gene was deemed to be essential for survival. If that gene also had an error, it meant the gene was not only essential but also performed a function that made the cell behave like cancer.

Each cancer cell line has a unique "functional gene signature," explained Ethier.

Therapies that target these functional genes that drive cancer growth are likely to be most effective. From a library of more than 800 targeted experimental medications, the "Druggable Signature Tool" identifies those that are likely to be effective against the cancer cells because they target the essential genes.

The SLKBase website is open to anyone who wants to know more about breast cancer cell lines or access the immense genomic and proteomic research knowledge base.

However, breast cancer is just the beginning. There are more than 500 cancer cell lines derived from patients with virtually every type of cancer, and Ethier hopes eventually to include them all in SLKBase.

For Ethier, the gene changes driving cancer matter more than the tissue in which they occur. Cancers are a disease of the genome, no matter in which part of the body they occur. Therefore, any cancer would be expected to respond to therapy targeted to its genomic signature.

"At some point, we have to stop worrying about whether it's breast cancer, lung cancer or colon cancer," said Ethier. "We should be putting more emphasis on the genomic features of that cancer because cancer is a disease of the genome."

Ethier recently signed an option agreement with the MUSC Foundation for Research Development that will enable his startup, Sextant Oncology LLC, to continue to promote the use of cancer cell lines and their functional derivatives. The mission of Sextant Oncology is to develop strategies for the reverse engineering of individual cell lines that will ultimately be useful for making targeted drug treatment predictions for patients.

When it comes to brain cells, one size does not fit all. Neurons come in a wide variety of shapes, sizes, and contain different types of brain chemicals. But how did they get that way? A new study in Nature suggests that the identities of all the neurons in a worm are linked to unique members of a single gene family that control the process of converting DNA instructions into proteins, known as gene expression. The results of this study could provide a foundation for understanding how nervous systems have evolved in many other animals, including humans. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

"The central nervous systems of all animals, from worms to humans, are incredibly intricate and highly ordered. The generation and diversity of a plethora of neuronal cell types is driven by gene expression," said Robert Riddle, Ph.D., program director at NINDS. "So, it is surprising and exciting to consider that the cell diversity we see in the entire nervous system could come from a just a single group of genes."

Researchers led by Oliver Hobert, Ph.D., professor of biochemistry and molecular biophysics at Columbia University in New York City and graduate student Molly B. Reilly, wanted to know how brain cells in the C. elegans worm got their various shapes and functions. For these experiments, the researchers used a genetically engineered worm in which individual neurons were color coded. In addition, coding sequences for green fluorescence protein were inserted into homeobox genes, a highly conserved set of genes known to play fundamental roles in development. Homeobox gene expression patterns were determined by examining the patterns of the glowing fluorescent marker.

Dr. Hobert's team discovered that across the entire worm nervous system, each type of neuron contained a unique set of homeobox proteins. In other words, the identity of every neuron could be traced to a specific combination of homeobox genes that were switched on or off.

Homeobox genes were initially discovered for their role in ensuring that body parts end up in their proper places. These genes have since been found across all animal species, as well as in plants and fungi. Homeobox genes contain instructions for making transcription factors, which are proteins that can control the activity of other genes.

The nervous system of an adult C. elegans contains 302 neurons, which can be divided into 118 types. Dr. Hobert's team determined that 70 homeobox genes are involved in characterizing the neuronal types. In addition, further analysis suggested that the homeobox codes could be used to subdivide classes of neurons. For example, the additional analysis identified not only that a cell was a motor neuron, but its location in the ventral nerve cord, the worm's version of a spinal cord.

"The diversity in neurons may be driven by a gene family that distinguishes individual cell types in the brain," said Dr. Hobert, "There is a simplicity to this arrangement in the sense that just one gene family may explain all brain cell types. The complexity that arose from this simple 'barcode' gene family suggests a potential role for homeobox genes in the evolution of the nervous system."

Future studies will investigate whether brain cells in other organisms can also be identified by specific protein codes. In addition, researchers will examine the effects of changing the codes on identity and function of neurons.