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Researchers from Kumamoto University, Japan have found that a component derived from turmeric essential oil, aromatic turmerone (ar-turmerone), and its derivatives act directly on dopaminergic nerves to create a neuroprotective effect on tissue cultures of a Parkinson's disease model. This appears to be due to enhanced cellular antioxidant potency from the activation of Nrf2. The researchers believe that the ar-turmerone derivatives identified in this study can be used as new therapeutic agents for Parkinson's disease.

Parkinson's disease is a neurodegenerative disease caused by the selective death of dopaminergic neurons that transmit information from the substantia nigra of the midbrain to the striatum which results in decreased dopamine production. Symptoms include limb tremors, immobility, muscle rigidity, and other movement disorders. Treatments, such as dopamine supplements, are currently available but there still no way to inhibit dopaminergic neurodegeneration.

Previous studies have reported that the inflammatory response caused by the activation of microglia (cells responsible for immune function in the brain) is observed in the substantia nigra of the midbrain of Parkinson's disease patients. Further experiments designed to mimic the in vivo state of the midbrain (midbrain slice culture) revealed that microglial activation triggers the selective degeneration of dopaminergic neurons in the substantia nigra, and that nitric oxide (NO) derived from activated microglia was involved in the neurodegeneration. These findings suggest that compounds with anti-inflammatory effects on microglia may suppress dopaminergic degeneration.

Thus, researchers analyzed aromatic tumerone (ar-turmerone), a major component of turmeric essential oil that has been reported to exhibit anti-tumor and anti-inflammatory effects on microglia. They used the BV2 microglial cell line and midbrain slice cultures to 1) determine if ar-turmerone suppresses dopaminergic neurodegeneration through its anti-inflammatory effects, and 2) identify structurally similar compounds (derivatives) that might have stronger anti-inflammatory and neuroprotective effects.

Ar-turmerone has an asymmetric carbon (S-Tur) so researchers prepared eight analogues and attempted to identify those with stronger anti-inflammatory effects. They used the inhibitory effects on the inflammatory response as induced by lipopolysaccharide (LPS)-stimulated activation of BV2 cells as an indicator. The analogues with stronger anti-inflammatory effects than S-Tur were (R)-ar-turmerone (R-Tur), ar-atlantone (Atl), and analog 2 (A2).

To examine whether these compounds, including S-Tur, have an inhibitory effect on dopaminergic degeneration, researchers then observed midbrain slice cultures in which microglial activation was induced by interferon-γ and LPS stimulation (IFN-γ/LPS). All four compounds significantly suppressed a decrease in the number of dopaminergic neurons as induced by IFN-γ/LPS. However, the production of NO, which is released from activated microglia and is involved in dopaminergic neurodegeneration, was not inhibited at all. In addition, three compounds, S-Tur, Atl and A2, inhibited dopaminergic degeneration that is induced by MPP+, a toxin that selectively damages dopaminergic neurons independent of microglial activity. These results indicate that S-Tur and its derivatives, Atl and A2, have a direct effect on dopaminergic neurons and exhibit neuroprotective effects. Furthermore, analysis using dopaminergic progenitor cell lines and midbrain slice cultures revealed that the neuroprotective effects of Atl and A2 are mediated by activation of Nrf2, a transcription factor that enhances the antioxidant potency of cells.

"Our study elucidated a new mechanism by which ar-turmerone and its derivatives directly protect mesencephalic slice dopaminergic neurons, independent of their previously reported anti-inflammatory effects on microglia," said Associate Professor Takahiro Seki, who led the study. "We showed that two derivatives, Atl and A2, exhibit neuroprotective effects by increasing the expression of antioxidant proteins through the activation of Nrf2. In particular, the analog A2 identified in this study is a potent activator of Nrf2 and is assumed to have a strong antioxidant effect. We think it is possible that this compound may be a new dopaminergic neuroprotective agent for Parkinson's disease treatment, and it could also be used to treat other diseases caused by oxidative stress, such as liver and kidney diseases."

When it comes to the medicinal and therapeutic properties of Cannabis sativa, an unsolved mystery is whether there exists an "entourage effect," whereby the pain-relieving effects of the plant as a whole are greater than any of its individual parts. New research from the University of Arizona Health Sciences has found evidence that favors the entourage effect theory and positions Cannabis terpenes, the part of the plant that provides flavor and aroma, as a promising new target for pain therapies that would require lower doses and produce fewer side effects.

"A lot of people are taking cannabis and cannabinoids for pain," said lead researcher John Streicher, PhD, a member of the UArizona Health Sciences Comprehensive Pain and Addiction Center and associate professor of pharmacology at the College of Medicine - Tucson. "We're interested in the concept of the entourage effect, with the idea being that maybe we can boost the modest pain-relieving efficacy of THC and not boost the psychoactive side effects, so you could have a better therapeutic."

Terpenes are aromatic compounds found in many plants and are the basic component in essential oils. The terpene linalool, for example, gives lavender its distinctive floral scent. In addition to terpenes, Cannabis sativa contains naturally occurring compounds known as cannabinoids, the most well-known of which are cannabidiol, or CBD, and tetrahydrocannabinol, or THC, the psychoactive component of cannabis.

Researchers found that Cannabis terpenes, when used by themselves, mimic the effects of cannabinoids, including a reduction in pain sensation. When combined with cannabinoids, the pain-relieving effects were amplified without an increase in negative side effects. The paper, "Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity," was published in Scientific Reports.

"It was unexpected, in a way," said Dr. Streicher. "It was our initial hypothesis, but we didn't necessarily expect terpenes, these simple compounds that are found in multiple plants, to produce cannabinoid-like effects."

Dr. Streicher and the research team, including former graduate student and first author Justin LaVigne, PhD, former undergraduate researcher Ryan Hecksel and former postdoctoral fellow Attila Kerestztes, PhD, focused on four Cannabis terpenes: alpha-humulene, geraniol, linalool and beta-pinene. They evaluated each terpene alone and in combination with WIN55,212-2, a synthetic cannabinoid agonist that stimulates the body's natural cannabinoid receptors.

When a cannabinoid such as THC enters the body, it binds to one of two cannabinoid receptors - CB1R, which is the most abundant, or CB2R. The receptor then activates neurons that affect physiological processes and behavior. In laboratory experiments, researchers found that all four terpenes activated the CB1R, just like THC.

Behavioral studies in mouse models revealed that when administered individually, all four terpenes lowered pain sensitivity, and at least three of the four classic cannabinoid side effects: reduced pain sensation, lowered body temperature, reduced movement and catalepsy, a freezing behavior related to the psychoactive effects of cannabinoids. When terpenes were combined with WIN55,212-2, researchers saw a greater reduction in pain sensation compared with either the terpene or WIN55,212-2 alone, demonstrating a terpene/cannabinoid interaction in controlling pain.

Dr. Streicher's ongoing research is focusing on the use of terpenes in combination with opioids and for specific types of cancer-related pain. His long-term goal is to develop a dose-reduction strategy that uses terpenes - generally recognized as safe by the U.S. Food and Drug Administration - in combination with cannabinoids or opioids to achieve the same levels of pain relief with lower doses of drugs and fewer side effects.

Sea-level rise threatens to produce more frequent and severe flooding in coastal regions and is expected to cause trillions of dollars in damages globally if no action is taken to mitigate the issue. However, communities trying to fight sea-level rise could inadvertently make flooding worse for their neighbors, according to a new study from researchers at The University of Texas at Arlington and the Stanford Natural Capital Project published in Proceedings of the National Academy of Sciences.

Michelle Hummel, an assistant professor of civil engineering at UTA, was lead author of the report, which shows how seawalls constructed along the San Francisco Bay shoreline in California could increase flooding and incur hundreds of millions of dollars in damages for communities throughout the region. The team's findings could also be applied to other coastal regions, such as Texas' Galveston Bay and Chesapeake Bay on the East Coast.

The researchers used complex mathematical models to map how floodwaters--and the economic damages related to floods--would flow depending on where new seawalls were built. They found that blocking certain areas of the bay's shoreline would be particularly damaging to communities throughout the region.

"It's critical to consider the regional impacts of local actions," Hummel said. "Studies like ours can identify actions that will have large impacts, either positive or negative, on the rest of the bay and help to inform decisions about how to manage the shoreline, including coordination on a regional level."

Damages to buildings and homes aren't the only losses that could result from walling shorelines--it also could cut off habitats for important bird and fish species, limit the natural area available to store carbon and create water quality issues by destroying wetlands that naturally provide water treatment.

The researchers emphasized how non-traditional approaches, like choosing to flood certain areas of land rather than build walls, can provide more sustainable solutions for the Bay Area and similar coastal bay communities.

"It's not practical to keep building taller and taller seawalls to hold back the ocean," said study co-author Anne Guerry, chief strategy officer and lead scientist at the Stanford Natural Capital Project. "Our goal was to show how the threat of sea-level rise is interconnected with the whole social-ecological system of the Bay Area. Communities need to coordinate their approaches to sea-level rise adaptation so we can find solutions that are best for the whole bay."

Not every city or county has a landscape suitable for strategic flooding, which requires wide plains or valleys where water will naturally flow. Therefore, the study notes that it's crucial that coastal communities work together to identify where nature-based solutions like flooding make the most sense.

The researchers also looked at demographic information in their models to better understand who would be affected by possible strategic flooding plans. They say that avoiding adaptation plans that add more pressure to poor or otherwise overburdened communities--by forcing them to move or creating increased economic stress--is key.

"Regional planning approaches that account for the interconnectedness of our coastal systems can improve the resilience of our communities, now and into the future," Hummel said.

Oncotarget published "Epigallocatechin-3-gallate modulates Tau Post-translational modifications and cytoskeletal network" which reported that the chemical modulators of Tau PTMs, such as kinase inhibitors and antibody-based therapeutics, have been developed, but natural compounds, as modulators of Tau PTMs are not much explored.

These authors applied biophysical and biochemical techniques like fluorescence kinetics, oligomerization analysis and transmission electron microscopy to investigate the impact of EGCG on Tau glycation in vitro.

EGCG inhibited methyl glyoxal -induced Tau glycation in vitro.

EGCG potently inhibited MG-induced advanced glycation endproducts formation in neuroblastoma cells as well modulated the localization of AT100 phosphorylated Tau in the cells.

They report EGCG, a green tea polyphenol, as a modulator of in vitro methylglyoxal-induced Tau glycation and its impact on reducing advanced glycation end products in neuroblastoma cells.

EGCG, a green tea polyphenol, as a modulator of in vitro methylglyoxal-induced Tau glycation and its impact on reducing advanced glycation end products in neuroblastoma cells.

Dr. Subashchandrabose Chinnathambi from The CSIR-National Chemical Laboratory as well as The Academy of Scientific and Innovative Research said, "Tau is a microtubule-associated protein, which aids in neuronal functioning [1, 2] and Tau neurofibrillary tangles is one of the important characteristic pathology in AD."

The clearance of hyperphosphorylated Tau is decreased by PTMs like glycation, nitration and polyamination whereas glycosylation and dephosphorylation prevents Tau hyperphosphorylation.

Glycation, unlike phosphorylation, is a non-enzymatic PTM, occurring between reducing sugars and protein, lipids etc. Glycation is triggered in presence of high blood sugar levels due to their metabolism via polyol pathway, which converts sugars into highly reactive intermediates like methyl glyoxal, gloxal etc. Glycation involves multistep reactions including complex re-arrangements forming advanced glycation end products .

Moreover, Tau glycation is modulated in an isoform-dependent manner and glycation along with phosphorylation increases the aggregation propensity of full-length Tau.

In this study, they demonstrate the effect of EGCG in inhibiting Tau glycation in vitro and global glycation in the neuroblastoma cells.

The Chinnathambi Research Team concluded in their Research Output that similar studies have reported decrease in MG-induced AGEs formation in neuro2a by AG.

The decrease in AGEs and ROS by EGCG has already been shown by previous studies via Nrf2 -dependent pathways in various cell types.

The exact mechanism of inhibiting AGEs formation in mouse neuroblastoma cells is unclear but it might be due to the quenching of carbonyls formed during glycation by EGCG.

EGCG was found to reduce the glycation of cytoskeletal elements like actin and tubulin.

Reduced glycation was accompanied with resumed tubulin assembly and enhanced actin extensions thus improving neuronal structural integrity.

A greater proportion of men than women exhibit bullying behaviours during medical training and academic practice, and only a minority of victims report their experiences, suggests new research published in the online journal BMJ Open.

Previous studies have reported that bullying is common in medicine with likely impacts on mental health, professional interactions, and career advancement. Surveys from the UK's NHS have reported 55% of staff experienced bullying and around a third were doctors in training. The prevalence of academic bullying within medical settings is unknown.

Therefore a team of researchers led by Dr Harriette Van Spall from McMaster University in Hamilton, Canada, set out to investigate the dynamics and consequences of bullying in academic medical settings and identify useful interventions by reviewing existing studies.

They systematically reviewed 68 suitable studies carried out between 1999 and February 2021 that represented 82,349 consultants or trainees collectively, based in hospitals or clinics that were affiliated with universities or had trained medical students, residents or fellows.

The included studies addressed either the prevalence of and impact of bullying behaviours, characteristics of perpetrators and victims, barriers and facilitators of academic bullying, or potential interventions. Most of the included studies were set in the US and the UK.

The term "academic bullying" was described as the abuse of authority that impeded the education or career of the victim through punishing behaviours that included overwork, destabilisation and isolation in academic settings.

In their review and analysis, the researchers found that among individuals who responded about bullying patterns in 28 studies, the most commonly described (38.2% of respondents) was undue pressure to produce work.

In addition, among individuals in 33 studies who reported the impact of bullying, the most common impact was psychological distress (39.1% of respondents).

Collectively, respondents identified the most common bullies to be consultants (53.6% of respondents in 30 studies), followed by residents (22%), and nurses (14.9%).

Among demographic groups, men were identified as the most common perpetrators (67.2% of respondents in five studies) while women were the most common victims (56.2% of respondents in 27 studies).

Despite being bullied, less than a third of victims (28.9% of victims in 25 studies) reported the bullying and more than half (57.5%) of those who made a formal report did not have a positive outcome. Fear of career impact and lack of perceived benefit were the most common reasons cited for not reporting bullying.

Institutional factors that perpetuate bullying included hierarchical power structures, normalisation of bullying, and a lack of enforcement of anti-bullying policies.

In addition to addressing the hierarchies and permissive environments that make academic bullying common, a range of strategies were described in 49 of the studies reviewed.

These included anti-bullying policies, education, anti-bullying oversight committees, institutional support for victims, and mandatory workshops on mistreatment. The strategies had varying levels of success and the methods used to test these interventions in the studies were not robust.

The authors acknowledge several limitations in the surveys that they analysed, including the lack of a consistent definition of academic bullying, the variation in questions across studies, suboptimal response rates, the lack of validation of instruments, and selection bias.

Nevertheless, the authors' research was broad in scope with a large, diverse cohort including several specialties of medicine and countries.

They conclude: "Bullies are commonly men and senior consultants, and more than half the victims are women. The fear of reprisal, lack of impact of reporting, and non-enforcement of anti-bullying policies are the greatest barriers to addressing academic bullying. Methodologically robust trials of anti-bullying interventions are needed."

Communities trying to fight sea-level rise could inadvertently make flooding worse for their neighbors, according to a new study from the Stanford Natural Capital Project.

The research, published in Proceedings of the National Academy of Sciences, shows how seawalls constructed along the San Francisco Bay shoreline could increase flooding and incur hundreds of millions of dollars in damages for communities throughout the region. The researchers emphasize how non-traditional approaches, like choosing to flood certain areas of land rather than build walls, are smarter, more sustainable solutions for the Bay Area and similar coastal bay communities.

"It's not practical to keep building taller and taller seawalls to hold back the ocean," said Anne Guerry, chief strategy officer and lead scientist at the Stanford Natural Capital Project and senior author on the paper. "Our goal was to show how the threat of sea-level rise is interconnected with the whole social-ecological system of the Bay Area. Communities need to coordinate their approaches to sea-level rise adaptation so we can find solutions that are best for the whole bay."

By 2100, sea levels are projected to rise by almost seven feet in the Bay Area. Millions of people live and work in buildings that are collectively worth hundreds of billions of dollars within the Bay Area's projected sea-level rise zone. As water levels increase, governments are looking for ways to protect their communities and economies.

Following the flow

The researchers used complex mathematical models to map how floodwaters - and the economic damages related to floods - would flow depending on where new seawalls were built. They found that blocking certain areas of the bay's shoreline would be particularly damaging to communities throughout the region. For instance, if a seawall were built along the San Jose shoreline, communities throughout the bay, from Redwood City to Napa and Solano counties, would face an additional $723 million in flood damage costs after just one high tide, according to the models.

Damages to buildings and homes aren't the only losses that could result from walling shorelines - it also can cut off habitat for important bird and fish species, limit the natural area available to store carbon and create water quality issues by destroying wetlands that naturally provide water treatment.

"You may be protecting your immediate community, but you may be creating serious costs and damages for your neighbors," said Robert Griffin, an economist at the Natural Capital Project and co-author on the paper. "When it comes to current sea-level rise planning, there's some incomplete cost-benefit accounting going on."

Guiding the flood

The researchers identified places where Bay Area communities could strategically choose to guide floodwaters, rather than holding them back with walls. These strategic flood areas would act as overflow zones, absorbing the increased water and avoiding damage to communities.

One example is along the Napa-Sonoma shoreline, where Highway 37 is under threat of impending sea-level rise. Decision-makers are trying to decide how to adapt the road to prevent flooding in the future: either by building a taller embankment to raise the road or by rebuilding it as a causeway that allows water to flow between the bay and marshlands on the other side. The researchers modeled what would happen if the Napa-Sonoma shoreline were blocked by a concrete embankment and found that it would worsen flooding for almost all the Bay Area communities studied, from Martinez to San Jose. Building a causeway, on the other hand, would provide a natural absorption area for extra water to flow.

A Bay-wide strategy

"It's critical to consider the regional impacts of local actions," said Michelle Hummel, assistant professor at the University of Texas at Arlington and lead author on the paper. "Studies like ours can identify actions that will have large impacts, either positive or negative, on the rest of the bay and help to inform decisions about how to manage the shoreline."

Not every city or county has a landscape suitable for strategic flooding, which requires wide plains or valleys where water will naturally flow. Therefore, the researchers say it's crucial that Bay Area communities work together to identify the places where nature-based solutions like flooding make the most sense.

The researchers also looked at demographic information in their models to better understand who would be affected by possible strategic flooding plans. They say avoiding adaptation plans that add more pressure to poor or otherwise overburdened communities - by forcing them to move or creating increased economic stress - is key.

To understand the broader impacts of climate resilience decisions, including investments in nature, the researchers plan to model how sea-level rise adaptation strategies are connected with infrastructure, employment, community dynamics and more.

"Our plans should be as interconnected as our ecosystems," said Guerry.

AUSTIN, Texas -- Lead exposure in childhood may lead to less mature and less healthy personalities in adulthood, according to a new study lead by psychology researchers at The University of Texas at Austin.

The study, published in the Proceedings of the National Academy of Sciences, sampled more than 1.5 million people in 269 U.S. counties and 37 European nations. Researchers found that those who grew up in areas with higher levels of atmospheric lead had less adaptive personalities in adulthood -- lower levels of conscientiousness and agreeableness and higher levels of neuroticism.

"Links between lead exposure and personality traits are quite impactful, because we take our personalities with us everywhere," said Ted Schwaba, a postdoctoral fellow in the Department of Psychology at UT Austin. "Even a small negative effect of lead on personality traits, when you aggregate it across millions of people and all the daily decisions and behaviors that our personality influences, can have really massive effects on well-being, productivity and longevity."

In the study, researchers linked historical atmospheric lead data from the Environmental Protection Agency to online personality questionnaire responses from people who grew up in the sampled locations. Results showed that adults who were raised in U.S. counties with higher levels of atmospheric lead were less agreeable and conscientious and, among adults in their 20s and 30s, more neurotic than those who had less lead exposure during childhood.

"These three traits -- conscientiousness, agreeableness and low neuroticism -- make up a large part of what we would consider a mature, psychologically healthy personality and are strong predictors of our success or failure in relationships and at work," Schwaba said. "Normally, across the lifespan, people become more conscientious and agreeable, and less neurotic."

To further test whether lead exposure causes these differences, the researchers examined the effects of the 1970 Clean Air Act, finding that people born after atmospheric lead levels began to decline in their counties had more mature, psychologically healthy personalities in adulthood than those born before their counties phased out lead-based products.

To ensure these findings weren't simply reflecting cohort effects -- characteristics resulting from shared historical or social experiences -- researchers replicated their study in Europe, where lead was phased out later than in the U.S. There, they found that people who grew up in areas with more atmospheric lead were also less agreeable and more neurotic in adulthood, although the findings regarding conscientiousness did not replicate.

"For a long time, we've known lead exposure is harmful, but each new wave of research seems to identify new ways in which lead exposure harms society," Schwaba said. "Though there's much less lead in the atmosphere today, lead remains in pipes, the topsoil and groundwater. And these sources of lead exposure tend to disproportionately harm people of color -- Black children are twice as likely to have high levels of lead in their blood as white children. From an economic standpoint, from a social justice standpoint, or really any way you look at it, it's incredibly important to limit lead exposure as much as possible."

If we pay closer attention to how birds, rabbits and termites transform their local living spaces in response to varying climate conditions, we could become much better at predicting what impact climate change will have on them in future.

This is according to a group of researchers* from the Universities of Montana and Wyoming in the United States, the University of Tours in France and Stellenbosch University (SU) in South Africa. They examined how animals' ability to respond to climate change likely depends on how well they modify their habitats, such as the way they build nests and burrows.

The findings of their study were published recently in the high-impact journal Trends in Ecology and Evolution.

"It's crucial that we continuously improve our ability to predict and mitigate the effects of climate change. One of the ways we can do this is by gaining a better understanding of how animals influence their own small-scale experience of climate at the level of individual members in a population," says one of the researchers, Prof John Terblanche from SU's Department of Conservation Ecology and Entomology.

Terblanche and his co-authors mention that in order to enhance the predictive power of typical contemporary climate change models, it will be important for biologists to understand how animals transform their living space locally in response to climate variability.

"Improving such models will be key to forecasting the effects of climate change on species, and to predict future effects, including how species ranges may shift and what the relative risks of extinction are for different animal species with high levels of precision."

They add that knowing which species will proliferate with climate change is central to understanding pest outbreaks on crops, or disease vectors changing risks for humans.

"Climate change will impact the spread of disease vectors, the health of marine and terrestrial biomes around the world and will influence whether agriculture and fishing will be able to continue supporting human populations, as they have in the past."

In their study, the researchers point out how some animals have found unique ways to protect themselves against extreme climate conditions.

"Many animals dig burrows, construct nests for themselves or their offspring, build homes for entire colonies (ants and termites), induce plants to produce galls, build leaf mines, or simply modify the structure or texture of their local environments.

"For example, birds build nests to keep eggs and chicks warm during cool weather, but also make adjustments in nest insulation to keep the little ones cool in very hot conditions. Mammals, such as rabbits or mice, sleep or hibernate in underground burrows that provide stable, moderate temperatures and avoid above-ground conditions that often are far more extreme outside the burrow.

"We've also seen how termites and ants build mounds that capture wind and solar energy to drive airflow through the colony, which stabilizes temperature, relative humidity, and oxygen level experienced by the colony."

The researchers say these modifications, known as extended phenotypes, filter climate into local sets of conditions immediately around the organism - 'the microclimate', which is key for a better understanding of the impact of climate change.

"Two features of microclimates are important. First, microclimates typically differ strongly from nearby climates, which means that the climate in an area may provide little information about what animals experience in their microhabitats. Second, because extended phenotypes are built structures, they often are modified in response to local climate variation, and potentially in response to climate change."

The researchers call for a renewed effort to understand how extended phenotypes mediate how organisms experience climate change. "We need a much better understanding of how much animals can adjust these structures in response to varying climate conditions," says Terblanche.

"Another key challenge is to understand how much flexibility there is in extended phenotypes, and how rapidly they can evolve. At this point, we pretty much have no idea whether these processes can keep up with climate change," adds lead author Art Woods from the University of Montana.

 Pure quantum systems can undergo phase transitions analogous to the classical phase transition between the liquid and gaseous states of water. At the quantum level, however, the particle spins in states that emerge from phase transitions display collective entangled behavior. This unexpected observation offers a new avenue for the production of materials with topological properties that are useful in spintronics applications and quantum computing. 

The discovery was made by an international collaboration led by Julio Larrea, a professor at the University of São Paulo’s Physics Institute (IF-USP) in Brazil. Larrea is first author of an article on the study published in Nature. The research was supported by FAPESP. 

“We obtained the first experimental evidence of a first-order quantum phase transition in a quasi-two-dimensional system consisting entirely of spins. It was a groundbreaking study in terms of both experimental development and theoretical interpretation,” Larrea said.

To understand the significance of this discovery, it will help to examine the classical phase transition, which can be exemplified by the change in the state of water, and its quantum analogue, exemplified by the Mott metal-insulator transition.

“The change in the state of water, which occurs at 100 °C under standard atmospheric pressure, is what we call a first-order transition. It is characterized by a discontinuous jump in molecule density. In other words, the number of water molecules per unit volume varies drastically between one state and the other,” Larrea said. “This first-order discontinuous transition evolves in accordance with pressure and temperature until it is fully suppressed at the so-called critical point of water, which occurs at 374 °C and 221 bar. At the critical point, the transition is second-order, i.e. continuous.”

In the vicinity of the critical point, the properties of water behave anomalously, because the density fluctuations are infinitely correlated on the atomic length scale. As a result, the material manifests a unique state that differs both from a gas and a liquid (see Figure 1).

“In quantum matter, the Mott metal-insulator transition is a rare example of a first-order transition. Unlike ordinary metals and insulators, which have free electrons that don’t interact, a Mott state involves strong interaction between electron charges, configuring collective behavior,” Larrea explained. “The energy scales of these interactions are very low, so a first-order quantum phase transition between a metal and an insulator can happen at absolute zero, which is the lowest possible temperature. The interaction between charges varies with temperature and pressure until it is suppressed at the critical point. As the critical point approaches, volume charge density, which is the quantity of charge per unit volume, undergoes such an abrupt change that it can induce new states of matter such as superconductivity.”

In the two examples mentioned, the phenomena involve massive particles such as water molecules and electrons. The question posed by the researchers was whether the concept of phase transition could be extended to massless quantum systems, such as a system made up solely of spins (understood as a quantum manifestation of matter associated with magnetic states). A situation of this kind had never been observed before.

“The material we used was a frustrated quantum antiferromagnet SrCu2(BO3)2,” Larrea said. “We measured the specific heat of small samples under simultaneously extreme conditions of temperature [to 0.1 kelvin], pressure [to 27 kilobar] and magnetic field [to 9 tesla]. Specific heat is a physical property that gives us a measure of the internal energy in the system, and from this, we can infer different types of orderly or disorderly quantum state, and possible electronic states or entangled spin states.”

Obtaining these measurements with the precision required to reveal correlated quantum states, using samples submitted to extremely low temperatures, high pressures and strong magnetic fields, was a formidable experimental challenge, according to Larrea. The experiments were performed in Lausanne, Switzerland, at the Laboratory for Quantum Magnetism of the Federal Polytechnic School of Lausanne (LQM-EPFL), headed by Henrik Rønnow. The precision of the measurements motivated the theoretical collaborators, led by Frédéric Mila (EPFL) and Philippe Corboz (University of Amsterdam), to develop state-of-the-art computational methods with which to interpret the different anomalies observed.

“Our results showed unexpected manifestations of quantum phase transitions in pure spin systems,” Larrea said. “First, we observed a quantum phase transition between two different kinds of entangled spin state, the dimer state [spins correlated at two atomic sites] and the plaquette state [spins correlated at four atomic sites]. This first-order transition ends at the critical point, at a temperature of 3.3 kelvin and pressure of 20 kilobar. Although the critical points of water and the SrCu2(BO3)2 spin system have similar characteristics, the states that emerge near the critical point of the spin system comply with a different description of physics, of the Ising type.” The term Ising refers to a model of statistical mechanics named for German physicist Ernst Ising (1900-98).

“We also observed that this critical point has a discontinuity in magnetic particle density, with triplets or states correlated in different configurations of spin orientation, leading to the emergence of a purely quantum antiferromagnetic state,” Larrea said (see Figure 2).

The next step for Larrea is to find out more about the criticality and entangled spin states that emerge in the vicinity of the critical point, the nature of the discontinuous and continuous quantum phase transitions, and the energy scales that represent the interactions and correlations between electron spins and charges leading to quantum states such as superconductivity. “To this end, we plan to conduct a study with pressures around the critical point and higher pressures,” he said. A new facility, the Laboratory for Quantum Matter under Extreme Conditions (LQMEC), is being set up for this purpose in collaboration with Valentina Martelli, a professor in IF-USP’s Department of Experimental Physics.

Writing in the July 12, 2021 online issue of Nature Communications, researchers at University of California San Diego School of Medicine describe a new approach that uses machine learning to hunt for disease targets and then predicts whether a drug is likely to receive FDA approval.

The study findings could measurably change how researchers sift through big data to find meaningful information with significant benefit to patients, the pharmaceutical industry and the nation's health care systems.

"Academic labs and pharmaceutical and?biotech companies?have access to unlimited amounts of 'big data' and better tools than ever to analyze such data. However, despite these incredible advances in technology,?the success rates in drug discovery?are lower?today?than in the 1970s," said Pradipta Ghosh, MD, senior author of the study and professor in the departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine.

"This is mostly because drugs that work perfectly in preclinical inbred models, such as laboratory mice, that are genetically or otherwise identical to each other, don't translate to patients in the clinic, where each individual and their disease is unique. It is this variability in the clinic that is believed to be the Achilles heel for any drug discovery program."

In the new study, Ghosh and colleagues replaced the first and last steps in preclinical drug discovery with two novel approaches developed within the UC San Diego Institute for Network Medicine (iNetMed), which unites several research disciplines to develop new solutions to advance life sciences and technology and enhance human health.

The researchers used the disease model for inflammatory bowel disease (IBD), which is a complex, multifaceted, relapsing autoimmune disorder characterized by inflammation of the gut lining. Because it impacts all ages and reduces the quality of life in patients, IBD is a priority disease area for drug discovery and is a challenging condition to treat because no two patients behave similarly.

The first step, called target identification, used an artificial intelligence (AI) methodology developed by The Center for Precision Computational System?Network?(PreCSN), the computational arm of iNetMed. The AI approach helps model a disease using a map of successive changes in gene expression at the onset and during the progression of the disease. What sets this mapping apart from other existing models is the use of mathematical precision to recognize and extract all possible fundamental rules of gene expression patterns, many of which are overlooked by current methodologies.

The underlying algorithms ensure that the identified gene expression patterns are 'invariant' regardless of different disease cohorts. In other words, PreCSN builds a map that extracts information that applies to all IBD patients.

"In head-to-head comparisons, we demonstrated the superiority of this approach over existing methodologies to accurately predict 'winners' and 'losers' in clinical trials," said Ghosh.

The last step, called target validation in preclinical models, was conducted in a first-of-its-kind Phase '0' clinical trial using a living biobank of organoids created from IBD patients at?The?HUMANOID Center of Research Excellence?(CoRE), the translational arm of iNetMed.

The Phase '0' approach involves testing the efficacy of the drugs identified using the AI model on human disease organoid models--cultured human cells in a 3D environment that mimic diseases outside of the body. In this case, an IBD-afflicted gut-in-a-dish.

"The 'phase 0' trial concept was developed because most drugs fail somewhere between phases I and III. Before proceeding to patients in the clinic, 'phase 0' tests efficacy in the human disease models, where ineffective compounds can be rejected early in the process, saving millions of dollars," said Soumita Das, PhD, co-senior author of the study, director of the HUMANOID center and an associate professor in the Department of Pathology at UC San Diego School of Medicine.

Biopsy tissues for the study were taken during colonoscopy procedures involving IBD patients. Those biopsies were used as the source of stem cells to grow organoids.

"There were two major surprises. First, we saw that despite being away from the immune cells in the gut wall and the trillions of microbes that are in the gut lining, these organoids from IBD patients showed the tell-tale features of a leaky gut with broken cell borders," said Das.

"Second, the drug identified by the AI model not only repaired the broken barriers, but also protected them against the onslaught of pathogenic bacteria that we added to the gut model. These findings imply that the drug could work in both acute flares as well as for maintenance therapy for preventing such flares."

The researchers found the computational approach had a surprisingly high level of accuracy across diverse cohorts of IBD patients, and together with the Phase '0' approach, they developed a first-in-class therapy to restore and protect the leaky gut barrier in IBD.

"Our study shows how the likelihood of success in phase III clinical trials, for any target, can be determined with mathematical precision," said Debashis Sahoo, PhD, co-senior author of the study who leads PreCSN and is associate professor in the departments of Pediatrics and Computer Science at UC San Diego School of Medicine and UC San Diego.

"Our approach could provide the predictive horsepower that will help us understand how diseases progress, assess a drug's potential benefits and strategize how to use a combination of therapies when current treatment is failing," Sahoo said.

The authors said next steps include testing if the drug that passed the human phase '0' trial in a dish can pass phase III trials in clinic; and whether the same methodologies can be used with other diseases, ranging from diverse types of cancers and Alzheimer's disease to non-alcoholic fatty liver disease.

"Our blueprint has the potential to shatter status quo and deliver better drugs for chronic diseases that have yet to have good therapeutic solutions," said Ghosh.

North Carolina State University researchers have developed a new technique that can alter plant metabolism. Tested in tobacco plants, the technique showed that it could reduce harmful chemical compounds, including some that are carcinogenic. The findings could be used to improve the health benefits of crops.

"A number of techniques can be used to successfully reduce specific chemical compounds, or alkaloids, in plants such as tobacco, but research has shown that some of these techniques can increase other harmful chemical compounds while reducing the target compound," said De-Yu Xie, professor of plant and microbial biology at NC State and the corresponding author of a paper describing the research. "Our technology reduced a number of harmful compounds - including the addictive nicotine, the carcinogenic N-nitrosonornicotine (NNN), and other tobacco-specific nitrosamines (TSNAs) - simultaneously without detrimental effects to the plant."

The technique uses transcription factors and regulatory elements as molecular tools for new regulation designs. Regulatory elements are short, non-coding DNA fragments that control the transcription of nearby coding genes. Transcription factors are proteins that help turn certain genes on or off by binding to regulatory elements. Xie hypothesized that these could be useful molecular tools to design new regulations for engineering new plant traits. Two Arabidopsis transcription factors in particular, PAP1 and TT8, are known to regulate the biosynthesis of anthocyanins, or classes of nutraceutical compounds with antioxidant properties. Xie further hypothesized that these proteins could be used as molecular tools to help repress a number of harmful chemical compound levels, such as nicotine.

"PAP1 regulates pigmentation, so tobacco plants with our overexpressed PAP1 genes are red," Xie said. "We screened plant DNAs and found that tobacco has PAP1- and TT8-favored regulatory elements near JAZ genes, which repress nicotine biosynthesis. We then proposed that these elements were appropriate tools for a test. In all, we found four JAZ genes activated in red tobacco plants with a designed PAP1 and TT8 cassette overexpressed."

Xie and his colleagues tested the hypothesis by examining tobacco plants in the greenhouse and in the field and showed the reductions of harmful chemical compounds and nicotine in both types of experiments. NNN levels were reduced from 63 to 79% in leaves from tobacco plants that had PAP1 and TT8 overexpressed, for example. Overall, four carcinogenic TSNAs were significantly reduced by the technique.

Xie believes that the technique holds the potential to be used in other crop plants to promote other beneficial traits and make some foods healthier.

The paper appears in Journal of Advanced Research. Research associate Mingzhu Li is a first author of the paper. Former postdoctoral fellows Xianzhi He and Christophe La Hovary are co-first authors. The research was supported by the R.J. Reynolds Tobacco Co.

Being immersed in a stunning 'virtual' Icelandic landscape can reduce the pain caused by uncomfortable medical procedures, new research has found.

The study compared patients with and without virtual reality (VR) headsets having rigid cystoscopies, where a rigid telescope is inserted through the urethra into the bladder. The research is being presented today at the European Association of Urology congress, EAU21.

Diagnosing and treating bladder cancer usually requires checking the bladder through a cystoscopy, which is perceived by patients as unpleasant and painful. Some patients avoid follow-up and as a result suffer uncontrolled and irreversible development of the disease. It is possible to have a flexible cystoscopy, which is less painful, but certain treatments can only be done with a rigid cystoscopy. Rigid cystoscopy may be performed under local anaesthesia. It can also be performed under both general and spinal anaesthetic, but those procedures bring additional risk of complications.

In some fields of medicine, VR has been shown to be an effective pain relief tool; for example, in burns patients while dressings are changed. In these applications patients have tended to be upright and the VR experience interactive.

Dr Wojciech Krajewski and colleagues at the Wroc?aw Medical University in Poland recruited 103 patients, with a mean age of 66 years, who were listed for rigid cystoscopy with just local, intraurethral anaesthesia. Some were for a first diagnosis and others required follow up having experienced the procedure in the past. Individuals were randomised to undergo classic cystoscopy or the procedure with VR goggles and headphones presenting an image of the Skógafoss waterfall in Iceland.

Patients were asked about their level of fear and completed a questionnaire on anxiety and depression before the procedure. During the cystoscopy, the team measured blood pressure, oxygen saturation and heart rate in patients, as well as taking pain-related observations using a measurement score called FLACC - observing face, legs, consolability and cry - which is used in children but here adjusted for adults. After the procedure, patients were also asked to rate the pain perception and nausea related with the cystoscopy.

The pain scale scores were lower in the VR group than the controls, and though nausea and vertigo were higher with the headsets and goggles, patients found it bearable and no procedures had to stop as a result.

Blood pressure and heart rate increased in all patients during the procedure, but less so in the VR group. Oxygen saturation remained stable but these measurements are less reliable because masks were introduced during the trial when the COVID-19 pandemic began.

The findings were the same for male, female, first and follow-up cystoscopies, and the researchers believe the technology could be used for other uncomfortable or painful procedures to help reduce patient pain.

Dr Krajewski says: "Cystoscopy is uncomfortable for patients and they can be anxious about it. My colleagues and I were keen to find new ways to make them more comfortable and had seen VR technology used for younger patients to alleviate pain in interactive ways. In this instance we wanted to try presenting a calming image, more suited to older patients, and see if we could better support them during their procedures."

"Patients reported less pain, and this was also reflected in our observations of their experience. VR is certainly an option for pain reduction in cystoscopies and we are looking into whether it will have the same effect in other medical interventions such as lithotripsy to break down kidney stones or prostate biopsy."

Professor James N'Dow, from the University of Aberdeen, who chairs the EAU Guidelines Office, says: "Improving patients' experience of the care they receive is as important as improving treatment outcomes. While it makes sense to avoid general anaesthesia whenever possible, telescopic bladder examinations under local anaesthetic can be very uncomfortable and frightening for some patients. This study increases our understanding of how virtual reality can distract patients and reduce their anxiety and pain. What's needed now is a larger trial, which would also do a cost-benefit analysis, to determine whether this approach should be considered as part of standard clinical practice."

A lump in the thyroid gland is called a thyroid nodule, and 5-10% of all thyroid nodules are diagnosed as thyroid cancer. Thyroid cancer has a good prognosis, a high survival rate, and a low recurrence rate, so early diagnosis and treatment are crucial. Recently, a joint research team in Korea has proposed a new non-invasive method to distinguish thyroid nodules from cancer by combining photoacoustic (PA) and ultrasound image technology with artificial intelligence.

The joint research team - composed of Professor Chulhong Kim and Dr. Byullee Park of POSTECH's Department of Electrical Engineering, Department of Convergence IT Engineering and Department of Mechanical Engineering, Professor Dong-Jun Lim and Professor Jeonghoon Ha of Seoul St. Mary's Hospital of Catholic University of Korea, and Professor Jeesu Kim of Pusan National University - conducted a research to acquire PA images from patients with malignant and benign nodules and analyzed them with artificial intelligence. In recognition of their significance, the findings from this study were published in Cancer Research.

Currently, the diagnosis of a thyroid nodule is performed using a fine-needle aspiration biopsy (FNAB) using an ultrasound image. But about 20% of FNABs are inaccurate which leads to repetitive and unnecessary biopsies.

To overcome this problem, the joint research team explored the use of PA imaging to obtain an ultrasonic signal generated by light. When light (laser) is irradiated on the patient's thyroid nodule, an ultrasound signal called a PA signal is generated from the thyroid gland and the nodule. By acquiring and processing this signal, PA images of both the gland and the nodule are collected. At this time, if multispectral PA signals are obtained, oxygen saturation information of the thyroid gland and thyroid nodule can be calculated.

The researchers focused on the fact that the oxygen saturation of malignant nodules is lower than that of normal nodules, and acquired PA images of patients with malignant thyroid nodules (23 patients) and those with benign nodules (29 patients). Performing in vivo multispectral PA imaging on the patient's thyroid nodules, the researchers calculated multiple parameters, including hemoglobin oxygen saturation level in the nodule area. This was analyzed using machine learning techniques to successfully and automatically classify whether the thyroid nodule was malignant or benign. In the initial classification, the sensitivity to classify malignancy as malignant was 78% and the specificity to classify benign as benign was 93%.

The results of PA analysis obtained by machine learning techniques in the second analysis were combined with the results of the initial examination based on ultrasound images normally used in hospitals. Again, it was confirmed that the malignant thyroid nodules could be distinguished with a sensitivity of 83% and a specificity of 93%.

Going a step further, when the researchers kept the sensitivity at 100% in the third analysis, the specificity reached 55%. This was about three times higher than the specificity of 17.3% (sensitivity of 98%) of the initial examination of thyroid nodules using the conventional ultrasound.

As a result, the probability of correctly diagnosing benign, non-malignant nodules increased more than three times, which shows that overdiagnosis and unnecessary biopsies and repeated tests can be dramatically reduced, and thereby cut down on excessive medical costs.

"This study is significant in that it is the first to acquire photoacoustic images of thyroid nodules and classify malignant nodules using machine learning," remarked Professor Chulhong Kim of POSTECH. "In addition to minimizing unnecessary biopsies in thyroid cancer patients, this technique can also be applied to a variety of other cancers, including breast cancer."

"The ultrasonic device based on photoacoustic imaging will be helpful in effectively diagnosing thyroid cancer commonly found during health checkups and in reducing the number of biopsies," explained Professor Dong-Jun Lim of Seoul St. Mary's Hospital. "It can be developed into a medical device that can be readily used on thyroid nodule patients."

Drs. Nobuo Noda (Director) and Tatsuro Maruyama (Researcher) et al. at the Institute of Microbial Chemistry (BIKAKEN, Tokyo, Japan) discovered that lipidated Atg8(1), the most famous factor that mediates autophagy, has membrane perturbation activity and elucidated that this activity is responsible for efficient autophagosome formation.

Autophagosome formation is an essential step in determining the target of degradation in autophagy, which is one of the mechanisms of intracellular protein degradation. It is known that lipidated Atg8 plays a primary role in autophagy processes; however, the molecular function of lipidated Atg8 on the autophagy-related membranes remains unknown.

The research group demonstrated through in vitro experiments that yeast Atg8 exhibits membrane transforming activity. Moreover, on examining the three-dimensional structure of lipidated Atg8 by solution NMR spectroscopy(2), they found that lipidated Atg8 interacts with the membrane via two aromatic amino acids(3). In addition, they found that mutant aromatic amino acids resulted in the loss of the membrane transforming activity of lipidated Atg8 in vitro, inhibited the autophagosome formation in yeast, and attenuated autophagy in mammalian cells. Consequently, they revealed a novel mechanism wherein lipidated Atg8 perturbs and transforms membranes through direct interaction, thereby promoting autophagosome formation.

The elucidation of the molecular role of the main autophagy factor, Atg8, which has been a long-standing issue in the field of autophagy, holds promise in accelerating research that will contribute to a complete understanding of the molecular mechanisms of autophagosome formation. Furthermore, it is expected to promote research and development for treating and preventing various diseases through the artificial control of autophagy by deepening our understanding of autophagosome formation mechanisms.

The present research was conducted in collaboration with the group of Drs. Hitoshi Nakatogawa (Associate Professor, Tokyo Institute of Technology), Yoshinori Ohsumi (Honorary Professor), Tomotake Kanki (Professor, Niigata University), Masaaki Komatsu (Professor, Juntendo University), and Ichio Shimada (Team Leader, RIKEN) in JST Strategic Basic Research Programs (CREST).

(1) Lipidated Atg8

The functional state of Atg8 involves its covalent conjugation with a phospholipid via enzymatic reactions. Since lipidated Atg8 is abundant in the membranes of autophagosomes and their precursors, it is widely utilized as the main autophagy marker protein in autophagy research.

(2) NMR spectroscopy

Atomic nuclei in a strong magnetic field interact with electromagnetic waves having a specific frequency (named resonance frequency), which reflects the nuclear property and chemical environment. NMR spectroscopy is a technique used for obtaining information regarding the structure and property of compounds by detecting the electromagnetic waves as NMR signals. NMR is an abbreviation for Nuclear Magnetic Resonance.

(3) Aromatic amino acids

Aromatic amino acids, such as tryptophan, tyrosine, and phenylalanine, have an aromatic side chain. It is known that buried aromatic amino acids contribute to the stabilization of protein folding, whereas exposed aromatic amino acids mediate interactions with other proteins and membranes.

A new study from Queen Mary University of London has demonstrated that immune cells can be stimulated to assemble into special structures within pancreatic cancer such that, at least in a pre-clinical model, researchers can demonstrate an improvement in the efficacy of chemotherapy.

The body's immune system is a critical defence against illness such as infections, as has been highlighted by the recent COVID-19 pandemic. The same immune system can also help us fight cancer. However, pancreatic cancer is different; a key feature of this cancer type is that the pancreatic cancer cells are surrounded by a dense, impenetrable barrier known as the stroma, which often blocks the access of immune cells to the tumour. For this reason, immunotherapies - drugs that harness the power of the body's immune system to kill cancer cells - have shown limited success in the treatment of pancreatic cancer, whilst they are effective in fighting other cancer types including skin and lung cancer.

Research has found that in some patients with pancreatic cancer, immune cells can assemble into clusters known as tertiary lymphoid structures (TLS) within the stroma, which are associated with improved survival outcomes in patients. However, TLS do not form naturally in all patients with pancreatic cancer. With this in mind, in this study the team set out to investigate the structure and role of TLS in pancreatic cancer when present, and to evaluate their anti-tumour activity.

The research was published in Cellular and Molecular Gastroenterology and Hepatology, and funded by Cancer Research UK, Pancreatic Cancer Research Fund and Medical Research Council.

To determine the presence of TLS within human pancreatic cancer, the team analysed tissue samples donated by patients to the Pancreatic Cancer Research Fund Tissue Bank. In this study, TLS were defined by the presence of tissue zones rich in B cells, T cells and dendritic cells - three cell types that have an important role in the immune response. By using specialised staining techniques to visualise the different cell types present within the samples, the team found that TLS were only in a third of patients whose samples were analysed.

To study the development of TLS in pancreatic cancer, the team generated a pre-clinical murine model of pancreatic cancer. TLS were not present in the model initially; however, following the injection of two signalling proteins (known as lymphoid chemokines) into the tumours of the mice, B cells and T cells infiltrated into the tumour site and assembled into TLS.

TLS induction can improve the effectiveness of chemotherapy

The team then combined the chemokine injection with administration of gemcitabine - a chemotherapy commonly used in the treatment of pancreatic cancer patients. The combination of gemcitabine and chemokine injection resulted in smaller tumours in mice, an effect that was not achieved by either treatment alone.

Hemant Kocher, Professor of Liver and Pancreas Surgery at Queen Mary University of London and consultant at Barts Health NHS Trust, who led the study, said: "Pancreatic cancer is known as a cold tumour, which means it does not have many immune cells near the cancer trying to fight it. In this study we have shown that immune cells can not only be harnessed but also made to assemble into TLS within a pre-clinical model of pancreatic cancer to make chemotherapy more effective."

"Formation of TLS is critical in mounting the anti-tumour response close to the tumour to overcome the problem posed by the barrier of the stroma. These findings suggest that combining chemotherapy with appropriate immunotherapy to stimulate immune cells in the tumour microenvironment could be used to tailor more personalised treatments against pancreatic cancer."

The anti-tumour activity seen after TLS formation in the pre-clinical model was associated with B cells triggering the activation of dendritic cells, which is required for the initiation of an immune response. The findings suggest that lymphoid chemokines, when used in combination with chemotherapy, may represent a viable therapeutic strategy for promoting an anti-tumour immune response that could lead to better clinical outcomes.

As this study used a mouse model, further research is now required to determine whether the same outcomes can be observed in other experimental models and in patients. The team believe that a more detailed understanding of TLS formation may aid in the development of personalised therapies that can harness the potential of the body's own immune system to fight cancer.