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DALLAS, May 17, 2021 -- Detecting a critical heart defect before birth (congenital heart defects) is less likely when a mother lives in a rural area, lives in a neighborhood with low socioeconomic status or is Hispanic, according to new research published today in the American Heart Association's flagship journal Circulation.

Diagnosing a heart defect before birth reduces infant death rates, increases access to prompt medical treatment, improves neurodevelopmental outcomes and decreases the risk of brain injury for the infant after birth.

"The benefits of prenatal diagnosis for heart defects have been recognized for years, yet prenatal detection occurs in less than 60% of congenital heart disease cases in many U.S. regions," said the study's first author Anita Krishnan, M.D., an associate professor of pediatrics and associate director of echocardiography at Children's National Hospital in Washington, D.C.

"This is one of the largest studies to define specific populations at risk for missed prenatal screening and diagnosis of congenital heart disease," she said. "With these conditions, minutes can make a difference, and prenatal planning allows for improved care before, during and after birth."

Researchers evaluated data on more than 1,800 infants from 21 cardiology centers in the United States and Canada to determine whether a relationship exists between prenatal detection of transposition of the great arteries and hypoplastic left heart syndrome and socioeconomic, racial/ethnic and geographic factors.

Congenital heart defects are heart conditions present at birth. According to the American Heart Association's Heart Disease and Stroke Statistics -- 2021 Update, an estimated minimum of 40,000 infants are expected to be affected each year by congenital heart defects in the United States. At least 18 distinct types of congenital heart defects are recognized, with many additional anatomic variations.

Transposition of the great arteries occurs when the two main arteries leaving the heart are reversed and accounts for 2.6% of congenital heart defects. Hypoplastic left heart syndrome involves an underdeveloped left side of the heart and accounts for about 0.3% of the defects.

The study focused on clinical data from fetuses and infants with a first-time evaluation between 2012 and 2016 at a participating institution in the Fetal Heart Society, a non-profit multicenter research collaborative whose mission is to advance the field of fetal cardiovascular care and science. Researchers defined prenatal detection as having a fetal echocardiogram - a test that uses high frequency sound waves, or ultrasound, to view structures and functioning of the fetus' heart. Patients are referred for fetal echocardiograms for a variety of maternal or fetal conditions per the guidelines from the American Institute of Ultrasound in Medicine, or if an anomaly is suspected on a second trimester ultrasound examination. Most cases are referred due to suspected cardiac disease and not for one of the routine indications for fetal echocardiography, Krishnan explained.

Hypoplastic left heart syndrome is identifiable through echocardiogram imaging of the heart's four chambers; however, detecting transposition of the great arteries requires additional views on prenatal ultrasound screening and may be more difficult to detect prenatally than hypoplastic left heart syndrome, the authors noted.

Socioeconomic and residential information came from federal census data for the mothers, and distance from a cardiology center was derived from the mothers' address at the time of her first visit for prenatal detection. For U.S. patients, socioeconomic neighborhood status was measured in quartiles that considered median household income; median household value; neighborhood percentage of high school graduates; neighborhood percentage of college graduates; percentage of neighborhood residents in executive, managerial or professional specialty occupations; and the percentage of households receiving rental income.

Among Canadian patients - all from Alberta and Ontario - socioeconomic status was calculated from 22 variables related to cultural identities, environmental pollutants, environmental injustice studies and a deprivation index, which is a marker of social inequalities in health. These factors were then converted to be comparable with the U.S. quartiles.

The study revealed that about 92% of hypoplastic left heart syndrome cases and 58% of transposition of the great arteries cases were diagnosed before birth. However, significant socioeconomic and racial and ethnic differences emerged among the women diagnosed with fetal transposition of the great arteries.

"Mothers who lived in neighborhoods with the lowest socioeconomic position were up to 22% less likely to receive a prenatal diagnosis of transposition of the great arteries than the mothers who lived in the wealthiest neighborhoods," Krishnan said. "While the findings are not completely surprising and resonate with clinical experience, the strength of the associations was surprising."

Other findings include:

Hispanic ethnicity in the United States was associated with a 15% lower likelihood of prenatal detection of transposition of the great arteries compared to non-Hispanic mothers, and living in rural areas was associated with a 22% lower likelihood of prenatal detection of transposition of the great arteries compared to mothers who lived in more urban areas.

Among the patients in Canada, only longer distance to a cardiology center was associated with lower prenatal detection rates of hypoplastic left heart syndrome - those driving more than 135 miles for care were 24% less likely to have transposition of the great arteries detected.

Lower socioeconomic status was associated with about a four-week delay in diagnosing prenatal congenital heart disease for pregnant women in both the U.S. and Canada.

The standards of care for congenital heart disease are similar in both countries, yet some of the associations were different in the United States compared to Canada, where health care is publicly funded and available to all Canadian citizens or permanent residents without financial limitations. "This suggests that factors related to the different health care delivery systems may also play a role in the rates of screening and diagnosis," Krishnan said.

"While prenatal detection rates of congenital heart disease are lower than they should be across the board, there are striking sociodemographic and geographic disparities," she said. "Strengthening relationships among cardiology and surgery centers and the populations identified in this study, through outreach and potentially telemedicine, may improve prenatal detection rates within these communities.

"Telehealth linkages to the tertiary care center may improve timeliness of detection as well as overall detection rates, but is likely not the only solution," Krishnan continued. "In-person collaboration or consultation is also needed. There is ongoing study of whether socioeconomic barriers exist to participation with telemedicine and internet, and our center is currently doing pilot work in rural Maryland. To successfully implement telemedicine requires investing in the hardware, educating sonographers and establishing the security infrastructure to make telemedicine easier to perform."

The study created a new registry of data variables that had not been possible using hospital databases that typically do not include prenatal care information linking maternal and pediatric records. A significant limitation is that the study only included patients who received care at one of the 21 participating fetal cardiology centers.

What The Study Did: Researchers assessed the feasibility of using positive behavior supports to promote the use of face coverings in school-aged children with autism spectrum disorders and/or attention-deficit/hyperactivity disorder (ADHD) attending a summer program during the COVID-19 pandemic.

Authors: Benjamin Aaronson, Ph.D., of the University of Washington in Seattle, 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/jamanetworkopen.2021.10281)

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Early diagnosis and improvement of breast cancer treatments have reduced breast cancer mortality in recent years, with survival rates reaching 85% today. In spite of these data, breast cancer was still the most frequently diagnosed tumour in the world in 2020, mainly due to increased population screening and social factors such as ageing. RANK protein plays a key role in the development of these tumours. Located in the membrane of cells, when it binds to its partner RANKL, it sends signals that stimulate the development of the mammary gland. When these proteins do not work properly, breast cells begin to divide and multiply uncontrollably, resulting in breast cancer.

Researchers from the Spanish National Cancer Research Centre (CNIO) and the Bellvitge Biomedical Research Institute (IDIBELL), led by Eva González-Suárez at the CNIO, have found that the hyperactivation of the RANK pathway plays a double function in breast cells: in the early stages of cancer, it activates senescence, which has a protective effect and delays the appearance of tumours; in more advanced stages, RANK-induced senescence favours the accumulation of stem cells in the breast tissue, which promotes tumour growth and increased aggressiveness. The results of the work are published this week in the journal Developmental Cell.

The authors describe throughout the paper how this double activation of senescence and tumour stem cells occurs in response to high RANK levels, using mice that produced large amounts of this protein in the epithelial cells of breast tissue. "We observe that high levels of RANK protein induce senescence and at the same time an accumulation of stem cells, which in principle seems contradictory, but is not," explains González-Suárez.

RANK protein, from bone formation to cancer

RANK proteins have been linked to bone tissue remodelling, and blocking these proteins by means of inhibitors such as denosumab antibodies has been shown to be effective in the treatment of bone-related pathologies such as osteoporosis and bone metastases.

These proteins also participate in the development of the mammary gland, which occurs mainly in women during puberty, pregnancy and the menstrual cycle in response to sex hormones. When these proteins do not work properly, breast cells begin to divide and multiply uncontrollably. "In this paper, we have detected abnormally high levels of RANK in pre-neoplastic lesions in patients with breast cancer," the researchers report. How does RANK act on epithelial cells in the mammary glands to promote cancer?

In 2010, González-Suárez first described the key role of this protein in the development of breast cancer and proposed that drug inhibition by means of RANKL inhibitors could prevent breast cancer. Over the course of a few years, "we demonstrated its therapeutic potential for the treatment of breast tumours by reducing recurrence and metastases, both because of its role in tumour cells and because of a reactivation of the anti-tumour immune response," the researcher said.

A protective mechanism that becomes harmful

Senescence is a process historically associated with the protection of cells and tissues. Cells begin their senescence programme in response to stimuli such as the activation of oncogenes - cancer-promoting genes -, the absence or failure of anticancer genes, or the shortening of telomeres - the protein structures that protect the ends of chromosomes. All of these stimuli are harmful, and senescence causes cells to enter a state of lethargy to facilitate cell integrity. But today it is known that, in addition to the protective role of senescence against the development of diseases such as cancer, it can be a double-edged sword and favour pathological processes; for example, in obesity and diabetes, it promotes the disease, increasing insulin resistance and inflammation.

In the paper published in Developmental Cell, the researchers have found that, in the early stages of breast cancer, high levels of RANK protein in the breast epithelium in mice induce senescence and a delay in tumour development. In contrast, in more advanced stages of tumours, they observed that senescence favoured the accumulation of stem cells in the breast tissue, leading to increased tumour growth and aggressiveness.

"The mammary gland contains stem cells, which are like primitive cells that have the ability to differentiate into different cell types and promote tumour formation and increase their metastatic capacity," says González-Suárez. The researcher had already seen in previous studies that RANK promotes stem cell properties in the mouse mammary epithelia. Now, the authors of the study have for the first time in breast cancer linked senescence to an increase in the stem cell properties of RANK regulated tissue, and how this leads to an increase in tumour progression and aggressiveness.

Non-tumour cells that send signals to favour cancer

In this sequence of events in which RANK is activated, the team has observed that in the earliest stages of the disease, senescence was activated primarily in the luminal cells of the breast epithelium, those that are most exposed to the lumen of the breast ducts.

In the work they suggest that these senescent, non-tumour cells release a series of substances that act in a paracrine way - at a distance from neighbouring cells- on luminal and basal cells, the latter of which are far from the lumen of the ducts. In response to this stimulus, luminal and basal cells acquire stem cell characteristics, and despite the misleading initial delay, the resulting tumours are more aggressive, growing rapidly, causing lung metastases.

Previous studies by González-Suárez and other research groups suggest that RANK inhibitors could prevent breast cancer and improve the prognosis of patients. "Preventive clinical trials on this type of compounds are currently underway in a subgroup of BRCA1 gene mutation-bearing women, who are at high risk of developing breast tumours. The inhibition of RANKL offers a much less aggressive alternative to mastectomy. Other trials are testing the potential of RANKL inhibitors to improve survival in breast cancer, among other tumours," explains González-Suárez

Doctors often recommend Omega-3s to help patients lower their cholesterol and improve heart health. Those Omega-3s can come from fatty fish like salmon and mackerel, or supplements that often contain a combination of the acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Now, new research from the Intermountain Healthcare Heart Institute in Salt Lake City finds that higher EPA blood levels alone lowered the risk of major cardiac events and death in patients, while DHA blunted the cardiovascular benefits of EPA. Higher DHA levels at any level of EPA, worsened health outcomes.

Results of the Intermountain study, which examined nearly 1,000 patients over a 10-year-period, will be presented virtually at the 2021 American College of Cardiology's Scientific Session on Monday, May 17.

"The advice to take Omega-3s for the good of your heart is pervasive, but previous studies have shown that science doesn't really back this up for every single omega-3," said Viet T. Le, MPAS, PA, researcher and cardiovascular physician assistant at the Intermountain Heart Institute and principal investigator of the study. "Our findings show that not all Omega-3s are alike, and that EPA and DHA combined together, as they often are in supplements, may void the benefits that patients and their doctors hope to achieve."

In this study, Intermountain researchers used the INSPIRE registry, an Intermountain Healthcare database started in 1993 that has more than 35,000 blood samples from nearly 25,000 patients.

Through INSPIRE, researchers identified 987 patients who underwent their first documented coronary angiographic study at Intermountain Healthcare between 1994 and 2012. From those blood samples, the circulating levels of EPA and DHA in their blood was measured. Researchers then tracked those patients for 10 years, looking for major cardiac adverse events, which included heart attack, stroke, heart failure requiring hospitalization or death.

They found that patients with the highest levels of EPA had reduced risk of major heart events. When evaluating how EPA and DHA affect one another, they found that higher DHA blunts the benefit of EPA. In particular, they also found that those patients with higher levels of DHA than EPA, were more at risk for heart problems.

Le said that these results raise further concerns about the use of combined EPA/DHA, particularly through supplements.

"Based on these and other findings, we can still tell our patients to eat Omega-3 rich foods, but we should not be recommending them in pill form as supplements or even as combined (EPA + DHA) prescription products," he said. "Our data adds further strength to the findings of the recent REDUCE-IT (2018) study that EPA-only prescription products reduce heart disease events."

Mitochondria - the 'batteries' that power our cells - play an unexpected role in common diseases such as type 2 diabetes and multiple sclerosis, concludes a study of over 350,000 people conducted by the University of Cambridge.

The study, published today in Nature Genetics, found that genetic variants in the DNA of mitochondria could increase the risk of developing these conditions, as well influencing characteristics such as height and lifespan.

There was also evidence that some changes in mitochondrial DNA were more common in people with Scottish, Welsh or Northumbrian genetic ancestry, implying that mitochondrial DNA and nuclear DNA (which accounts for 99.9% of our genetic make-up) interact with each other.

Almost all of the DNA that makes up the human genome - the body's 'blueprint' - is contained within the nuclei of our cells. Among other functions, nuclear DNA codes for the characteristics that make us individual as well as for the proteins that do most of the work in our bodies.

Our cells also contain mitochondria, often referred to as 'batteries', which provide the energy for our cells to function. They do this by converting the food that we eat into ATP, a molecule capable of releasing energy very quickly. Each of these mitochondria is coded for by a tiny amount of 'mitochondrial DNA'. Mitochondrial DNA makes up only 0.1% of the overall human genome and is passed down exclusively from mother to child.

While errors in mitochondrial DNA can lead to so-called mitochondrial diseases, which can be severely disabling, until now there had been little evidence that these variants can influence more common diseases. Several small-scale studies have hinted at this possibility, but scientists have been unable to replicate their findings.

Now, a team at the University of Cambridge has developed a new technique to study mitochondrial DNA and its relation to human diseases and characteristics in samples taken from 358,000 volunteers as part of UK Biobank, a large-scale biomedical database and research resource.

Dr Joanna Howson, who carried out the work while at the Department of Public Health and Primary Care at the University of Cambridge, said: "Using this new method, we've been able to look for associations between the numerous features that have been recorded for participants of UK Biobank and see whether any correlate with mitochondrial DNA.

"Aside from mitochondrial diseases, we don't generally associate mitochondrial DNA variants with common diseases. But what we've shown is that mitochondrial DNA - which we inherit from our mother - influences the risk of some diseases such as type 2 diabetes and MS as well as a number of common characteristics."

Among those factors found to be influenced by mitochondrial DNA are: type 2 diabetes, multiple sclerosis, liver and kidney function, blood count parameters, life span and height. While some of the effects are seen more extremely in patients with rare inherited mitochondrial diseases - for example, patients with severe disease are often shorter than average - the effect in healthy individuals tends to be much subtler, likely accounting for just a few millimetres' height difference, for example.

There are several possible explanations for how mitochondrial DNA exerts its influence. One is that changes to mitochondrial DNA lead to subtle differences in our ability to produce energy. However, it is likely to be more complicated, affecting complex biological pathways inside our bodies - the signals that allow our cells to operate in a coordinated fashion.

Professor Patrick Chinnery from the MRC Mitochondrial Biology Unit at Cambridge said: "If you want a complete picture of common diseases, then clearly you're going to need to factor in the influence of mitochondrial DNA. The ultimate aim of studies of our DNA is to understand the mechanisms that underlie these diseases and find new ways to treat them. Our work could help identify potential new drug targets."

Unlike nuclear DNA, which is passed down from both the mother and the father, mitochondria DNA is inherited exclusively from the mother. This suggests that the two systems are inherited independently and hence there should be no association between an individual's nuclear and mitochondrial DNA - however, this was not what the team found.

The researchers showed that certain nuclear genetic backgrounds are associated preferentially with certain mitochondrial genetic backgrounds, particularly in Scotland, Wales and Northumbria. This suggests that our nuclear and mitochondrial genomes have evolved - and continue to evolve - side-by-side and interact with each other.

One reason that may explain this is the need for compatibility. ATP is produced by a group of proteins inside the mitochondria, called the respiratory chain. There are over 100 components of the respiratory chain, 13 of which are coded for by mitochondrial DNA; the remainder are coded for by nuclear DNA. Even though proteins in the respiratory chain are being produced by two different genomes, the proteins need to physically interlock like pieces of a jigsaw.

If the mitochondrial DNA inherited by a child was not compatible with the nuclear DNA inherited from the father, the jigsaw would not fit together properly, thereby affecting the respiratory chain and, consequently, energy production. This might subtly influence an individual's health or physiology, which over time could be disadvantageous from an evolutionary perspective. Conversely, matches would be encouraged by evolution and therefore become more common.

This could have implications for the success of mitochondrial transfer therapy - a new technique that enables scientists to replace a mother's defective mitochondria with those from a donor, thereby preventing her child from having a potentially life-threatening mitochondrial disease.

"It looks like our mitochondrial DNA is matched to our nuclear DNA to some extent - in other words, you can't just swap the mitochondria with any donor, just as you can't take a blood transfusion from anyone," explained Professor Chinnery. "Fortunately, this possibility has already been factored into the approach taken by the team at Newcastle who have pioneered this therapy."

In the largest genetic study of bipolar disorder to date, researchers have identified 64 regions of the genome containing DNA variations that increase risk of bipolar disorder - more than double the number previously identified.

The research team also found overlap in the genetic bases of bipolar disorder and other psychiatric disorders. Furthermore, the study supports a role of sleep habits, alcohol, and substance usage in the development of bipolar disorder, although further research is needed to confirm these findings. The study results are published May 17 in Nature Genetics.

Bipolar disorder, a complex psychiatric disorder characterized by recurrent episodes of severely high and low mood, affects an estimated 40 to 50 million people worldwide. It typically begins in young adulthood, often takes a chronic course, and carries an increased risk of suicide, making it a major public health concern and cause of global disability.

To help elucidate the underlying biology of bipolar disorder, an international team of scientists from within the Psychiatric Genomics Consortium conducted a genome-wide association study. This means they scanned the DNA of lots of people, looking for genetic markers that were more common in those who had bipolar disorder. This involved scanning more than 7.5 million common variations in the DNA sequence of nearly 415,000 people, more than 40,000 of whom had bipolar disorder. The study identified 64 regions of the genome that contain DNA variations that increase risk of bipolar disorder.

"It is well-established that bipolar disorder has a substantial genetic basis and identifying DNA variations that increase risk can yield insights into the condition's underlying biology," says Niamh Mullins, PhD, Assistant Professor of Psychiatric Genomics at the Icahn School of Medicine at Mount Sinai and lead author of the paper. "Our study found DNA variations involved in brain cell communication and calcium signaling that increase risk of bipolar disorder.

The findings suggest that drugs, such as calcium channel blockers that are already used for the treatment of high blood pressure and other conditions of the circulatory system, could be investigated as potential treatments for bipolar disorder, yet it's important to note that future research to directly assess whether these medications are effective is essential."

The study also found overlap in the genetic basis of bipolar disorder and that of other psychiatric disorders and confirmed the existence of partially genetically distinct subtypes of the disorder. Specifically, they found that bipolar I disorder shows a strong genetic similarity with schizophrenia and bipolar II disorder is more genetically similar to major depression.

"This research would not have been possible without the collaborative efforts of scientists worldwide that enabled the study of hundreds of thousands of DNA sequences," said Ole Andreassen, MD, PhD, Professor of Psychiatry, Institute of Clinical Medicine and Oslo University Hospital and senior author of the paper. "Through this work, we prioritized some specific genes and DNA variations which can now be followed up in laboratory experiments to better understand the biological mechanisms through which they act to increase risk of bipolar disorder."

The biological insights gained from this research could ultimately lead to the development of new and improved treatments or precision medicine approaches to stratify patients at high genetic risk who may benefit from targeted treatment or intervention strategies. Understanding causal risk could aid clinical decision-making in the prevention or management of the illness. Future genetic studies in larger and more diverse populations are now needed to pinpoint the genes relevant to risk of bipolar disorder in other areas of the genome.

The Psychiatric Genomics Consortium (PGC) is an international consortium of scientists dedicated to studying the genetic basis of psychiatric disorders and includes over 800 researchers, from more than 150 institutions from over 40 countries.

A study published in the scientific journal Addiction provides the most comprehensive evidence to date of the association between recreational cannabis laws (RCLs) in US states and responses in the illegal markets for cannabis, heroin, and other drugs in those states.

As of 2021, 17 US states and the District of Columbia have implemented RCLs that allow people aged 21 and older to possess, use and supply limited amounts of cannabis for recreational purposes. This study found that the implementation of RCLs was associated with the following responses in the illegal drug market in those states:

9.2% decrease in street/illegal cannabis prices.

19.5% decrease in low-quality street/illegal cannabis prices.

64% increase in heroin prices.

54% increase in heroin potency.

7.3% increase in street/illegal oxycodone prices.

5.1% increase in street/illegal hydrocodone prices.

93% decrease in law enforcement seizures of street/illegal cannabis

>50% decrease in law enforcement seizures of heroin, oxycodone, and hydrocodone

Lead author Dr. Angélica Meinhofer (Assistant Professor of Population Health Sciences at Weill Cornell Medicine) says "Our exploratory findings suggest that markets for illegal drugs may not be independent of legal cannabis market regulation. As more states move towards legalization and additional post-RCL implementation data become available, we'll need to do more research to determine whether recreational cannabis laws cause those changes in the illegal market and what happens in the long-term."

This study used a difference-in-differences analysis of the staggered implementation of RCLs in 11 states to compare changes in outcomes between RCL and non-RCL states. This study used crowdsourced data from Price of Weed and StreetRx on the price and quality of illegal drugs, which may be subject to error and sampling bias.

Gears and mechanical transmissions are at home in the Emilia-Romagna region, the Motor Valley of northern Italy. A team of researchers from the University of Bologna and the Institute for Organic Synthesis and Photoreactivity of the National Research Council (Cnr-Isof) in Bologna, led by Massimo Baroncini and Alberto Credi, has planned, constructed and operated NanoGear, a device consisting of interlocked molecular components and designed to function as a gear. Since molecules are nanometric objects (1 nanometer = 1 millionth of a millimetre), it is an exceedingly small device: certainly, the tiniest gear ever produced in the Italian land of motors.

"The transmission and transformation of nanometric movements in biological molecules are the basis of the main functions of living organisms. Nevertheless, these phenomena are poorly understood in artificial molecules because they are extremely difficult to identify and observe. The construction of molecular devices such as NanoGear is a first step forward towards the development of ultra-miniaturized mechanical devices based on molecular motors, with potential breakthrough applications in various fields of technology and medicine ", says Alberto Credi.

THE DEVICE

The NanoGear molecule belongs to the class of rotaxanes and consists of three components: a ring that can slide along an axle that bears a rotor installed in its centre.

"The ring is free to shuttle along the axle for its entire length, but it cannot escape because two bulky groups (stoppers) positioned at the ends of the axle prevent it from slipping off. The rotor is free to rotate around its own axis and has two different 'blades' to facilitate observation of the movement", explains Massimo Baroncini. "The main design element of NanoGear lies in the fact that the rotor is directly linked to the axis with a regular chemical (covalent) bond, whereas the ring is mechanically locked around the axis by the presence of the stoppers. Both the translation of the ring and the rotation of the rotor are random oscillations determined by the thermal energy of the molecule; in other words, the gear is not coupled to any motor and functions 'in neutral'. Sophisticated nuclear magnetic resonance techniques were used to observe the movements and measure their rates".

At 65 °C, the ring shuttles from one end of the axle to the other about 7 times per minute, passing over the rotor; in the same amount of time, the latter completes about 260 rotations. Therefore the two motions are not synchronized; however, they mutually influence each other, as demonstrated by experiments carried out on molecules similar to NanoGear but devoid of the rotor or the ring.

Another significant and unexpected result is the effect of the medium in which the molecule is dispersed: by changing the solvent, one of the two movements is slowed down, while the other is accelerated. Such a 'specific lubrication' finds no correspondence in the macroscopic world, and constitutes one of the unconventional properties of nanodevices that could lead to radical technological innovations.

THE PROJECT

Artificial molecular machines, awarded with the Nobel Prize in Chemistry in 2016, convert energy from a source into controlled nanoscale movements and are one of the most striking results of nanotechnology. In order to exploit these movements, however, passive elements capable of processing them and transmitting them to other components, as it happens in macroscopic devices, are necessary. In this research, chemists operate in the same way as engineers and architects, but manipulating objects a billion times smaller, since their building blocks are atoms and molecules.

NanoGear is the result of a project born about five years ago and is part of a research activity in which the Center for Light Activated Nanostructures (Clan), a joint laboratory of the University of Bologna and the Italian National Research Council, is an international reference point.

NanoGear was created with the support of an Advanced Grant from the European Research Council (ERC), the most prestigious and competitive grant for scientific research in Europe. In the past, the same laboratory had already attracted public attention by developing molecular-based pumps (Nature Nanotechnology, 2015) and sponges (Nature Chemistry, 2015) powered by light. The central role of the research performed in Bologna on the subject of molecular machines was recognized during the "MolecularMachinesDays" event, held in Bologna in November 2018 with the participation of the three 2016 Nobel laureates in Chemistry.

THE RESULTS

The realization of artificial devices consisting of molecules is of great interest for the development of nanotechnology. "As shown by the results obtained in recent years in laboratories worldwide, nanotechnology can provide us with lighter and stronger materials, smaller and more powerful computers and robots, better systems for transforming and storing energy, new methods for medical diagnostics and therapies", says Alberto Credi. "NanoGear is a small but significant step in this direction. While it is currently difficult to identify a specific use of NanoGear, the basic research that led to its development has a revolutionary potential for science and technology that goes far beyond short-term practical applications".

Humans leave their "footprints" on the land area all around the globe. These land-use changes play an important role for nutrition, climate, and biodiversity. Scientists at the Karlsruhe Institute of Technology (KIT) combined satellite data with statistics from the past 60 years and found that global land-use changes affect about 32 percent of the land area. This means that they are about four times as extensive as previously estimated. The researchers publish their findings in the scientific journal Nature Communications.

Whether it is deforestation, urban growth, agricultural expansion, or reforestation - land-use changes are diverse and have shaped human history at all times. "To face the global challenges of our time, we need to better understand the extent of land-use change and its contribution to climate change, biodiversity, and food production," says Karina Winkler from the Institute of Meteorology and Climate Research - Atmospheric Environmental Research (IMK-IFU) Division, KIT Campus Alpin in Garmisch-Partenkirchen. "In fact, land use also plays a critical role in achieving the Paris climate targets."

Despite the availability of satellites, "Big Data," and the increasing amount of information, existing studies of land-use change are only of fragmentary nature, and they are limited in space or time. A research team from IMK-IFU and Wageningen University in the Netherlands now combined various data from free sources to develop a set of new, high-resolution maps called "HILDA+" (Historic Land Dynamics Assessment +). It traces and reconstructs global land-use changes and their spatio-temporal patterns between 1960 and 2019 using high-resolution satellite data and land-use statistics. "Our work is highly challenging as we have to deal with very different data sets," explains Winkler. "For example, if land-use maps have different spatial resolutions, temporal coverage, or land-use classifications, we need a strategy for harmonizing them."

The set of maps reveals that land-use changes have affected nearly one-third of the global land area in just six decades, i.e. they were about four times as extensive as previously known from long-term analyses. "However, land-use changes do not show the same patterns all over the world," Winkler says. In their study, the researchers point to North-South differences. Hence, in the Global North, for example in Europe, the USA, or Russia, forests have expanded and the arable land area has decreased, while in the Global South, for example in Brazil or Indonesia, forest areas have decreased and arable as well as pasture lands have increased.

Another aspect is that the rate of land-use change has changed over time. For the period between 1960 and about 2005, the researchers identified a period of accelerated land-use change and from about 2006 to 2019, land-use change had slowed down. "This trend reversal could be related to the increasing importance of global trade for agricultural production and to the global economic crisis of 2007/2008," Winkler adds.

The new land-use data could provide an improved data basis for climate and Earth system models - and thus contribute to political debates on strategies on how to achieve sustainable land use in the future. The data is freely available and can be viewed in an online map application. (jwa)

The cover for issue 7 of Oncotarget features Figure 14, "A hypothetical model of how a specific remodeling of cellular metabolism by CR slows down yeast chronological aging," published in "Caloric restriction creates a metabolic pattern of chronological aging delay that in budding yeast differs from the metabolic design established by two other geroprotectors" by Mohammad, et al. which reported that caloric restriction and the tor1Δ mutation are robust geroprotectors in yeast and other eukaryotes.

The authors demonstrate that caloric restriction generates a unique metabolic pattern.

Unlike the tor1Δ mutation or lithocholic acid, it slows down the metabolic pathway for sulfur amino acid biosynthesis from aspartate, sulfate and 5-methyltetrahydrofolate.

Consequently, caloric restriction significantly lowers the intracellular concentrations of methionine, S-adenosylmethionine and cysteine.

They also noticed that the low-calorie diet, but not the tor1Δ mutation or lithocholic acid, decreases intracellular ATP, increases the ADP:ATP and AMP:ATP ratios, and rises intracellular ADP during chronological aging. The Oncotarget authors propose a model of how the specific remodeling of cellular metabolism by caloric restriction contributes to yeast chronological aging delay.

The Oncotarget authors propose a model of how the specific remodeling of cellular metabolism by caloric restriction contributes to yeast chronological aging delay.

Dr. Vladimir I. Titorenko from Concordia University said, "A body of evidence indicates that metabolism is an essential contributor to the aging and longevity of eukaryotic organisms across phyla."

Indeed, healthy aging of the evolutionarily distant eukaryotes coincides with age-related changes in the concentrations of specific metabolites within cells, tissues, organs and biological fluids.

Furthermore, such dietary interventions as caloric restriction, reduced protein intake, a limited supply of single amino acid and alternating cycles of feeding and fasting are robust geroprotectors that specifically rewire cellular and organismal metabolism in various eukaryotic organisms.

Moreover, allelic variants of the genes implicated in diverse metabolic pathways delay aging and extend longevity in eukaryotic organisms across species.

Besides, pharmacological interventions that target distinct aspects of metabolism are potent geroprotectors in diverse eukaryotes; these interventions include metformin, rapamycin, resveratrol, spermidine and others.

It remains unclear if different dietary, genetic and pharmacological anti-aging interventions set up a similar metabolic pattern of aging delay or each of them generates a distinct metabolic profile.

The Titorenko Research Team concluded in their Oncotarget Research Output that:

1. What is the mechanism responsible for ATP decline under CR conditions? They hypothesize that CR might affect the transcription and/or translation of enzymes involved in ATP synthesis and/or degradation in the cytosol, mitochondria or other cellular locations.

Of note, a transcription/translation-based mechanism of suppressing methionine biosynthetic enzymes and transporters underlies the ability of CR to lower intracellular methionine and extend yeast RLS.

2. What are the metabolic changes underlying the extremely efficient longevity extension in yeast culture under CR conditions with LCA? Their findings indicate that LCA applied under CR conditions “overrides” the CR-specific metabolic profile of aging delay.

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DOI - https://doi.org/10.18632/oncotarget.27926

Full text - https://www.oncotarget.com/article/27926/text/

Correspondence to - Vladimir I. Titorenko - vladimir.titorenko@concordia.ca

Keywords -
cellular aging,
geroprotectors,
caloric restriction,
metabolism,
methionine

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Journal

Oncotarget

DOI

10.18632/oncotarget.27926

A research group from Kumamoto University, Japan has discovered that cysteinylated albumin (oxidized albumin) in serum can be used as an early diagnostic marker for diabetic kidney disease. Compared with urinary albumin, serum oxidized albumin not only reflects renal pathology at an earlier stage, but can also predict the progression of renal pathology by its degree of elevation. The researchers believe that it can be used as a new diagnostic marker for early diagnosis of diabetic kidney disease.

Diabetic kidney disease is one of three major complications of diabetes. Its prognosis is difficult to improve as it progresses so diagnosing it as early as possible and providing appropriate therapeutic intervention is important. Albumin is the most abundant protein in blood serum and urine, and urinary albumin (albuminuria) is used to diagnose diabetic kidney disease. Albumin maintains osmotic pressure in serum and functions as a carrier of fatty acids and drugs. It is also frequently used as an early marker for diabetic nephropathy because albuminuria increases as kidneys begin failing. However, it is now clear that there are many cases of negative albuminuria in diabetic kidney diseases, especially those derived from type 2 diabetes. Thus, there is a need to develop new early diagnostic markers for these complex and diverse conditions.

In this study, the research group evaluated the association between pathological renal progression and post-translational modifiers of serum albumin in 257 type 2 diabetic patients. Serum albumin has a half-life of about 20 days and is known to undergo various chemical modifications (post-translational modifications) depending on the environment in the body. Researchers measured five post-translational modifications using a mass spectrometer and found that the level of cysteinylated albumin (oxidized albumin), an oxidized modification of albumin with one molecule of cysteine added, increased with the progression of diabetic kidney disease. This indicated that oxidized albumin can be used as a diagnostic marker for renal pathology. They also found that oxidized albumin may reflect earlier renal pathology compared to urinary albumin. Furthermore, patients with high levels of oxidized albumin showed faster progression of renal disease after two years, indicating that oxidized albumin can also be used to predict renal disease progression.

"Our study has shown that oxidized albumin may reflect early renal pathology even better than urinary albumin, which is the current gold standard," said Associate Professor Hiroshi Watanabe, who led this study. "In particular, since kidney disease derived from type 2 diabetic patients includes many cases of negative albuminuria, we expect serum oxidized albumin can be used as a new diagnostic marker for diabetic kidney disease."

Tsukuba, Japan--Researchers at the University of Tsukuba found that, despite only covering about one-third of the distance in HIIT compared with that covered in endurance training, similar improvements in exercise capacity and brain function were observed for both forms of exercise.

"We investigated how rats' muscles and brains--specifically, the region of the brain involved in spatial learning called the hippocampus--adapted to these types of exercise, and how the rats consequently learned and remembered navigating mazes," explains Professor Hideaki Soya, the principal investigator.

In the experiment, rats were assigned to 1 of 3 groups--resting, endurance running, or alternating intervals (short sprints and rest)--during training sessions on treadmills 5 days/week for 4 weeks.

Both endurance running and HIIT resulted in weight loss, greater muscle mass, and the ability to exercise longer compared with controls; however, increased cellular aerobic capacity was found in the soleus (a muscle with predominantly slow-twitch fibers that makes it functionally well suited to endurance) and in the plantaris (a muscle with predominantly fast-twitch fibers for meeting high-energy functional demands) in the endurance-running and HIIT groups, respectively.

Rats in both groups demonstrated having better memory of spatial learning trials in searching for an escape platform in a water maze. In the hippocampus, increased cell development--neurogenesis--was also observed for both forms of exercise; however, levels of a signaling protein that promotes neurogenesis (BDNF) were increased by HIIT but not by endurance running, whereas the levels of its receptor (TrkB) were increased by both.

Given that BDNF expression is known to be affected by exercise, why didn't endurance running increase BDNF expression? The answer may lie in the mediating role of stress on BDNF expression; exercise is a type of stress. While stress indicators in both exercise groups were found to be similar, this line of enquiry may lead to future studies:

"In this study, we showed that an HIIT exercise regimen with a low exercise volume nevertheless improves spatial memory, and we demonstrated that these improvements are supported by changes in neuronal plasticity in the hippocampus. In a previous study, we found that continuous light-intensity training had a similar beneficial effect, whereas continuous high-intensity training did not," Professor Soya summarizes. "Thus, it seems that the benefits yielded by exercise may actually depend on optimization, that is, a trade-off between exercise time and intensity."

A future where exercise regimens can be tailored to improve both physical and cognitive features may be on the horizon.

The way in which banks react to climate risks and uncertainty could impact financial stability as well as the world's transition to a low-carbon economy. A new study by researchers from IIASA and the Vienna University of Economics and Business explored the role that banks' expectations about climate-related risks will play in fostering or hindering an orderly low-carbon transition.

According to the study published in a special issue on climate risks and financial stability of the Journal of Financial Stability, banks and their expectations about climate-related risks - and especially climate transition risk stemming from a disorderly introduction of climate policies - play an important role in the successful transition to a low-carbon economy, as lower credit costs could make green (low-carbon) investments more competitive, allowing such investments to be made at scale. Depending on the timing and structure of implementation, climate policies could however also lead to a reduced profitability of brown (carbon intensive) firms, in turn leading to unanticipated loan defaults by such companies. This could pose a credit-risk for banks and investors, potentially threatening financial stability and leading to a credit crunch that would also affect green firms negatively, thus putting the success of an orderly low-carbon transition at risk.

The authors explain that they set out to assess the role of banks' expectations about climate-related risks - climate sentiments - in fostering or hindering the low-carbon transition.

"We wanted to determine under which conditions a carbon tax or green supporting factor can foster green loans and investments in the economy, and also to identify the conditions that would be conducive for the onset of credit market instability, focusing on loan contracts. In addition, we wanted to see what role - if any - the climate sentiments of the banking sector may play in fostering or hindering the expected effect of climate policies on the green economy and financial stability," says IIASA researcher and study author Asjad Naqvi.

In order to analyze the macro-financial implications and feedback effects of climate fiscal and macro-prudential policies, the researchers developed a Stock-Flow Consistent model that adopts a forward-looking approach to the pricing of climate risks in banks' lending contracts and credit risk born by firms. With this newly developed model and its innovative characteristics, the researchers assessed the transmission channels of two main policies and regulations, namely a carbon tax and a green supporting factor on the credit market and on macroeconomic performance and stability.

"A carbon tax would put a tax on carbon-intense production thus making low-carbon production and investment in such production facilities more attractive. However, to prevent unintended effects, the introduction of a carbon tax should be complemented with distributive welfare measures. A green supporting factor on the other hand, would lower the capital requirements for loans that banks give out for green investments, thus making green lending for banks more attractive and potentially resulting in better credit conditions for green investment projects," explains study author Irene Monasterolo, a researcher at the Vienna University of Economics and Business.

According to the authors, the effects of banks' climate sentiments demonstrate the important role of timely and credible climate policy strategies to signal the market and allow an orderly low-carbon transition. Their work could help financial regulators and Central Banks to identify financial instability implications of credit risk, and for banks, to manage their loans portfolio in the face of climate transition shocks, thus avoiding the risk of losses driven by non-performing loans.

"Climate sentiments could play a defining role in fostering an orderly low-carbon transition. Policy credibility is crucial to building trust in the banking sector, which in turn determines successful policy implementation and minimize the negative impacts on economic and financial instability via its lending conditions. A single policy might not be enough to trigger the low-carbon transition at the pace needed. In this regard, the conditions for synergies between different climate policies and green investment policies such as the so-called European Green Deal should be further analyzed," concludes study author and IIASA researcher Nepomuk Dunz.

Devices that deliver nicotine without smoke inhalation have potential to help smokers who cannot or do not want to stop using nicotine to reduce dramatically the risk of smoking-related disease and death.

However, for smokers to switch to these alternatives, the products need to provide what smokers expect from cigarettes.

The newest study from Queen Mary University of London evaluates safety and effects of these products and has focused on the most popular "heat not burn" product, IQOS.

The researchers compared nicotine delivery and user ratings of IQOS with those of cigarettes, Juul (the US version of a 'pod' based e-cigarette with high nicotine content), and refillable e-cigarettes.

IQOS delivered less nicotine than cigarettes. It had also lower nicotine delivery than Juul, and was less effective in reducing urges to smoke. Compared to traditional refillable e-cigarettes, IQOS provided nicotine faster, but received less favourable ratings.

The study concludes that, for quitting smoking, IQOS may be less effective than the US version of Juul (the version sold in the UK has very low nicotine delivery because of EU regulations and so it is less likely to be useful). IQOS could be as effective as refillable e-cigarettes, although study participants preferred refillable e-cigarettes.

Author Professor Peter Hajek from Queen Mary University of London said: "IQOS is likely to be useful to help smokers quit, particularly in countries like Japan, where e-cigarettes are banned; but in countries where e-cigarettes are available, they are likely to remain the more popular choice."

The Korea Institute of Machinery and Materials (KIMM) under the Ministry of Science and ICT developed a roll-based damage-free transfer technique that allows two-dimensional (2D) nanomaterials to be transferred into wafer scale without damage. The proposed technique has a variety of applications from transparent displays and semiconductors to displays for self-driving cars, and is expected to accelerate the commercialization of 2D nanomaterial-based high-performance devices.

Dr. Kwang-Seop Kim, principal researcher of the Department of Nano-Mechanics at KIMM, succeeded in developing a technique of transferring 2D nanomaterials, as thin as 1/50,000 of a strand of hair, to a substrate of at least 4 inches (approx. 10 cm) without damage.

The roll-based transfer is a process in which 2D nanomaterials on a transfer film are transferred to a desired substrate. It is a highly efficient technique that enables large-area continuous transfer of nanomaterials, similar to paper printing.

The transfer process involves nanomaterials on a transfer film (A) and a target substrate (B). In roll transfer, the nanomaterials are transferred to B when A is rolled onto B. This is similar to the process of transferring a tattoo onto skin using a tattoo sticker. The sticker plays the role of the transfer film, the tattoo represents the 2D nanomaterials, and the skin is the substrate.

The key point in the proposed technique is to identify two different types of the damage mechanisms in relation to the deformation of adhesive layer in the transfer film through computer simulation and experiments. The team optimizes the thickness of the adhesive layer to minimize the deformation of the adhesive layer during the transfer process, leading to achieve the damage-free transfer of large-area 2D nanomaterials.

The team discovered the principle behind the damage-free transfer of an extremely thin tattoo to skin through optimizing the tattoo sticker.

The technique can be utilized in the roll-based transfer process for the production of 2D nanomaterial-based flexible transparent displays and transparent semiconductors, decreasing the damage in 2D nanomaterial down to 1% compared to the existing 30%.

Principal researcher Kwang-Seop Kim said, "Our technique of transferring large-area 2D nanomaterials and micro-devices without damage to substrates will significantly lower manufacturing costs of wearable devices, flexible transparent displays, and high-performance bio/energy sensors, thus accelerating the commercialization of related applications. We also expect to see new businesses across industries from next-generation semiconductors to future vehicles."