Culture

Alzheimer's disease is the most common neurodegenerative disorder in which neurons gradually die off, leading to dementia. The exact mechanism and causes of this disorder have not yet been identified. However, it is known that amyloid plaques form in the brains of patients. Plaques consist of amyloid fibrils, which are special filamentous assemblies formed by amyloid proteins.

'The number of patients with neurodegenerative disorders will continue to grow in the future. Thanks to the success of humanity in the treatment of cancer and cardiovascular diseases, more and more people are living into their 80s. At this age, the risk of developing neurodegenerative disorders, including Alzheimer's disease, becomes very high. Unfortunately, no cures for these diseases have yet been found' says Nikolai Skrynnikov, a co-author of the research, Ph.D., Professor, Head of the Biomolecular NMR Laboratory at St Petersburg University.

According to Nikolai Skrynnikov, scientists have deciphered the structural features of amyloid deposits relatively recently. However, a more detailed study of amyloidogenesis is faced with a number of difficulties. In particular, this is because in brain tissues amyloid fibrils coexist with other structural forms of amyloidogenic protein. These are monomers, proteolytic fragments, and various oligomers, some of which serve as 'seeds' for building new fibrils. Analysing such a mixture is a major challenge. For example, when studying amyloidogenic samples by means of nuclear magnetic resonance (NMR) spectroscopy, one obtains a multitude of signals that originate not only from fibrils that are of interest to scientists, but also from other protein species. Experts are therefore looking for ways to separate the spectral signals of fibrils and other concomitant structural forms.

The most obvious and straightforward method to achieve this goal is the so-called 'diffusion filter'. This is a special NMR experiment that makes it possible to separate signals from heavy fibrils and other more mobile components of the sample. However, about ten years ago scientists from Oxford University published two articles in which the feasibility of such a filter for samples of amyloid fibrils has been put into question. After that, the research in this field has come to a halt.

'The motion of a fibril can be likened to random motion of a log on the surface of a lake, while the motion of a monomer is like that of a pine needle. The researchers from Oxford argued that the rotation of the log might be faster - while turning, the linear speed at the ends of the log proves to be sufficiently high. For this reason, according to the authors, it becomes impossible to distinguish between a rapidly turning log and a nimble needle,' explains Nikolai Skrynnikov. 'But this is far from the truth'.

The scientists from St Petersburg University put the assertion of their Oxford colleagues to a rigorous test, and not only disproved it, but also created a new theory of the diffusion NMR experiment. Moreover, the researchers described the essence of the effect by three methods: the analytical method, i.e. by deriving a compact formula that reflects the outcome of the experiment; the numerical method, i.e. by solving certain differential equation by means of a suitable numerical algorithm; and the Monte Carlo method, i.e. by using computer simulation to capture random fibril movements in solution. All three methods showed virtually identical results, thereby validating the new theory.

For the experimental verification of the new theory, the researchers have turned to yeast protein Sup35, which is known to have amyloidogenic properties. Scientists from St Petersburg University played a prominent role in the early studies of this protein. Professor Sergey Inge-Vechtomov, his students and followers were among the first investigators of Sup35. The research team from the Biomolecular NMR Laboratory at St Petersburg University together with the scientists from the University's Department of Genetics and Biotechnology used Sup35 as a model system to demonstrate that the use of a diffusion filter in samples containing amyloid fibrils is indeed possible. The researchers successfully obtained a spectrum of fibrils, 'cleared' from other spectral signals.

'Twenty to thirty years ago, scientists had little understanding of what happens in the human brain with the onset of dementia. Gradually, knowledge has been accumulated and new research methods have been developed. Thanks to these methods, we now know about the existence of amyloid deposits and have a fairly detailed idea of their structure,' notes Nikolai Skrynnikov. 'Our theory and its proof is a contribution to the body of fundamental knowledge that medicinal chemists rely on in their search for new drugs. In the future, our proposed diffusion filter for NMR experiments in amyloidogenic systems may help in this search.'

Killer flies can reach accelerations of over 3g when aerial diving to catch their prey - but at such high speeds they often miss because they can't correct their course.

These are the findings of a study by researchers at the Universities of Cambridge, Lincoln, and Minnesota, published today in the Journal of the Royal Society Interface.

Killer flies (Coenosia attenuata) perform high-speed aerial dives to attack prey flying beneath them, reaching impressive accelerations of up to 36 m/s2, equivalent to 3.6 times the acceleration due to gravity (or 3.6g). This happens because they beat their wings as they fall, combining the acceleration of powered flight with the acceleration of gravity.

This is an impressive feat: diving Falcons, the fastest animals that predate in the air, achieve much lower accelerations of only 6.8m/s2. Falcons dive by folding their wings and simply letting gravity accelerate them towards their prey.

For the tiny Killer fly though, the high speeds achieved in aerial dives could come as a surprise - because the researchers think the fly doesn't take the effect of gravity into account when diving to intercept a target.

To get their results, the researchers built a transparent 'flight arena' and flew a dummy prey target through it at constant velocity. Killer flies were filmed with high speed video cameras as they attacked the target, and the researchers watched the footage back in slow motion - using this data to reconstruct the entire attack sequence in 3D.

The study found that Killer flies reached much higher accelerations in flight when taking off from the ceiling of the arena, compared to from the floor or walls. The flies beat their wings at a similar rate wherever they launched from, indicating that their flight speed is determined by a combination of wing power and gravity.

"When Killer flies took off from the floor or walls of the arena, they moved at the time when they could take the shortest path to the target. But they couldn't manage that when they took off from the ceiling because the high acceleration caused by gravity changed the expected flight path," said Sergio Rossoni, a PhD student in the University of Cambridge's Department of Zoology and first author of the paper.

By diving with super-high acceleration the Killer fly sometimes catches its target prey extremely quickly, but it often misses because its speed makes it challenging to change course mid-dive if the prey moves. But even if the fly doesn't land on target, the dive quickly reduces its distance from the prey so it can keep sight of it while making the final manoeuvers to catch it.

The researchers think the effect of not accounting for gravity during downward dives might be compensated by another advantage. High speed dives force the potential prey to change direction as the attacker approaches, but to do this the prey has to slow down - making it easier to catch.

Insects that hunt in the air usually attack their prey upwards, because the contrast of the prey against the sky makes it easier to see. Killer flies are unusual insect predators in this respect; hunting downwards against a visually cluttered ground, using eyes that have only coarse resolution, is more difficult.

"This research into miniature flies helps us understand what shortcuts are acceptable when survival depends on fast decisions and accurate actions, but the sensory capabilities and processing power of the predator are heavily constrained," said Professor Gonzalez-Bellido at the University of Minnesota, who led the study.

The researchers Juan A. Fernández-Ontiveros, of the Istituto Nazionale di Astrofisica (INAF) in Rome and Teo Muñoz-Darias, of the Instituto de Astrofísica de Canarias (IAC), have written an article in which they describe the different states of activity of a large sample of supermassive black holes in the centres of galaxies. They have classified them using the behaviour of their closest "relations", the stellar mass black holes in X-ray binaries. The article has just been published in the journal Monthly Notices of the Royal Astronomical Society (MNRAS).

Black holes range in mass from objects which have only a few times the mass of the sun up to those with thousands of millions of solar masses. To understand their activity cycles from a global perspective has been the object of research for decades. Those of stellar mass are found in binary systems together with a companion star from which they suck out the gas which they need to sustain their activity, while the supermassive variety are found in the centres of the majority of galaxies and they feed on the gas, dust, and stars which are fall into the gravitational well of the galactic nucleus.

Stellar mass black holes evolve rapidly. Their activity cycles usually last a few months or years, during which they pass through different states, or phases. These are characterized by changes in the properties of their accretion discs (where the hot gas accumulates before falling into the black hole), their winds, and the jets of material which they produce. There are two principal states, the first dominated by the accretion disc, and the second by the jet. The 'soft' state is noted by the thermal emission by the plasma of the disc, while the jet is observed in the 'hard' state, when the disc cools down, and the emission at radio wavelengths becomes very intense.

Because they are much more massive, the supermassive black holes evolve much more slowly than their stellar mass equivalents. So, to show the presence of states and transitory phenomena in these would imply observing them for millions of years, because the changes during a human lifetime would be too small to measure. In addition, the nuclei of galaxies are regions with dense populations of stars, and the absorption of light by hydrogen and dust masks and hides the radiation from the accretion disc around the central black hole.

In this study Fernández-Ontiveros and Muñoz-Darias have used a sample of 167 active galaxies to be able to identify the possible accretions states of supermassive black holes with good statistics. The emission from the accretion disc cannot be detected directly, but the gas in the central region absorbs and processes the radiation in the form of spectral lines. Using the lines of oxygen and neon, which are observed in the mid-infrared, it is possible to test the presence of the disc in these object. "The study demonstrates the presence of accretion states in supermassive black holes, with properties very similar to those we know from stellar mass black holes, where the systems in the 'soft' state harbour a bright disc, and those in the 'hard' state show intense radio emission while the disc is very weak", explains Juan A. Fernández-Ontiveros, an INAF researcher who was trained at the IAC.

"This work opens a new window to understand the behaviour of material (gas) when it falls into black holes with a wide range of masses, and helps a more precise understanding of the activity cycles of the supermassive black holes which are in the centres of most galaxies", adds Teo Muñoz-Darias, a researcher at the IAC.

The figure illustrates how the population of active Seyfert-1 galaxies is typically dominated by the emission of the accretion disk ('soft' state), while the population of LINERs is much less luminous and is dominated by jets ('hard' state), which emit intensely in radio waves. The Seyfert-2 galaxies, on the other hand, do not show a homogeneous behaviour and while a good part behave in a similar way to the Seyfert-1, a large group of them are located in intermediate states. The latter are also observed in stellar black holes for short periods of time.

Mitochondria are the cell's power plants and produce the majority of a cell's energy needs through an electrochemical process called electron transport chain coupled to another process known as oxidative phosphorylation. A number of different proteins in mitochondria facilitate these processes, but it's not fully understood how these proteins are arranged inside mitochondria and the factors that can influence their arrangement.

Now, scientists at the University of Copenhagen have used state-of-the-art proteomics technology to shine new light on how mitochondrial proteins gather into electron transport chain complexes, and further into so-called supercomplexes. The research, which is published in Cell Reports, also examined how this process is influenced by exercise training.

"This study has allowed for a comprehensive quantification of electron transport chain proteins within supercomplexes and how they respond to exercise training. These data have implications for how exercise improves the efficiency of energy production in muscle," says Associate Professor Atul S. Deshmukh from the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen.

Traditional methods provide too little detail

It is already well established that exercise training stimulates mitochondrial mass and affects the formation of supercomplexes, which allows mitochondria in skeletal muscle to produce energy more efficiently. But questions remain about which complexes cluster into supercomplexes and how.

To better understand supercomplex formation, particularly in response to exercise, the team of scientists studied two groups of mice. One group was active, and given an exercise wheel for 25 days, and the second group was sedentary, and was not provided the exercise wheel. After 25 days, they measured the mitochondrial proteins in skeletal muscle from both groups to see how the supercomplexes had changed over time.

When scientists typically analyze how supercomplexes form, they use antibodies to measure one or two proteins per electron transport chain complex. But as there can be up to 44 proteins in a complex, this method is both time consuming and provides limited information about what happens to the remainder of the proteins in each complex.

As a result, there is a lack of detailed knowledge in the field.

Proteomics helps supercomplexes give up their secrets

To generate much more detailed data, the team applied a proteomic technology called mass spectrometry to measure the mitochondrial proteins. By applying proteomics instead of antibodies, the scientists were able to measure nearly all of the proteins in each complex. This provided unprecedented detail of mitochondrial supercomplexes in skeletal muscle and how exercise training influences their formation. Their approach demonstrated that not all of the proteins in each complex or a supercomplex respond to exercise in the same manner.

"Mitochondrial protein content is known to increase with exercise, thus understanding how these proteins assemble into supercomplexes is crucial to decipher how they work. Our research represents a valuable and precious resource for the scientific community, especially for those studying how the mitochondrial proteins organize to be better at what they do best: produce energy under demand,", explains Postdoc Alba Gonzalez-Franquesa.

The interdisciplinary project was a collaboration between the Deshmukh, Treebak and Zierath Groups at CBMR, and the Mann Group at the Novo Nordisk Foundation Center for Protein Research.

For the first time, a prospective, international study has shown that chest pain caused by problems with the very small vessels supplying blood to the heart is an important health problem that increases the risk of heart attacks, stroke and death due to cardiovascular reasons.

The study, which is published today (Thursday) in the European Heart Journal [1], recruited 686 patients from 14 institutions in seven countries on four continents [2] between July 2015 and December 2018 to investigate microvascular angina (MVA). Until now, MVA was widely thought to be a benign disease that mainly occurs in women. However, the study showed that during one to two years of follow-up until December 2019, events such as stroke, heart attack and hospitalisation for chest pain (angina) occurred in nearly 8% of patients each year. Men and women were almost equally affected and the prognosis was no different according to sex or ethnicity.

Until relatively recently, little was known about MVA and it can be difficult to diagnose, partly because diagnostic criteria were proposed only in 2018 by the COronary VAsomotor Disorders International Study (COVADIS) Group. Patients with MVA can experience chest pains similar to those of a heart attack and/or shortness of breath, which can lead to them being admitted to hospital. However, standard tests, such as electrocardiograms (ECGs), angiograms and echocardiography, do not detect significant problems with heart rhythm or the main coronary arteries, meaning that MVA is often not diagnosed.

First author of the study and member of the COVADIS Group, Professor Hiroaki Shimokawa, said: "Microvascular angina is an under-researched area, partly because no definite universal definition was available before the COVADIS definition and partly because cardiologists are mainly interested in the large coronary arteries but not the smaller vessels that are also part of the coronary circulation. The former are easily visible by coronary angiography, whereas the latter are not.

"Currently, many doctors are not aware of the importance of coronary microvascular dysfunction. As a result, many patients with MVA are misdiagnosed as having postmenopausal disorders or an imbalance of conscious and unconscious nervous system, for instance. However, previous research has suggested that the number of patients with MVA is three to four million in USA, which is equal to or greater than the number of patients with breast cancer, so it is an important global problem." [3]

Prof. Shimokawa, who is Vice Dean of the Graduate School at the International University of Health and Welfare (Narita, Japan) and Emeritus/Visiting Professor at the Graduate School of Medicine, Tohoku University (Sendai, Japan), and colleagues applied the COVADIS diagnostic criteria in the current study: 1) signs and symptoms suggesting reduced blood flow to the heart (myocardial ischaemia); 2) no evidence of the main coronary arteries being blocked; 3) objective evidence of myocardial ischaemia provided by non-invasive stress testing of the heart using ECGs or non-invasive imaging such as cardiac magnetic resonance; and 4) evidence of impaired coronary microvascular function showing, for instance, inability of the coronary arteries to increase blood flow under stress, heart microvascular spasms, indications of abnormal resistance to blood flow in the heart's tiny blood vessels, or delayed flow in the arteries of the contrast agent used for angiograms, indicating increased resistance to blood flow in more distant vessels (known as "coronary slow flow") but with no evidence of disease in the main coronary arteries.

During the follow-up period, there were 78 cases of death or hospitalisation due to major cardiovascular problems such as heart attack and stroke, heart failure or unstable angina (6.4% in men and 8.6% in women) - an annual incidence of 7.7% among all the patients in the study. Hospitalisation for unstable angina was the commonest event.

Analysis showed that high blood pressure, previous history of coronary artery disease and stable angina were all important and independent predictors of these major cardiovascular events. Although Caucasians had a higher risk than Asians (annual incidences of 9.3% versus 4.5%), there was no significant difference between the two ethnic groups after adjustments were made for factors that could affect the results, such as age, sex, high blood pressure, diabetes, smoking etc. Women had significantly worse quality of life than men, although they had a similar long-term prognosis; the researchers say this could be due to the effect of female hormones on pain perception.

Prof. Shimokawa said: "Angina is usually thought to be caused mainly by narrowing of the large coronary arteries. However, even after treatment of these arteries with stents or bypass surgery, approximately 40% of patients will still experience chest pains, suggesting problems with microvascular dysfunction are very common. In addition, it has been recently and convincingly demonstrated that the treatment of the large coronary arteries with stent or bypass surgery alone does not significantly improve the long-term prognosis of patients with coronary artery disease, again suggesting the prognostic importance of coronary microvascular dysfunction.

"Our international study demonstrates the importance of coronary microvascular dysfunction in patients with MVA. Considering the fact that coronary microvascular dysfunction is involved not only in MVA but also in other forms of cardiovascular disease, including large coronary artery disease and myocardial disease, we believe clinicians should pay closer attention to it."

The researchers say that the management and treatment of MVA represents a major unmet need and more research is needed. Patients are usually treated with drugs to prevent blood clotting, such as statins, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), or drugs to dilate blood vessels such as beta-blockers, calcium channel blockers and nitrates.

Editor-in-Chief of the European Heart Journal, Filippo Crea, Professor of Cardiology and Director of the Department of Cardiovascular and Pneumological Sciences at the Catholic University of the Sacred Heart (Rome, Italy), is a co-author of the study. He said: "It can be estimated that in most European countries, 20,000-40,000 people per million of the population suffer from angina. Thus, the total number of angina patients is about 21 million in Europe. As several studies have shown that about 50% of angina patients do not have coronary narrowing, this means that about ten million people in Europe have angina caused by functional alterations in either the large or small coronary arteries or both. The situation is similar in Asia and US. This huge number of patients deserves to be carefully identified and treated. In addition, these data should stimulate the development of drugs that specifically target coronary microcirculation. Last but not least, these functional alterations are frequent not only in angina patients but also in those who present with myocardial infarction."

Limitations of the study include the fact that it was an observational study with no reference group against which to compare results; there was a relatively small number of major cardiovascular events during the follow-up period, which may affect the statistical power of the study; the majority of these events were hospitalisation for unstable angina; patients with obstructive coronary artery disease diagnosed by conventional or coronary computed angiography were excluded from the study; and there are no data on changes or adherence to medical therapy, or on symptoms or quality of life during the follow-up period.

A new study by Cardiff University in collaboration with the University of Hertfordshire has revealed the huge "secondary burden" placed on those closest to people living with Long Covid.

The researchers surveyed more than 700 Covid-19 survivors along with their partners and close relatives to understand for the first time the impact of the disease on families as a whole.

The findings, published today in BMJ Open, suggest family quality of life is being "severely affected" and a major system of support is needed for both survivors - and those closest to them.

Survivors and their families spoke of the huge impact on their lives and backed calls for more support.

Billie-Jo Redman, 27, a mum from Essex, suffers from fatigue, brain fog and daily waves of pins and needles, and at times has such a high heart rate she has to wear a 24-hour heart monitor.

"My life feels like it's over. I used to go on adventures with my son Roman - now I have days where I can't even get him to school," she said.

Lead author Rubina Shah, a PhD student at Cardiff University's School of Medicine, said: "We have all seen the devastating impact Long Covid can have on survivors, but we have heard very little about how it can affect the lives of their nearest and dearest.

"Our study reveals a domino effect from the Covid patient themselves through to all those closest to them, affecting everything from how worried and frustrated they feel to their ability to enjoy family activities, or for partners the impact on their relationship and sex life.

"The impact of Covid can be profound and long lasting; there needs to be a holistic support system that is sensitive to the needs of both survivors and their families to help ease this burden."

About one in five people have symptoms of Long Covid five weeks after an initial infection and one in seven after 12 weeks, according to the Office for National Statistics. In the four weeks from 6 February, 1.1 million people in the UK were estimated to be affected.

The researchers carried out the study because there was so little information about what families go through when a member has Long Covid. They say it is vital to assess this to help understand what support they might need.

A global online survey to measure impact was carried out last summer and was completed by 735 Covid-19 survivors around 12 weeks after diagnosis and by 571 partners and 164 family members.

The biggest impact was found to be on "feeling worried" (94%), followed by family activities (83%), feelings of frustration (82%), feeling sad (78%), sleep (69%) and sex life (68%). Two-thirds (66%) reported impact on holidays, and more than half (56%) reported an increase in family expenses.

There was a significant gender difference among family members, with females feeling more sad, experiencing more impact on everyday travel and on their sleep. Impact on sex life was experienced by significantly more men than women.

The researchers said the findings suggested policymakers should consider developing and commissioning a range of support services, including needs-based mental health counselling and local support groups.

'Tragic effect on our lives'

Billie-Jo, who previously had no health issues, tested positive on 9 January with usual Covid symptoms. After 10 days she was fine but by the end of February she felt like she was "dying upon standing".

She moved from London to Essex before the first lockdown so has little family support because they live too far away and feels her illness has had a huge impact on life with her son.

"The hospital just doesn't know what to do with me. They can see my heart rate is way too high, but they don't know why," she said.

"Everything has changed. My life feels like it's over. I used to go on adventures with my son Roman - now I have days where I can't even get him to school. It's had a tragic effect on our daily lives. There needs to be more support for families."

Ms Shah said: "Our research is the first to look at the impact of this devastating disease on the partners and families of survivors.

"It is so important that we understand the needs of those closest to survivors to ensure the overall wellbeing of families."

The researchers said future work was needed to measure the persistence of the impact on family members and to find out whether there are differences in family impact between ethnic groups.

Further research could also include assessing the impact of interventions, carrying out local studies to inform policy and practice in planning of local support services.

CHAMPAIGN, Ill. -- When the worsening COVID-19 pandemic prompted colleges to shutter their campuses and shift to remote learning in spring 2020, concerns arose that many underrepresented students in science, technology, engineering and mathematics disciplines would be demotivated and drop out in even greater numbers.

However, a study of 182 undergraduate students in a biology course at one university found little evidence to support that belief. Instead, across all demographic groups, the impact varied: Some students were more motivated, some were less so, and some saw no changes in their level of interest in the subject matter, researchers at the University of Illinois Urbana-Champaign found.

"There's resilience and a lack of resilience across all groups," said educational psychology professor Jennifer Cromley, the first author of the study, which was co-written by graduate student Andrea Kunze.

Published in the Journal of Microbiology and Biology Education, the findings are a caution against making stereotypical assumptions about individuals' commitment and persistence based on their demographic characteristics such as socioeconomic status or being a first-generation student, according to the researchers.

"We shouldn't assume that they're going to be resilient or not resilient," Cromley said.

"We should check in with them and see how they're doing. Stereotyping people as downtrodden or resilient doesn't reflect the realities of the situation."

The students were participants in an introductory biology course that was traditionally taught with in-person lectures but changed to online instruction during the final eight weeks of the Spring 2020 Semester. When face-to-face instruction was suspended to mitigate the spread of COVID-19 on campus, most students moved back home.

At the time, the researchers had a semester-long study of changes in motivation among the biology students in progress. When instruction went online, they shifted their focus to examine how the motivation of at-risk students - specifically, women, students from underrepresented minority and ethnic groups, and first-generation students - was affected.

Students who agreed to participate in the study were surveyed monthly from January to April, repeatedly completing the same two of 10 possible questionnaires that examined various factors associated with motivation according to several theories.

For example, some of the questionnaires asked about students' goals, such as whether their aim was to thoroughly understand the concepts being taught or to just avoid performing worse than their classmates or failing. Other surveys explored whether the students believed they could master the material in the course or if they considered themselves good at biology.

Some surveys asked students whether they intended to remain in a STEM major and whether they believed the effort required would be worth it in the end. While 42% of the students indicated they were completely committed to remaining in STEM when surveyed in January, the researchers found that this declined as the semester progressed.

By April, changes in each of the motivational variables indicated more students were at risk of dropping out. However, the team found no significant differences between demographic groups, Cromley said.

Because the students experienced numerous changes concurrently - such as concerns about health, their finances and living at home with their families and away from social and academic supports they had on campus - changes in their motivation could not be ascribed to remote learning alone, Cromley said.

While the researchers had hypothesized that students' interest in the material would decline during the semester, they found that some students' interest increased instead. Media stories about scientists' efforts to decipher COVID-19 and develop effective vaccines promoted a greater appreciation for the utility and societal value of science for some students, Kunze said.

This effect was particularly significant among some first-generation students, who represented 24% of those surveyed, according to the study.

One of these students, who also was from an underrepresented minority or ethnic group, wrote that she was motivated every day to achieve her dreams of becoming a doctor "and helping to end disparities within the healthcare system."

Despite predictions that underrepresented students' achievement and persistence would be adversely affected by the challenges associated with remote learning, some "students weren't just giving up. Some were inspired and still trying," Kunze said.

Women showed greater declines in the self-oriented variables, and the researchers hypothesized that their separation from supportive friends on campus may have negatively affected their confidence and feelings of competence in the course.

Conversely, living at home may have been beneficial for some first-generation students, whose academic goal orientation shifted during the semester from failure avoidance to a focus on future achievement and economic mobility. Separation from the highly competitive academic environment and social milieu on campus may have helped these students focus on more positive goals, the researchers said.

Students were asked an open-ended question on the surveys about any factors in their lives that influenced their feelings about their courses that day, and their answers provided glimpses into the impact of family dynamics on the students' achievement.

For example, one student wrote about having to lock themselves in the bathroom to escape pressure from their family members and get their schoolwork done in peace, Cromley said.

LA JOLLA--In a new paper, scientists from La Jolla Institute for Immunology (LJI) bring together research findings from COVID-19 researchers around the world. The results are striking: human T cells can target more than 1,400 sites on the SARS-CoV-2 virus.

"Our lab and many others have shown this very broad and diverse T cell response," says LJI Research Assistant Professor Daniela Weiskopf, Ph.D., co-author of the Cell Host & Microbe review.

This kind of research review, called a "meta-analysis," pools the results of multiple studies, and the researchers give close consideration to how the studies were conducted.

In the case of COVID-19, a global meta-analysis of T cell response studies is especially helpful because different patient populations can have vastly different immune responses, based on their genetic differences and past disease history.

"This really highlights how the study of SARS-CoV-2 has been a global undertaking," says LJI Professor Alessandro Sette, Dr.Biol.Sci, senior author of the review and member of the LJI Center for Infectious Disease and Vaccine Research. "To combine information from all the different labs is a powerful thing."

Key points:

The researchers evaluated all 25 known human T cell response studies conducted between the beginning of the COVID-19 pandemic and March 15, 2021.

The studies show human T cell responses against 1,434 CD4 and CD8 epitopes. Epitopes are sites on SARS-CoV-2 that T cells can recognize.

Grouping these studies together for this larger analysis has revealed several "immunodominant" sites on the virus. These sites are where T cells are most prone to homing in on.

This broad T cell response makes it difficult for SARS-CoV-2 variants to acquire enough mutations to "escape" the body's response against the virus.

Sette adds that this analysis can help researchers monitor whether T cells are mounting effective responses as they encounter viral variants--and vaccines. "Knowing what the key sites on the SARS-CoV-2 spike protein are especially important for monitoring immune responses to COVID-19 vaccines," he says.

Despite these encouraging results, the review is limited. The researchers emphasize that current studies tend to include mainly Caucasian participants. By broadening this research to include many ethnic groups, the researchers can better understand disparities in COVID-19 mortality.

Specifically, the researchers want to understand how variations in the human leukocyte antigen (HLA) system affects T cell responses. The immune system's HLA molecules control which epitopes a T cell can "see." The frequency of different HLA molecule types varies between ethnic groups, so research need to consider how these differences affect T cell responses and potentially COVID-19 case severity.

"This is a global pandemic, so it is important that we expand our studies," says LJI Instructor Alba Grifoni, Ph.D., who served as first author of the review.

The new review also highlights the value of the Immune Epitope Database (IEDB), a free, LJI-run resource funded by the National Institute of Allergy and Infectious Diseases (NIAID). By adding the known epitope data to the IEDB, the researchers were able to see the different study results side-by-side.

"We know there is a strong T cell response to SARS-CoV-2," says Grifoni. "Now we are trying to identify where we have knowledge gaps."

An in vitro study conducted by a group of researchers at São Paulo State University (UNESP) in Araraquara, Brazil, shows how fungi and bacteria can activate genes associated with head and neck tumors, as the metabolism of biofilms (communities in which these microorganisms self-organize in a structured and coordinated manner) stimulate tumor cells by favoring the cell signaling pathways required for tumor development and resistance to treatment. The findings include entirely novel information on the links between microbial biofilms and cell behavior in head and neck cancer.

The researchers discovered that metabolites secreted by biofilms, termed the secretome, can modulate the expression of proto-oncogenes and cell cycle genes associated with tumor cell growth and survival. Their analysis of gene expression focused on two signaling pathways (EGFR/RAS/RAF/MEK/ERK and EGFR/PI3K/AKT/mTOR) that play a key role in tumor cell proliferation, differentiation, and survival. Alterations to gene expression in these pathways are highly prevalent in various types of tumor.

The researchers analyzed head and neck and oral cavity squamous carcinoma cells. Squamous cell carcinoma is the most common type of mouth cancer, which produces functional and aesthetic changes that degrade the patient’s quality of life.

The cells were challenged via stimulation by metabolites from biofilms of Candida albicans fungi and Staphylococcus aureus bacteria. These microorganisms are very frequent in users of dentures: prior research found both in 30%-40% of subjects examined.

Oral microbiota is known to play an important role in the development of cancer. Genetic markers associated with the presence of microorganisms have been identified for some types, such as stomach cancer, but there is no consensus regarding the most prevalent genes linked to head and neck cancer, and no molecular markers had hitherto been found for this disease, especially HPV-negative cancer, which has a worse prognosis.

According to a report on the study published in Frontiers in Cellular and Infection Microbiology, metabolites from C. albicans and S. aureus biofilms can endanger the homeostasis of normal and neoplastic oral epithelial cells, altering the expression of important genes such as CDKN1A, Bcl-2, PI3K, BRAF, hRAS and mTOR, impairing cell viability and survival, and disrupting the cell cycle profile.

The study was supported by FAPESP and the National Council for Scientific and Technological Development (CNPq). The project was also awarded funding by Colombia’s COLCIENCIAS and SAPIENCIA agencies (2015 call for doctorates abroad), and involved partnerships with UNESP’s Araraquara Dental School (FOAr) and Araraquara School of Pharmaceutical Sciences (FCFAr).

Understanding the cell cycle is important because cancer entails unchecked cell division and growth, with tumor cells potentially invading tissues and organs throughout the body. Failure of the inhibitors of this cycle and excessive signaling by cell division regulators can lead to tumor progression.

The oral microbiome is a diversified community of microorganisms with as many as 700 species of viruses, protozoans, bacteria and fungi. When biofilms develop, they produce metabolites that alter the immune response and can lead to chronic inflammation and even production of cancerous substances.

According to Paula Aboud Barbugli, a professor at FOAr-UNESP and co-leader of the study, the findings show that “molecules secreted by these microorganisms in biofilms may modulate host cell activities even far away from the primary infection site”.

For Carlos Eduardo Vergani, also a professor at FOAr-UNESP and principal investigator for the project, the results serve as a warning on the treatment of cancer patients who have dentures. “Control of biofilms, including denture and oral cavity hygiene, is extremely important to minimize inflammatory processes, as shown by our prior research and the study just published, which points to interference with the expression of genes associated with tumor progression,” Vergani told Agência FAPESP.

Another study led by Vergani and published in 2017 showed that soluble factors in methicillin-sensitive C. albicans and S. aureus biofilm promoted cell death and inflammatory responses.

According to a report issued in March by Brazil’s National Cancer Institute (INCA), some 22,800 new cases of laryngeal and oral cavity cancer are reported each year, most of them in male patients.

Future

The COVID-19 pandemic forced the group to interrupt the clinical trial they had planned to conduct on the basis of their research. Barbugli said a PhD project supervised by another member of the group and approved by the Ministry of Health’s Research Ethics Committee (CONEP) will investigate the prevalence of C. albicans and S. aureus biofilms in the dentures and oral cavities of head and neck cancer patients treated at Araraquara’s Santa Casa de Misericórdia Hospital to understand how they influence prognosis in these cases.

For Vergani, the results obtained so far pave the way for future metabolomics and proteomics research into oral biofilms.

Geothermal ecosystems, such as volcanoes and hot terrestrial and deep-sea springs, are characterized by severe conditions. The temperatures are high and the environment could be extremely acidic or very alkaline. Moreover, there are chemically active compounds in them that can be fatal to living organisms, because they are capable of destroying the membrane of an ordinary cell.

"Exclusively very adapted microorganisms can exist here. They do not only have unique protective systems but are also able to get energy from chemical transformations of those substances that are available to them. Humans are actively using the peculiarities of their metabolism, for example some enzymes help biologists to amplify DNA molecules in a test tube," says Vitaly Kadnikov, Ph.D., senior researcher at the Federal Research Centre "Fundamentals of Biotechnology" of the Russian Academy of Sciences and the principal investigator of the grant from the Russian Science Foundation.

New and so far poorly understood analogs of these natural ecosystems (called simply thermal) are places of hydrocarbon production, that is, oil wells and coal pits. The latter is the research object of a group of scientists from the Federal Research Centre "Fundamentals of Biotechnology" of RAS (Moscow) and Tomsk State University (Tomsk). The authors studied quarries near the city of Kiselevsk, Kemerovo region, and took samples of soil layers from places where there were signs of an underground fire-heated soil, smoke and where steam is coming out to the surface. They characterized the chemical and mineralogical composition of the samples to understand what substances could be used for energy by the bacteria that colonize the coal. Then biologists determined the composition of microbial communities from each layer by analyzing the DNA from it, namely, the gene sequence of one of the ribosome subunits usually used for such purposes.

It turned out that more than a dozen groups of microorganisms live in the Kuzbass quarry, the bacteria mostly. Archaea which are considered to be common inhabitants of extreme ecosystems turned out to be no more than 3%; they are all chemolithoautotrophs converting ammonia into nitrite. The latter compound became "food" for another small group of organisms that metabolize it into nitrate, which people use, for example, as fertilizer.

The representatives of the Chlorobacteria predominated among the bacteria, often found in ecosystems with a high carbon dioxide content; they are also capable of converting poisonous carbon monoxide into CO2. This might be applied for new air purification technologies wherever a furnace is used. Some bacteria found in coal seams can oxidize hydrogen with water formation.

There have also been found microbes that utilize methane as a growth substrate. Many of the identified organisms can fix carbon dioxide and grow autotrophically, but there have been those that feed on the dead remains of their fellows. The Kuzbass quarry turned out to be a well-balanced microbial community, surpassing similar objects studied earlier in China, the US, and Altai in diversity.

"Our research is another step towards understanding how these relatively young ecosystems emerged, what connections they have and whether we can use them. They have much in common with those that form around hot springs. Who knows, maybe they comprise very specific organisms that will help to develop new ways of obtaining valuable biotechnological products by using hydrogen and carbon monoxide generated during coal gasification," says Vitaly Kadnikov.

BOSTON -- A multidisciplinary team from MassGeneral Hospital for Children (MGHfC), Brigham and Women's Hospital and other institutions have identified the mechanism of how an extremely rare but serious post-COVID-19 complication develops in children and adolescents. Led by MGHfC pediatric pulmonologist Lael Yonker, MD, researchers determined that viral particles remaining in the gut long after an initial COVID-19 infection can travel into the bloodstream, instigating the condition called Multisystem Inflammatory Syndrome in Children (MIS-C).

The syndrome can occur several weeks after an initial infection; symptoms include high fever, abdominal pain, vomiting, diarrhea, rash and extreme fatigue. The hyperinflammatory response and "cytokine storm" seen in MIS-C can lead to extensive damage in the heart, liver and other organs.

Eighty percent of children hospitalized with MIS-C develop severe cardiac pathology and face a prolonged hospital stay and extensive recovery period. Current treatment strategies include an aggressive, long-term course of steroids and intravenous immunoglobulin.

MIS-C occurs in less than 1 percent of children with confirmed SARS-CoV-2 infection. As of May 3, 2021, the U.S. Centers for Disease Control and Prevention reported 3,742 children diagnosed with MIS-C and 35 deaths. U.S. statistics are skewed heavily toward Latino and Black children, with a total of 63 percent in cases with race or ethnicity listed.

In their recent study published in the Journal of Clinical Investigation, which included 100 children (19 with MIS-C, 26 with COVID-19 and 55 healthy controls), the researchers provide insight into the mechanics of MIS-C and identify potential biomarkers for early disease detection, treatment and prevention. They also describe the successful treatment of a 17-month-old infant with MIS-C.

"When we realized that 95 percent of the children with MIS-C had SARS-CoV-2 viral particles in their stool but no or low levels of particles in their noses or throats, we investigated further and found that viral material lingering in the gut long after the first COVID-19 infection could lead to MIS-C," says Yonker, lead author of the paper. The team hypothesized that SARS-CoV-2 viral particles found in the gastrointestinal tract of children move into the bloodstream, leading to the hyperinflammatory immune response characteristic of MIS-C. "This is the first study showing viral particles in the blood of MIS-C coinciding with the hyperinflammatory response," says Yonker.

Co-senior author Alessio Fasano, MD, head of MGHfC's Division of Pediatric Gastroenterology and Nutrition, is an expert on the mechanics of intestinal immune responses to pathogens. In 2000, Fasano and his team at the University of Maryland School of Medicine discovered zonulin, a protein that regulates intestinal permeability by opening the tight junctions between gut epithelial cells in the small intestine.

This opening of the spaces between epithelial cells allows the passage of substances from the gut lumen into the bloodstream, including gluten, which can cause symptoms for people genetically predisposed to celiac disease. In the early 2000s, Fasano developed larazotide acetate to work as a zonulin blocker in the treatment of celiac disease.

Prior to the advent of COVID-19, Fasano and Moshe Arditi, MD, director of the Infectious and Immunological Diseases Research Center at Cedars-Sinai in Los Angeles, co-authored a paper about a study on Kawasaki disease, a condition very similar to MIS-C, in which they showed that mice with elevated zonulin levels could be successfully treated with larazotide acetate. Subsequently, Arditi, Yonker and Fasano showed that the immune response in MIS-C is consistent with superantigenic activation. "The large spike protein--the superantigen--basically holds onto a T-cell and makes it fire off a continuous immune response," says Yonker.

In the current study, the researchers measured high levels of SARS-CoV-2 virus in the stools and high levels of zonulin in the blood of children with MIS-C. When they subsequently found viral particles in the blood, Fasano suggested the use of larazotide acetate as a therapeutic. Encouraging preliminary data on the efficacy of larazotide acetate in treating the first case of MIS-C, after obtaining compassionate use permission from the Food and Drug Administration, opened up the possible use of larazotide acetate as the first oral treatment for COVID-19 and its complications.

"Our hypothesis was that larazotide would reduce the hyperinflammation by closing the tight junctions and preventing the large spike proteins of the SARS-CoV-2 virus from entering the bloodstream," says Fasano.

Adds Yonker: "Our next plan is to develop a clinical trial to study the effect of larazotide on clinical outcomes in MIS-C. To go from characterizing a new disease, to understanding its cause, to identifying a possible new treatment is just incredible."

Cells are the building blocks of life, present in every living organism. But how similar do you think your cells are to a mouse? A fish? A worm?

Comparing cell types in different species across the tree of life can help biologists understand how cell types arose and how they have adapted to the functional needs of different life forms. This has been of increasing interest to evolutionary biologists in recent years because new technology now allows sequencing and identifying all cells throughout whole organisms. "There's essentially a wave in the scientific community to classify all types of cells in a wide variety of different organisms," explained Bo Wang, an assistant professor of bioengineering at Stanford University.

In response to this opportunity, Wang's lab developed an algorithm to link similar cell types across evolutionary distances. Their method, detailed in a paper published May 4 in eLife, is designed to compare cell types in different species.

For their research, the team used seven species to compare 21 different pairings and were able to identify cell types present in all species along with their similarities and differences.

Comparing cell types

According to Alexander Tarashansky, a graduate student in bioengineering who works in Wang's laboratory, the idea to create the algorithm came when Wang walked into the lab one day and asked him if he could analyze cell-type datasets from two different worms the lab studies at the same time.

"I was struck by how stark the differences are between them," said Tarashansky, who was lead author of the paper and is a Stanford Bio-X Interdisciplinary Fellow. "We thought that they should have similar cell types, but when we try analyzing them using standard techniques, the method doesn't recognize them as being similar."

He wondered if it was a problem with the technique or if the cell types were just too different to match across species. Tarashansky then began working on the algorithm to better match cell types across species.

"Let's say I want to compare a sponge to a human," said Tarashansky. "It's really not clear which sponge gene corresponds to which human gene because as organisms evolve, genes duplicate, they change, they duplicate again. And so now you have one gene in the sponge that may be related to many genes in humans."

Instead of trying to find a one-to-one gene match like previous methods for data matching, the researchers' mapping method matches the one gene in the sponge to all potentially corresponding human genes. Then the algorithm proceeds to figure out which is the right one.

Tarashansky says trying to find only one-to-one gene pairs has limited scientists looking to map cell types in the past. "I think the main innovation here is that we account for features that have changed over the course of hundreds of millions of years of evolution for long-range comparisons."

"How can we use the ever-evolving genes to recognize the same cell type that are also constantly changing in different species?" Said Wang, who is senior author of the paper. "Evolution has been understood using genes and organismal traits, I think we are now at an exciting turning point to bridge the scales by looking at how cells evolve."

Filling in the tree of life

Using their mapping approach, the team discovered a number of conserved genes and cell type families across species.

Tarashansky said a highlight of the research was when they were comparing stem cells between two very different flatworms.

"The fact that we did find one-to-one matches in their stem cell populations was really exciting," he said. "I think that basically unlocked a lot of new and exciting information about how stem cells look inside a parasitic flatworm that infects hundreds of millions of people all over the world."

The results of the team's mapping also suggest there's a strong conservation of characteristics of neurons and muscle cells from very simple animal types, such as sponges, to more complex mammals like mice and humans.

"That really suggests those cell types arose very early on in animal evolution," Wang said.

Now that the team has built the tool for cell comparison, researchers can continue to collect data on a wide variety of species for analysis. As more datasets from more species are collected and compared, biologists will be able to trace the trajectory of cell types in different organisms and the ability to recognize novel cell types will improve.

"If you only have sponges and then worms and you're missing everything in between, it's hard to know how the sponge cell types evolved or how their ancestors have diversified into sponges and worms," said Tarashansky. "We want to fill in as many nodes along the tree of life as possible to be able to facilitate this type of evolutionary analysis and transfer of knowledge across species."

One in five women experience pain during intercourse. The latest edition of the Diagnostic and Statistical Manual of Mental Disorders, the bible of American psychiatrists, lists it under "genito-pelvic pain or penetration disorder." However, this type of pain is not purely psychological.

Provoked vestibulodynia is a condition experienced by approximately 8% of women in North America. It is characterized by severe pain at the vaginal opening during sexual intercourse or when inserting tampons. To reduce the burning sensation, many women apply lidocaine, an anesthetic cream.

A new study of 108 couples found cognitive-behavioural therapy (CBT) for couples to be more effective than lidocaine. The study was conducted by Sophie Bergeron, professor in the Psychology Department in the Faculty of Arts and Science at Université de Montréal, director of the UdeM Sexual Health Laboratory and holder of the Canada Research Chair in Intimate Relationships and Sexual Wellbeing, and Natalie O. Rosen of Dalhousie University. Marc Steben and Marie-Hélène Mayrand of Université de Montréal, Marie-Pier Vaillancourt-Morel of Université du Québec à Trois-Rivières, Serena Corsini-Munt of the University of Ottawa, and Isabelle Delisle also contributed to the study, which has just been published in the Journal of Consulting and Clinical Psychology.

Unclear causation

The causes of provoked vestibulodynia have yet to be determined. There is a lengthy list of risk factors, including biomedical factors such as repeated infections causing inflammation in the vulvar area (cystitis, vaginal infections), the use of certain oral contraceptives, genetic predisposition, marital factors, and depression and anxiety. Abnormalities in the pelvic floor muscles are also associated with provoked vestibulodynia, but it is not known whether they are a consequence of the pain or its cause. Similarly, it is unclear whether anxiety is a cause or a result, but it has been found that the higher the level of anxiety, the greater the pain.

"Psychological intervention is recommended because once pain sets in, it has such a negative impact on sexuality and on the relationship that it becomes very important to break the vicious cycle of fear and avoidance," says Sophie Bergeron. "The pain often leads to loss of desire in women and frustration in both partners. This is a real problem; it's not imaginary."

Few validated treatments

Couple therapy is commonly offered by psychologists and sexologists. In the case of provoked vestibulodynia, the partner plays a critical role and can help alleviate the problem or aggravate it. It is therefore every important to include the partner in the intervention. However, some interventions were not previously supported by evidence.

Now for the first time, a randomized clinical trial has compared the efficacy of couple CBT and lidocaine.

Therapy was found to be more effective than lidocaine application in reducing women's fear of pain, sexual distress and alarm, and in improving their sexual experience. After six months, the women were twice as satisfied with their sex lives and their partners three times as satisfied.

Nature of the sessions

The couples attended acceptance and commitment therapy (ACT) sessions for 12 weeks.

"Acceptance means that instead of trying to get a person to change their thinking, we encourage them to accept it," Bergeron explains. "We practice cognitive defusion, a technique that creates a psychological distance between the person and his or her thoughts. At the beginning of the therapy, the women define themselves by their genito-pelvic pain. The therapy helps them reduce the hold those thoughts have over them. We also try to break the sexuality = pain association and replace it with new associations, such as sexuality = pleasure with my partner, intimacy with my partner."

The therapy also looks at sexual motivations. What is it about sexuality that is important to the couple? "We try to explore other aspects of sexuality that are pleasurable," she says. "In terms of behaviour, we can help them expand their repertoire of sexual activities that don't cause pain. Generally, it's vaginal penetration that's painful, so we try not to always focus on that."

Finally, the therapy works on the couple's emotional regulation. "When one partner reacts to a painful experience with anger or frustration, it only makes the problem worse. We help the couple manage their emotional relationship. We get the partner to be more empathetic to the woman's experience of pain and the woman to be more empathetic to her partner's frustration. We help them see themselves as a united team."

The importance of the partner in therapy

According to Sophie Bergeron, the partner's involvement "helps alleviate the woman's pain because she is no longer alone with her pain." Both partners report they understand the problem and the other's experience better, and they are relieved to be able to work together to improve the situation.

At the end of the therapy, couples report satisfaction with having reclaimed their sexuality in a non-threatening way by refocusing on pleasurable experiences rather than allowing the pain to take control. This treatment could well be effective for other types of genito-pelvic pain as well.

While some studies suggest female patients treated by female physicians have better outcomes, there does not appear to be a relationship between operator and patient gender and outcome in patients undergoing coronary angioplasty or stenting. These are the results of a first-of-its-kind study by the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) and published in Catheterizations and Cardiovascular Interventions.

The study looked at procedures performed by 385 male interventional cardiologists, and 18 female interventional cardiologists at 48 non-federal hospitals across the state of Michigan. Female interventional cardiologists continue to be markedly under-represented and only perform a small percentage of cases, with women accounting for only 4.5% of interventional cardiologists and performing only 3% of procedures.

Despite interventional cardiology remaining an overwhelmingly male-dominated specialty, female physicians in this field stand out as excellent practitioners. Coronary angioplasties done by female physicians were more frequently rated as appropriate as compared to procedures performed by their male counterparts, among those studied. Female interventional cardiologists also more frequently prescribe recommended medical therapies than male interventional cardiologists. No differences in death, kidney injury, major bleeding or blood transfusions were found between patients treated by male or female interventional cardiologists.

"While the overall care processes and outcomes in Michigan were great, and similar for operators of either sex, the female physicians scored higher on appropriateness and post-procedural therapy These findings would benefit female trainees who are considering interventional cardiology but are concerned about perceived barriers," says the lead author of the study, Prasanthi Yelavarthy, MD.

Gurm is an interventional cardiologist at the Michigan Medicine Frankel Cardiovascular Center, and Yelavarthy is a house officer at Michigan Medicine.

BMC2 is a collaborative consortium of health care providers in the State of Michigan comprised of three statewide quality improvement projects:

A prospective multicenter statewide registry of consecutive percutaneous coronary interventions (BMC2 PCI).

A prospective, longitudinal multicenter statewide registry of vascular surgeries and carotid interventions (BMC2-Vascular surgery).

Michigan TAVR, a structural heart quality improvement initiative focused on transcatheter aortic valve replacement in collaboration with the Michigan Society of Thoracic and Cardiovascular Surgeons.

All projects are designed to improve quality of care and patient outcomes. The collaboration across BMC2 overcomes the barriers of traditional market and academic competition. All projects collect, audit and organize data and report procedural variables and outcomes to individual operators and institutions.

Journal

Catheterization and Cardiovascular Interventions

DOI

10.1002/ccd.29774

CHAMPAIGN, Ill. -- Advanced microscope technology and cutting-edge geological science are giving new perspectives to an old medical mystery: How do kidney stones form, why are some people more susceptible to them and can they be prevented?

In a new paper published in the journal Nature Reviews Urology, researchers from the University of Illinois Urbana-Champaign, Mayo Clinic and other collaborators described the geological nature of kidney stones, outlined the arc of their formation, established a new classification scheme and suggested possible clinical interventions.

"The process of kidney stone formation is part of the natural process of the stone formation seen throughout nature," Illinois geology professor Bruce Fouke said. "We are bringing together geology, biology and medicine to map the entire process of kidney stone formation, step by step. With this road map in hand, more effective and targeted clinical interventions and therapies can now be developed."

Kidney stones are a painful problem that will strike one in 10 adults in their lifetime and send half a million people in the United States to emergency rooms each year, according to the National Kidney Foundation. Yet little is understood about the geology behind how kidney stones form, Fouke said.

Previous work from Fouke's group found that kidney stones form in the same way as geological stones in nature: Rather than crystalizing all at once, they partially dissolve and re-form multiple times, contrary to doctors' belief that they form suddenly and intact.

In the new work, the research team - brought together by the Mayo Clinic and Illinois Alliance for Technology-Based Healthcare - describes in detail the multiple phases kidney stones go through in forming, dissolving and re-forming, documented through high-resolution imaging technologies. The findings defy the typical classification schemes doctors use, which are based on bulk analyses of the type of mineral and the presumed location of formation in the kidney. Instead, the researchers developed a new classification scheme based on which phase of formation the stone is in and which chemical processes it is undergoing.

"If we can identify these phase transformations, what makes one step to go to another and how it progresses, then perhaps we can intervene in that progression and break the chain of chemical reactions happening inside the kidney tissues before a stone becomes problematic," said Mayandi Sivaguru, the lead author of the study and assistant director of core facilities at the Carl R. Woese Institute for Genomic Biology at Illinois.

One particularly revelatory finding was in the very beginnings of kidney stone formation: Stones start as microspherules, or tiny droplets of mineral, which merge to form larger crystals throughout kidney tissues. Normally they are flushed out, but when they coalesce together to form larger stones that continue to grow, they can become excruciatingly painful and even deadly in some cases, Fouke said.

"Stone formation is part of a natural, healthy process within kidneys where these tiny mineral deposits are shuttled away and excreted from the body," Fouke said. "But then there is a tipping point when those same mineral deposits start to grow together too rapidly and are physically unable to leave the kidney."

As the stone goes through the formation process, more microspherules merge, lose their rounded shape and transform into much larger, perfectly geometric crystals. Stones go through multiple cycles of partially dissolving - shedding up to 50% of their volume, the researchers found - and then growing again, creating a signature pattern of layered crystals much like those of agates, coral skeletons and hot-spring deposits seen around the world.

"Looking at a cross-section of a kidney stone, you would never guess that each of the layers was originally a bunch of little balls that lined up and coalesced. These are revolutionary new ways for us to understand how these minerals grow within the kidney and provide specific targets for stone growth prevention," Fouke said.

The study authors outlined several possible clinical interventions and treatment targets based on this expanded knowledge of kidney stone formation. They hope that researchers and clinicians can explore and test these options, from drug targets to changes in diet or supplements that could disrupt the chemical and biological cascade driving kidney stone formation, Sivaguru said.

To aid in this testing, Fouke's group developed the GeoBioCell, a microfluidic cartridge designed to mimic the intricate internal structures of the kidney. The group hopes the device can accelerate not only research, but also clinical diagnostic testing and the evaluation of potential therapies, especially for the more than 70% of kidney stone patients with recurring stones.

"Ultimately, our vision is that every operating room would have a small geology lab attached. In that lab, you could do a very rapid diagnostic on a stone or stone fragment in a matter of minutes, and have informed and individualized treatment targets," Fouke said.