Culture

AURORA, Colo. (May 6, 2021) - Scientists examining the remains of 36 bubonic plague victims from a 16th century mass grave in Germany have found the first evidence that evolutionary adaptive processes, driven by the disease, may have conferred immunity on later generations of people from the region.

"We found that innate immune markers increased in frequency in modern people from the town compared to plague victims," said the study's joint-senior author Paul Norman, PhD, associate professor in the Division of Personalized Medicine at the University of Colorado School of Medicine. "This suggests these markers might have evolved to resist the plague."

The study, done in conjunction with the Max Planck Institute in Germany, was published online Thursday in the journal Molecular Biology and Evolution.

The researchers collected DNA samples from the inner ear bones of individuals in a mass grave in the southern German city of Ellwangen which experienced bubonic plague outbreaks in the 16th and 17th centuries. Then they took DNA samples from 50 current residents of the town.

They compared their frequency spectra - the distribution of gene variants in a given sample - for a large panel of immunity-related genes.

Among the current inhabitants, the team found evidence that a pathogen, likely Yersinia pestis which causes bubonic plague, prompted changes in the allele distribution for two innate pattern-recognition receptors and four Human Leukocyte Antigen molecules, which help initiate and direct immune response to infection. An allele is a variant form of a gene.

"We propose that these frequency changes could have resulted from Y.pestis plague exposure during the 16th century," Norman said.

The findings are the first evidence that evolutionary processes, prompted by Y. pestis, may have been shaping certain human immunity-relevant genes in Ellwangen and possibly throughout Europe for generations.

And since the plague tormented Europe for nearly 5,000 years, the study suggests that these immunity genes may have been pre-selected in the population long ago but recently became selected through epidemic events.

"Although the lethality of the plague is very high without treatment it remains likely that specific individuals are protected from, or more susceptible to, severe disease through polymorphism in the determinants of natural immunity," the study said. "In this case, any change in allele frequencies that occurred during a given epidemic crisis could be evident as genetic adaptation and detectable in modern day individuals."

Later simulations showed that natural selection likely drove these allele frequency changes.

"I think this study shows that we can focus on these same families of genes in looking at immunity in modern pandemics," Norman said. "We know these genes were heavily involved in driving resistance to infections."

The study also demonstrates that, so far, no matter how deadly the pandemic there are always survivors.

"It sheds light on our own evolution," Norman said. "There will always be people who have some resistance. They just don't get sick and die and the human population bounces back."

Still, he doesn't want people to get the wrong message, especially in the era of Covid-19.

"I wouldn't want to discourage anyone from taking a vaccine for the current pandemic," Norman said. "It's a much safer bet than counting on your genes to save you."

Monash University researchers have engineered new antimicrobial surfaces that can significantly reduce the formation of bacteria on medical instruments, such as urinary catheters, and reduce the risk of patient infection while in hospital.

This world-first study demonstrates the potential for 3D engineered surfaces in preventing the initial formation of microcolonies of Escherichiacoli (E.coli), Klebsiellapneumoniae and Pseudomonas aeruginosa - the three most common urinary tract bacterial infections (UTIs) associated with catheters.

The study team, led by Dr Victor Cadarso, from Monash University's Department of Mechanical and Aerospace Engineering and the Centre to Impact AMR, engineered surfaces with smooth, 3D micro features, instead of the traditional sharp cross-sectional ones, to reduce the potential for harmful bacteria to attach on these surfaces in large numbers.

The tested surfaces demonstrated reduction in both attachment of bacteria and biofilm formation. One of the surfaces, P01, presented excellent properties against E.coli, K.pneumoniae, and P. aeruginosa with 55 per cent, 69 per cent and 68 per cent less bacterial cells attached, and 53 per cent, 77 per cent and 66 per cent less microcolonies being formed, respectively.

Urinary tract infections (UTIs), associated with urinary catheters, are the most common type of healthcare-associated infections. They have been identified by the World Health Organization (WHO) as an urgent global health threat.

Approximately one in five of hospitalised patients globally are administered urinary catheters during their hospital stay. It is estimated that 13,000 people across the world die each year from UTIs, and a further 700,000 die from associated antimicrobial resistance infections because of the resistance of superbugs to antibiotics and current sterilisation methods.

The study was published in the international journal ACS Applied Materials & Interfaces. Researchers from Monash University's Department of Microbiology were also involved and part of the work was done at the Melbourne Centre for Nanofabrication.

"Using E.coli as an example, we found bacterial cells that form on surfaces do so mostly on the sharp corners. By removing these sharp features, the bacteria can no longer colonise the surface as effectively. This same effect has been demonstrated for the two other pathogens in this study," said Sara Ghavamian, from the Monash Department of Mechanical and Aerospace Engineering, who created these surfaces.

"High-touch surfaces within hospitals, such as catheters and ventilators, are a significant source of microbial spread and healthcare-associated infections.

"Infection control through physically altering the micro architecture of these surfaces, rather than the traditional use of chemical agents, is not only a more durable approach but also an effective strategy for combating antimicrobial resistance."

The bacterial colonisation of surfaces takes place over time. Once bacteria attach to a surface, a series of cellular responses are triggered. After this initial phase, including a few rounds of cell division by this bacteria, microcolonies of hundreds of bacterial cells are formed.

After successful colonisation, the bacteria form a biofilm - a large population of bacteria in a 'secreted cellular matrix' that binds together and protects the cells from antibiotics and the immune system. This might create a superbug that can cause long-term health implications for patients.

Researchers demonstrated that their 3D engineered microtopographies with varying heights and smooth curved cross-sections can simultaneously deter both the initial attachment and the formation of biofilms for three clinically relevant bacteria.

Through an extensive screening process, researchers identified that the sharp corners of the vertical side walls within the conventional micropatterned surfaces gifted bacteria with perfect hiding spots to shelter themselves against the flow of fluids which could wash them away.

The researchers hypothesise that by smoothing out these corners, the bacteria would be left with nowhere to hide.

"After equivalent incubation periods with the same bacteria, we discovered that while the micropatterned surfaces were indeed successful in reducing the number of microcolonies formed they, problematically, increased the number of attached bacteria compared with traditional micro-flat surfaces," Sara said.

"Opposite the conventional sharp micropatterned surfaces, our smooth design demonstrated a simultaneous decrease in both the number of bacterial attachment and microcolony formation compared to the standard flat surfaces.

"Developing strategies to prevent the bacterial colonisation of surfaces, such as catheters, without requiring antimicrobial drugs or chemicals is critical to stop biofilm formation and the potential spread of harmful diseases."

A new survey study suggests that, for adolescents who received unplanned distance education due to the COVID-19 pandemic, experiencing one's own competence was linked to positive emotion, self-motivation to learn, and pro-learning behaviors. Feeling connected to others was also linked to positive emotion. Julia Holzer of the University of Vienna, Austria, and colleagues present these findings in the open-access journal PLOS ONE.

The new research draws on a psychological theory known as self-determination theory, which outlines three basic psychological needs for well-being: autonomy, connection to others, and experiencing one's own competence. Previous research has provided much evidence in support of this theory, but it was previously unclear how it applies to adolescents receiving distance education, which poses risks for well-being and learning.

To explore self-determination theory in the context of distance education, Holzer and colleagues conducted a survey study of 25,305 adolescents from eight countries in Europe, Asia, and North America. The survey ran from April to June 2020 and included questions about the three basic psychological needs, well-being, and learning behaviors. Links between these factors were uncovered by statistical mediation analyses of the survey data.

Across all eight countries, experiencing one's own competence--for example, being able to complete most of one's schoolwork--was linked to positive emotion, self-driven motivation to learn, and active learning behavior in the form of engagement and persistence. Perceived connectedness to others was also consistently linked to positive emotion. These findings were in line with the researchers' initial hypotheses.

Additional connections were found between the basic needs, well-being, and learning behaviors, but these were less consistent between countries. Additionally, contrary to initial hypotheses, adolescents' perceived autonomy was not strongly linked to positive emotion or motivation to learn.

Together, these findings could help inform the design of distance education programs, such as by incorporating ways to promote feelings of connection to others, or providing regular feedback and opportunities for improvement to promote experiences of competence. Further research could also help confirm or expand on these results.

The authors add: "Given the risks and challenges of the COVID-19 pandemic for adolesecents, the present research identifies characteristics that relate to adolescents' psychological well-being and learning quality during the pandemic. The sample encompasses students from altogether eight countries in Europe, Asia and North America, thus enabling to derive common conclusions applicable across different cultural contexts."

Almost 1 in 4 COVID-19 patients have another bacterial, viral or fungal infection simultaneously or subsequently, with such patients experiencing worse disease outcomes.

Tsukuba, Japan - Autoimmune diseases occur when an individual's immune system fights their own body as if it was a foreign invader. However, in healthy people, these responses are prevented by a process known as immune tolerance. Many complex biological mechanisms maintain the necessary balance between immune activation and suppression to ensure immune tolerance does not prevent the body from effectively fighting pathogens.

In a new study published in PNAS, a group of researchers from the University of Tsukuba uncovered how the relationship between two receptors called DNAM-1 and TIGIT helps preserve the balance for optimal immune function. Both of these molecules have previously been studied in a subset of immune cells called regulatory T cells, or Tregs.

Tregs are crucial mediators of immune tolerance and autoimmunity prevention. Treg activity is typically inhibited during inflammatory reactions to infection to allow the body to efficiently fight and clear the invader. However, the molecular mechanisms that control this balance in Treg behavior are not fully understood. When a specific activating molecule (CD155) binds to the receptors DNAM-1 and TIGIT, they trigger signals that tell the T cells how to behave and what functions to perform.

The Tsukuba team found that DNAM-1 and TGIT compete for CD155 under inflammatory conditions. When CD155 binds to DNAM-1, this receptor sends messages that tell the immune system to wake up and activate. However, when CD155 binds to TIGIT, this receptor acts the opposite way and suppresses the immune system, thereby telling the T cells to stop activating.

To investigate the molecular interplay between DNAM-1 and TIGIT, the researchers studied mice (an acute graft-versus-host disease mouse model) infused with either Tregs lacking DNAM-1 or normal Tregs. "We found that the absence of DNAM-1 resulted in enhanced TIGIT-mediated signaling. This shift in balance occurs because more CD155 is available to bind to TIGIT when DNAM-1 is not present. This help the Tregs maintain immune suppression during periods of inflammation," explains Professor Kazuko Shibuya, senior author of the study. "We observed similar dynamics in a humanized mouse model, supporting the relevance of these findings to humans." In short, this mechanism helps tell the Tregs to not block the immune system when a true danger is lurking.

Given that Tregs play an important role in autoimmune diseases, the results suggest that the balance between DNAM-1 and TIGIT may be improperly regulated in individuals suffering from autoimmunity. This potential disease mechanism will be the focus of future research. These findings in mice suggest DNAM-1 could be used as a novel molecular target for treating autoimmune diseases.

Recently published in the scientific journal Brain Communications, a new study distinguished structural patterns between individuals with corpus callosum dysgenesis (CCD), a congenital condition that consists of the absence or incomplete development in the connecting structure between the two brain hemispheres. The research was carried out by the D'Or Institute for Research and Education (IDOR), the University of Pittsburgh, Oswaldo Cruz Foundation (Fiocruz), and the Federal University of Rio de Janeiro (UFRJ).

Investigating CCD is an arduous task for doctors and neuroscientists. There aren't many patients available for research, and the anatomical variability of brains with CCD creates a broad clinical spectrum. Due to brain plasticity - the organ's ability to create alternative connections to ensure its functioning in adverse situations -, the clinical scenario range from the complete lack of symptoms to epilepsy and psychomotor retardation, in addition to being commonly found in autism spectrum disorder. "The CCD is one of the greatest mysteries of neuroscience. To this day, researchers don't fully know how this neuroplasticity occurs. But we've had new discoveries in the past years, mainly through in vivo methods that analyze these patients' brain connections via imaging", informs the study's corresponding author, Dr. Fernanda Tovar-Moll, M.D., radiologist and president of IDOR.

Considering the challenges presented by this pathological plurality, the study's researchers analyzed the structural and neurological alterations of 11 patients with CCD, men and women aged from 4 to 33 years old. Of these, 6 had a complete absence of the corpus callosum (agenesis) and the other 5 were characterized by its hypoplasia, which is the underdevelopment of the structure.

The research was carried out through functional and structural magnetic resonance imaging. The images were first evaluated by a neuroradiologist to confirm the diagnosis of CCD and then were examined again to map the patients' neural connections, which were compared with a control group composed of 45 healthy individuals.

As expected, the results showed that structural connectivity in individuals with agenesis or hypoplasia of the corpus callosum differed from the images in the control group. However, clear differences were also noted within the groups with CCD. 

Despite having fewer connections when compared to the other two groups, patients with agenesis connected brain regions in a functionally similar way to healthy patients, while individuals with hypoplasia showed a broader, but abnormal and variant reorganization between brain connections, which would justify the worsening of symptoms in patients with this type of CCD. "The hypoplastic corpus callosum usually connects regions of the brain that it shouldn't connect. Instead of positive neuroplasticity, this characteristic could be the cause of symptoms", explains Diego Szczupak, Ph.D. and the study's first author.

Although previous studies have already described the anatomical heterogeneity in brains with CCD, the different types of dysgenesis have not yet been widely compared to each other, and the distinctions between their adaptive brain plasticity are still unfamiliar. These findings show that the hypoplasia and agenesis in CCD have unique fingerprints and use distinct plastic mechanisms to compensate for the partial or complete lack of the corpus callosum. But the authors emphasize that this does not necessarily mean that the coherence, speed, and precision of these connections reflect the same brain functioning as in healthy individuals.

Dr. Fernanda Tovar-Moll is also part of an international research consortium, the IRC5, whose mission is to discover the causes, consequences, and possible interventions for corpus callosum dysgenesis and associated brain connectivity disorders. From June 27th to July 2nd, IDOR is organizing an IRC5 meeting addressed to family members, doctors, neuroscientists, and psychologists interested in the topic. Information about the event will be available soon on the website http://www.idor.org and on IDOR's social networks.

Philadelphia, May 18, 2021 - Many socioeconomically disadvantaged children face poor cognitive and mental health outcomes, and researchers are working to determine the specific factors that link childhood conditions to those poor outcomes, including how they might shape brain circuitry. In a new study, researchers have examined how "neighborhood disadvantage" can affect the developing brain, including the brain's connectivity between regions.

The study appears in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier.

Sarah Whittle, PhD, and Divyangana Rakesh, lead authors of the study, studied existing brain scans from 7,618 children aged 9-10 collected as part of the Adolescent Brain Cognitive Development (ABCD) Study. Previous studies have identified differences in some brain regions in disadvantaged children, but the current study used magnetic resonance imaging (MRI) to measure functional connectivity, or how well different regions of the brain are connected with one another, at rest.

Rather than considering a single measure of status such as household income, the new study classified children according to neighborhood disadvantage, which encompasses multiple risk factors such as pollution, crime, and access to lower-quality education and healthcare.

Dr. Whittle said the purpose of the study was to "inform us of the mechanisms through which disadvantage impacts children's development and functioning." The team also wanted to investigate the role of factors such as positive home and school environments that may help reduce the harmful effects of disadvantage.

Analysis of the brain scans revealed that, in children with higher scores reflecting greater disadvantage, functional connectivity was reduced both between and within several brain networks.

"Our findings suggest that growing up in a disadvantaged neighborhood indeed impacts the brain. Importantly, however, findings suggest that providing children with better home and school environments where they feel supported, receive positive feedback, and have opportunities to engage in different activities, can offset some of the negative effects of neighborhood disadvantage on children's brain development," Ms. Rakesh said.

The findings have policy implications in the context of designing interventions and policies targeted at youth and families exposed to disadvantage; they suggest a need to shift attention from a sole focus on family-level factors to community-level research and policies.

Cameron Carter, MD, Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, said of the study, "These remarkable results show that improvements in the home and school environments can mitigate against the otherwise deleterious effects of growing up in a disadvantaged setting, providing a powerful message for the importance of public policies that provide more support at home and at school."

EUGENE, Ore. -- May 19, 2021 -- High-resolution imaging of fruit flies at the University of Oregon has captured mechanical motions that stem cells use to make neurons, the cells that make up the brain.

These motions coordinate cell division with differentiation, where newly born cells become neurons. Differentiation is essential for building the brain circuitry in complex organisms that underlies human cognition and emotions, said Ken Prehoda, a professor in the UO's Department of Chemistry and Biochemistry.

Prehoda was principal investigator of a project published online May 18 in the journal Cell Reports.

Drosophila fly brains have some 100,000 neurons, while human brains have more than 50 billion. Developmental research in Drosophila often leads to advances in human medicine.

The discovery, Prehoda said, suggests that the mechanical process is vital to understanding brain development and, potentially, for regenerating neurons and their connections following injuries.

"To make so many neurons, the developing brain acts like a factory with individual stem cell 'machines' continually producing neurons," Prehoda said. "We discovered that stem cells have more in common with real machines on a factory floor than previously appreciated in that they undergo a mechanical cycle when producing each neuron."

In the project, Bryce LaFoya, a postdoctoral researcher in the UO's Institute of Molecular Biology, used spinning-disk confocal microscopy to examine fruit fly brains with their stem cell membranes embedded with fluorescent markers. That unveiled the membrane dynamics of neural stem cells and their progeny at high resolution, revealing the mechanical cycle as each neuron was produced.

To make neurons, Prehoda said, neural stem cells must place special molecules, proteins called fate determinants, into one of two daughter cells that result from division. How that was done had been unclear despite many previous studies of physical interactions in which fate determinants are involved.

In a 2019 study in the journal eLife, Prehoda and Krystal Oon, a graduate student in the Institute of Molecular Biology, reported that proteins undergo movements along the membrane, but what drove the movement was known.

"Mechanical forces within the cell segregate components that are responsible for cellular identity after division," LaFoya said. "After the cell divides in two, because of these forces, one cell will remain a stem cell while the other will go on to become a neuron."

The cellular-scale mechanical forces revealed in the imagery were so strong that surrounding cell membranes became highly distorted before returning to normal, Prehoda added. Understanding the process from beginning to end, he said, could have implications for regenerative therapies.

"Our results indicate that the neuroblast membrane plays a role in polarity initiation and maintenance," LaFoya and Prehoda wrote in their conclusion, describing the process that the neural stem cells use to make neurons.

A general practitioner, wife and mother has recounted her experience with COVID-19 which saw her stay in hospital 150 days and become one of the first patients to be treated with extracorporeal membrane oxygenation (ECMO), special equipment that completely takes over the function of the lungs and is a last resort option.

The self-written case report, which appears in the journal Anaesthesia Reports (a journal of the Association of Anaesthetists) is by Dr Anushua Gupta, who works as a general practitioner in Stockport, Greater Manchester, UK. It is thought to be the first patient-written account of ECMO to treat COVID-19 to appear in the medical literature.

Extracorporeal membrane oxygenation was introduced as a centrally commissioned NHS service following the H1N1 influenza pandemic ten years ago, and there are five centres that provide it in England. It involves the removal of deoxygenated venous blood, the addition of oxygen (and removal of carbon dioxide) outside the body and return of the now oxygenated venous blood to the patient. It requires specialist staff, advanced equipment and more space, yet it might provide more time for patients to potentially respond to treatment during the acute phase of their illness.

Dr Gupta explains: "I remained in hospital for 150 days, 34 of which I spent on ECMO. I have no recollection of my time on ECMO, but liberation from it was not the end of my story; I had to overcome numerous physical and mental challenges during recovery and rehabilitation. I hope my story is read by others who are recovering from COVID-19 or critical illness more generally, and that it provides hope that one can return towards a normal way of life and the challenges of rehabilitation can be overcome."

She was infected in the first wave of the pandemic, sometime during March 2020, around 2 weeks after her 40th birthday. On April 1, she was admitted to Wythenshawe Hospital, and on April 4 she suddenly deteriorated with severe breathlessness and due to low oxygen levels started to experience "visual hallucinations of a black-winged figure". She was transferred to ICU for tracheal intubation and mechanical ventilation, requiring a medically-induced coma with no guarantee of survival.

"My worst fears were coming true. I telephoned my husband Ankur, and asked to see our daughter Ariana - just 18 months old at that time - on a videocall, as I thought that I would never get to see her again," she recalls. "I feared that I would never get to fulfil the dream that my husband and I had of living into old age together. However, I had to remain composed for the sake of my husband, who likewise had to be strong for our daughter." She was sedated later that night, not knowing she would remain in a coma for the next two months.

It was sheer coincidence that the hospital where Dr Gupta was admitted is North West England's centre for ECMO, but her case had to be assessed on her chances of survival like any other patient. Doctors decided on April 13 to put her on ECMO, which was required for 34 days. On May 13, just 4 days before being weaned from ECMO, she began to show improvement. She went on to have a tracheostomy to help her breathing on May 23 and her sedatives were gradually reduced.

Dr Gupta then details her long battle to recover from the disease, both for the remaining time in hospital and after being discharged on September 1, 2020. "My daughter has been my driving force, underpinning my determination to get better. My husband, who held the fort when I was not there, has continued to support me in every way," she explains.

She suffered multiple lung complications, swallowing difficulties and completely lost her voice due to the length of time in ICU, which she has gradually recovered from thanks to extensive support from speech and language therapists, although she remains hoarse at times. She also explains that early on after the sedatives were weaned off, "I couldn't sit upright without support, I could not feed myself, brush my teeth or hair, wash myself or even hold a pen; like a baby in its first year of life. I had to be moved by hoist for two months despite being completely awake and alert. In that time, with immense input from the physiotherapy team, I mustered the physical and mental strength to slowly be able to pull myself to stand up using a special device called a rota stand. It took a further few weeks to progress to taking my first few steps. I learned that one can certainly not underestimate the vital role of rehabilitation following critical care."

She also received extensive psychological support to help deal with the anxiety of separation from her daughter and family, and also the trauma of her physical recovery, learning various coping strategies including meditation.

She concludes: "My recovery is by no means complete. I have significant changes to my lungs. It remains unknown whether those changes are reversible. I still get breathless, but this is improving, and my exercise tolerance is getting better too. I was suffering significantly with pains in multiple joints for many months. I feel this may well be what others have described as 'long-COVID'. However, this is also improving, and I am getting fitter and more active. My liver function has improved but is not quite normal. My mental health is much better. I try to keep a very positive outlook on life, and I feel like I have been given a second chance."

Researchers at Michigan Medicine found that people with venom allergies are much more likely to suffer mastocytosis, a bone marrow disorder that causes higher risk of fatal reactions.

The team of allergists examined approximately 27 million United States patients through an insurance database - easily becoming the nation's largest study of allergies to bee and wasp stings, or hymenoptera venom. The results, published in the Journal of Allergy and Clinical Immunology, revealed mastocytosis in fewer than 0.1% of venom allergy patients - still near 10 times higher than those without allergies.

"Even though there is mounting interest, mast cell diseases are quite understudied; there are probably many people who go through life as some sort of 'medical mystery,' unaware of that diagnosis," says lead investigator Charles Schuler, M.D., a clinical assistant professor of allergy and immunology at Michigan Medicine. "One way to find them is to find people with a venom allergy. This research strongly supports that and will help us more properly treat these patients."

A life-threatening reaction to a bee sting can often be the first manifestation of mastocytosis. It's the most common anaphylaxis trigger in that patient population.

While mastocytosis diagnoses are more prevalent in U.S. venom allergy patients, the numbers are significantly higher in Europe, says Cem Akin, M.D., senior author and clinical professor of allergy and immunology at Michigan Medicine.

"This suggests that there may be differences in sensitization patterns to bee and wasp venoms between Europe and the U.S.," Akin says. "However, the European numbers may be overestimated due to referral and patient selection bias, as most of the centers publishing on the topic are referral facilities for mastocytosis. While Michigan Medicine is one of the world's largest referral centers for mastocytosis, we also have a large population of patients we follow for venom allergy."

The study included a five-year analysis of patients with history of severe venom allergy who underwent venom desensitization immunotherapy at Michigan Medicine. The research team found that elevated levels of tryptase, a chemical secreted by allergy cells, may predict if a person is at higher risk for reaction to immunotherapy.

"This study helps us account for the side effects or adverse outcomes associated with our current therapy," Schuler says. "Knowing this, allergists can be more watchful during sessions and watch for systemic reactions."

This study started out as a Michigan Medicine quality assurance project, and the paper is now the most comprehensive analysis of incidence of hymenoptera venom allergy and mastocytosis in the country, says James Baldwin, M.D., chief of Michigan Medicine's division of allergy and clinical immunology.

"It creates a picture of the burden of these conditions," Baldwin says. "It will inform both future research and public policy decisions in the field moving forward."

When a person views a familiar image, even having seen it just once before for a few seconds, something unique happens in the human brain.

Until recently, neuroscientists believed that vigorous activity in a visual part of the brain called the inferotemporal (IT) cortex meant the person was looking at something novel, like the face of a stranger or a never-before-seen painting. Less IT cortex activity, on the other hand, indicated familiarity.

But something about that theory, called repetition suppression, didn't hold up for University of Pennsylvania neuroscientist Nicole Rust. "Different images produce different amounts of activation even when they are all novel," says Rust, an associate professor in the Department of Psychology. Beyond that, other factors—an image's brightness, for instance, or its contrast—result in a similar effect.

In a paper published in the Proceedings of the National Academy of Sciences, she and postdoctoral fellow Vahid Mehrpour, along with Penn research associate Travis Meyer and Eero Simoncelli of New York University, propose a new theory, one in which the brain understands the level of activation expected from a sensory input and corrects for it, leaving behind the signal for familiarity. They call it sensory referenced suppression.

The visual system

Rust's lab focuses on systems and computational neuroscience, which combines measurements of neural activity and mathematical modeling to figure out what's happening in the brain. One aspect relates to the visual system. "The big central problem of vision is how to get the information from the world into our heads in an interpretable way. We know that our sensory systems have to break it down," she says.

It's a complicated process, greatly simplified here for clarity: Information comes into the eye via the rods and cones. It travels neuron by neuron through a stack of brain areas that make up the visual system and finally to a visual brain area called the IT cortex. Its 16 million neurons activate in different patterns depending on what's being viewed, and the brain must then interpret the patterns to understand what it's seeing.

"You get one pattern for a specific face. You get a different pattern for 'coffee cup.' You get a different pattern for 'pencil,'" Rust says. "That's what the visual system does. It builds the world back up to help you decipher what you're looking at."

In addition to its role in vision, activation of the IT cortex is also thought to play a role in memory. Repetition suppression, the old theory, relies on the idea that there's an activation threshold that gets crossed: More neural activity tells the brain the image is novel, less indicates one that's previously seen.

Because several factors affect the total amount of neural activity, also called spikes, in the IT cortex, the brain can't discern what's specifically causing the reaction. It could be memory, image contrast, or something else altogether, Mehrpour says. "We propose a new idea that the brain corrects for the changes caused by these other factors, in our case contrast," he says. After that calibration, what remains is the isolated brain activation for familiarity. In other words, the brain understands when it is viewing something that it has previously seen.

Long-term implications

To draw this conclusion, the researchers presented sequences of grayscale images to two adult male rhesus macaques. Every image appeared exactly twice, the first time as novel, the second time as familiar, in a range of high- and low-contrast combinations. Each viewing lasted precisely half a second. The animals were trained to use eye movements to indicate whether an image was new or familiar, disregarding the contrast levels.

As the macaques performed this memory task, the researchers recorded neural activity in the IT cortex, measuring the spikes for hundreds of individual neurons, a unique method that differs from those that measure proxies of neural activity averaged across 10,000 neurons firing. Because Rust and colleagues wanted to understand the neural code, they needed information for individual neurons.

Using a mathematical approach, they deciphered the patterns of spikes that accounted for how the macaques could distinguish memory from contrast. This ultimately confirmed their hypothesis. "Familiarity and contrast both change the overall firing rate," Rust says. "What we're saying is the brain can tease apart and isolate one from the other."

In the future, better understanding this process could have applications for artificial intelligence, Mehrpour says. "If we know how the brain represents and rebuilds information in memory in the presence of changes in sensory input like contrast, we can design AI systems that work in the same way," he says. "We could potentially build machines that work in the same way that our brain does."

Beyond that, Rust says that down the line the findings could have implications for treating memory-impairing diseases like Alzheimer's. "By understanding how memory in a healthy brain works, you can lay the foundations to develop preventions and treatments for the memory-related disorders plaguing an aging population."

But for any of this to come to pass, it will be crucial to keep digging, she says. "To get this right, we have to understand the memory signal that's driving behavior." This work brings neuroscientists one step closer.

The combination of a carb-heavy diet and poor oral hygiene can leave children with early childhood caries (ECC), a severe form of dental decay that can have a lasting impact on their oral and overall health.

A few years ago, scientists from Penn's School of Dental Medicine found that the dental plaque that gives rise to ECC is composed of both a bacterial species, Streptococcus mutans, and a fungus, Candida albicans. The two form a sticky symbiosis, known scientifically as a biofilm, that becomes extremely virulent and difficult to displace from the tooth surface.

Now, a new study from the group offers a strategy for disrupting this biofilm by targeting the yeast-bacterial interactions that make ECC plaques so intractable. In contrast to some current treatments for ECC, which use antimicrobial agents that can have off-target effects, potentially harming healthy tissues, this treatment uses an enzyme specific to the bonds that exist between microbes.

"We thought this could be a new way of approaching the problem of ECCs that would intervene in the synergistic interaction between bacteria and yeast," says Geelsu Hwang, an assistant professor in Penn Dental Medicine and senior author on the study, published in the journal mBio. "This offers us another tool for disrupting this virulent biofilm."

The work builds off findings from a 2017 paper by Hwang and colleagues, including Hyun (Michel) Koo of Penn Dental Medicine, which found that molecules call mannans on the Candida cell wall bound tightly to an enzyme secreted by S. mutans, glycosyltransferases (Gftb). In addition to facilitating the cross-kingdom binding, Gftb also contributes to the stubbornness of dental biofilms by manufacturing gluelike polymers called glucans in the presence of sugars.

While some cases of ECC are treated with drugs that kill the microbes directly, potentially reducing the number of pathogens in the mouth, this doesn't always effectively break down the biofilm and can have off-target effects on "good" microbes as well as the soft tissues in the oral cavity.

Hwang and colleagues wanted to try a different approach that would directly target the insidious interaction between yeast and bacteria and opted to target the mannans in the Candida cell surface as a point of contact.

Using three different mannan-degrading enzymes, they applied each to a biofilm growing on a tooth-like surface in a human saliva medium and left it for five minutes. Following the treatment, they noted that the overall biofilm volume was reduced. Using powerful microscopy, they also observed drastic reductions in the biofilm thickness and interactions between bacteria and yeast. The pH of the surrounding medium was higher when exposed to the enzymes, indicating an environment that is not as acidic and thus less conducive to tooth decay.

They also measured how easy it was to break up the biofilm after treatment, using a device that applies a stress, akin to tooth brushing.

"The biofilm structure was more fragile after the enzyme treatment," Hwang says. "We were able to see that the biofilms were more easily removed."

To confirm the mechanism of their approach--that the mannan-degrading enzymes were weakening the binding between yeast and bacteria--the team used atomic-force microscopy to measure the bonds between Candida and Gftb. The therapy, they found, reduced this binding force by 15-fold.

Finally, they wanted to get a sense of how well-tolerated these enzymes would be when used in the oral cavity, especially since children would be the patient group targeted.

Applying the enzymes to human gingival cells in culture, they found no harmful impact, even when they used a concentrated form of the enzymes. In addition, they observed that the treatment didn't kill the bacteria or yeast, a sign that it could work even if the microbes developed mutations that would lend them resistance against other types of therapies.

The researchers kept the application time relatively short at five minutes though they hope to see activity in an even shorter time, like the two minutes that is recommended for tooth brushing. Hwang says they may consider a non-alcohol-based mouthwash with these enzymes added that could be used by children as a preventive measure against ECC.

The researchers hope to continue pursuing this possibility with additional follow up, including testing these enzymes in an animal model. With more successes, they aim to add another tool for fighting the public health threat of ECC.

In studying COVID-19 testing and positivity rates in West Virginia between March and September 2020, West Virginia University researchers found disparities among Black residents and residents experiencing food insecurity.

Specifically, the researchers found communities with a higher Black population had testing rates six times lower than the state average, which they argue could potentially obscure prevalence estimates. They also found that areas associated with food insecurity had higher levels of testing and a higher rate of positivity.

"This could mean that public health officials are targeting predominately rural areas to keep tabs on how the pandemic will unfold in isolated communities within higher food insecurity," said Brian Hendricks, a research assistant professor with the West Virginia University School of Public Health's Department of Epidemiology and Biostatistics.

Hendricks said a unique element of this research is the Census-level data. While there are 55 counties in West Virginia, there are 484 Census tracts, which allowed the researchers to hone in on individual communities, almost on a scale of 1 to 100. This allowed researchers to compare testing and positivity rates with demographic data such as income level, sex, race, etc. "This is community-level modeling," Hendricks said. "We're doing something at a very granular level. Most modeling is at a county-level or above."

Among tracts included in the spatial analysis, Hendricks and his team identified 14 Census tracts which had among the state's highest percent Black/African American populations and testing disparities (defined as one or less tests per 1,000 people), contained within the cities of Fairmont, Wheeling, Bluefield, Beckley, Huntington, Dunbar and Charleston. These findings are in line with the study's overall findings of more testing occurring in higher food insecure locations with lower percent of the population identifying as Black/African American.

Hendricks said the team wanted to look at rurality and racial disparities, as adverse impacts of socio-economic and racial inequalities are oftentimes worsened in rural areas. Rural communities often have less access to healthcare, higher levels of food insecurity and poverty, and observe overall higher prevalence of pre-existing conditions, which can impact severity of COVID-19 infection.

The researchers incorporated a measure called the area deprivation index, which is essentially a scoring comprised of 17 socio-economic indicators, which indicates the extent which a community is vulnerable compared to other communities in the state. In addition to income, the measure controls for percent blue collar workers, household crowding, households with plumbing and transportation, and etc.

Before the vaccine was readily available, social distancing was the major defense against the virus.

"However, not all communities can socially distance equally," Hendricks said. "That was the motivating fire behind this paper -- where are these disparities?"

Recognizing this issue early in the pandemic, the West Virginia National Guard, the West Virginia Department of Health and Human Resources, and local health departments began holding targeted testing events. A COVID-19 Advisory Commission on African American Disparities was also formed.

While rural Black/African Americans have historically utilized health care at lower rates than their white counterparts due to medical mistrust, access to care, and a myriad of other factors, the article concludes by stating further research is needed to determine the underlying barriers restricting coronavirus testing among Black communities, and to better understand the role food insecurity in isolated areas has on risk of COVID-19 infection.

"This paper is making traction, already informing what do we do next," Hendricks said. For example, a subsequent grant was awarded which focused on putting more testing in vulnerable communities.

Scientists have long thought that there was a direct connection between the rise in atmospheric oxygen, which started with the Great Oxygenation Event 2.5 billion years ago, and the rise of large, complex multicellular organisms.

That theory, the "Oxygen Control Hypothesis," suggests that the size of these early multicellular organisms was limited by the depth to which oxygen could diffuse into their bodies. The hypothesis makes a simple prediction that has been highly influential within both evolutionary biology and geosciences: Greater atmospheric oxygen should always increase the size to which multicellular organisms can grow.

It's a hypothesis that's proven difficult to test in a lab. Yet a team of Georgia Tech researchers found a way -- using directed evolution, synthetic biology, and mathematical modeling -- all brought to bear on a simple multicellular lifeform called a 'snowflake yeast'. The results? Significant new information on the correlations between oxygenation of the early Earth and the rise of large multicellular organisms -- and it's all about exactly how much O2 was available to some of our earliest multicellular ancestors.

"The positive effect of oxygen on the evolution of multicellularity is entirely dose-dependent -- our planet's first oxygenation would have strongly constrained, not promoted, the evolution of multicellular life," explains G. Ozan Bozdag, research scientist in the School of Biological Sciences and the study's lead author. "The positive effect of oxygen on multicellular size may only be realized when it reaches high levels."

"Oxygen suppression of macroscopic multicellularity" is published in the May 14, 2021 edition of the journal Nature Communications. Bozdag's co-authors on the paper include Georgia Tech researchers Will Ratcliff, associate professor in the School of Biological Sciences; Chris Reinhard, associate professor in the School of Earth and Atmospheric Sciences; Rozenn Pineau, Ph.D. student in the School of Biological Sciences and the Interdisciplinary Graduate Program in Quantitative Biosciences (QBioS); along with Eric Libby, assistant professor at Umea University in Sweden and the Santa Fe Institute in New Mexico.

Directing yeast to evolve in record time

"We show that the effect of oxygen is more complex than previously imagined. The early rise in global oxygen should in fact strongly constrain the evolution of macroscopic multicellularity, rather than selecting for larger and more complex organisms," notes Ratcliff.

"People have long believed that the oxygenation of Earth's surface was helpful -- some going so far as to say it is a precondition -- for the evolution of large, complex multicellular organisms," he adds. "But nobody has ever tested this directly, because we haven't had a model system that is both able to undergo lots of generations of evolution quickly, and able to grow over the full range of oxygen conditions," from anaerobic conditions up to modern levels.

The researchers were able to do that, however, with snowflake yeast, simple multicellular organisms capable of rapid evolutionary change. By varying their growth environment, they evolved snowflake yeast for over 800 generations in the lab with selection for larger size.

The results surprised Bozdag. "I was astonished to see that multicellular yeast doubled their size very rapidly when they could not use oxygen, while populations that evolved in the moderately oxygenated environment showed no size increase at all," he says. "This effect is robust -- even over much longer timescales."

Size -- and oxygen levels -- matter for multicellular growth

In the team's research, "large size easily evolved either when our yeast had no oxygen or plenty of it, but not when oxygen was present at low levels," Ratcliff says. "We did a lot more work to show that this is actually a totally predictable and understandable outcome of the fact that oxygen, when limiting, acts as a resource -- if cells can access it, they get a big metabolic benefit. When oxygen is scarce, it can't diffuse very far into organisms, so there is an evolutionary incentive for multicellular organisms to be small -- allowing most of their cells access to oxygen -- a constraint that is not there when oxygen simply isn't present, or when there's enough of it around to diffuse more deeply into tissues."

Ratcliff says not only does his group's work challenge the Oxygen Control Hypothesis, it also helps science understand why so little apparent evolutionary innovation was happening in the world of multicellular organisms in the billion years after the Great Oxygenation Event. Ratcliff explains that geologists call this period the "Boring Billion" in Earth's history -- also known as the Dullest Time in Earth's History, and Earth's Middle Ages -- a period when oxygen was present in the atmosphere, but at low levels, and multicellular organisms stayed relatively small and simple.

Bozdag adds another insight into the unique nature of the study. "Previous work examined the interplay between oxygen and multicellular size mainly through the physical principles of gas diffusion," he says. "While that reasoning is essential, we also need an inclusive consideration of principles of Darwinian evolution when studying the origin of complex multicellular life on our planet." Finally being able to advance organisms through many generations of evolution helped the researchers accomplish just that, Bozdag adds.

University of California scientists have discovered genetic data that will help food crops like tomatoes and rice survive longer, more intense periods of drought on our warming planet.

Over the course of the last decade, the research team sought to create a molecular atlas of crop roots, where plants first detect the effects of drought and other environmental threats. In so doing, they uncovered genes that scientists can use to protect the plants from these stresses.

Their work, published today in the journal Cell, achieved a high degree of understanding of the root functions because it combined genetic data from different cells of tomato roots grown both indoors and outside.

"Frequently, researchers do lab and greenhouse experiments, but farmers grow things in the field, and this data looks at field samples too," said Neelima Sinha, a UC Davis professor of plant biology and the paper's co-author.

The data yielded information about genes that tell the plant to make three key things.

Xylem are hollow, pipe-like vessels that transport water and nutrients from the roots all the way up to the shoots. Without transport in xylem, the plant cannot create its own food via photosynthesis.

"Xylem are very important to shore up plants against drought as well as salt and other stresses," said lead study author Siobhan Brady, a professor of plant biology at UC Davis.

In turn, without plant mineral transport in xylem, humans and other animals would have fewer vitamins and nutrients essential for our survival. In addition to some typical players needed to form the xylem, new and surprising genes were found.

The second key set of genes are those that direct an outer layer of the root to produce lignin and suberin. Suberin is the key substance in cork and it surrounds plant cells in a thick layer, holding in water during drought.

Crops like tomatoes and rice have suberin in the roots. Apple fruits have suberin surrounding their outer cells. Anywhere it occurs, it prevents the plant from losing water. Lignin also waterproofs cells and provides mechanical support.

"Suberin and lignin are natural forms of drought protection, and now that the genes that encode for them in this very specific layer of cells have been identified, these compounds can be enhanced," said study co-author Julia Bailey-Serres, a UC Riverside professor of genetics.

"I'm excited we've learned so much about the genes regulating this moisture barrier layer. It is so important for being able to improve drought tolerance for crops," she said.

Genes that encode for a plant's root meristem also turned out to be remarkably similar between tomato, rice, and Arabidopsis, a weed-like model plant. The meristem is the growing tip of each root, and it's the source of all the cells that make up the root.

"It's the region that's going to make the rest of the root, and serves as its stem cell niche," said Bailey-Serres. "It dictates the properties of the roots themselves, such as how big they get. Having knowledge of it can help us develop better root systems."

Brady explained that when farmers are interested in a particular crop, they select plants that have features they can see, such as bigger, more attractive fruits. Much more difficult is for breeders to select plants with properties below ground they can't see.

"The 'hidden half' of a plant, below ground, is critical for breeders to consider if they want to grow a plant successfully," Brady said. "Being able to modify the meristem of a plant's roots will help us engineer crops with more desirable properties."

Though this study analyzed only three plants, the team believes the findings can be applied more broadly.

"Tomato and rice are separated by more than 125 million years of evolution, yet we still see similarities between the genes that control key characteristics," said Bailey-Serres. "It's likely these similarities hold true for other crops too."