Based on massive stimulation of the patient’s immune system, immunotherapies have saved many lives. Unfortunately, they are not without consequences. “When the immune system is activated so intensively, the resulting inflammatory reaction can have harmful effects and sometimes cause significant damage to healthy tissue,” says Mikaël Pittet, holder of the ISREC Foundation Chair in Onco-Immunology at UNIGE Faculty of Medicine Department of Pathology and Immunology and Centre for Translational Research in Onco-Haematology, and a member of the Swiss Cancer Centre Leman. “Therefore, we wanted to know if there are differences between a desired immune response, which aims to eliminate cancer, and an unwanted response, which can affect healthy tissue. The identification of distinctive elements between these two immune reactions would indeed allow the development of new, more effective and less toxic therapeutic approaches.”

Using liver biopsy samples from patients treated at the CHUV and the HUG who had suffered such toxic reactions, the scientists studied the cellular and molecular mechanisms at work to reveal similarities and dissimilarities.

A similar response, but with different cells

In an immunotherapy-related toxic response, two types of immune cells — macrophage and neutrophil populations — appear to be responsible for attacking healthy tissue, but are not involved in killing cancer cells. In contrast, another cell type — a population of dendritic cells — is not involved in attacking healthy tissue but is essential for eliminating cancer cells. “Immunotherapies can trigger the production of specialised proteins that alert the immune system and trigger an inflammatory response, explains Mikaël Pittet. In a tumour, these proteins are welcome because they allow the immune system to destroy cancerous cells. In healthy tissue, however, the presence of these same proteins can lead to the destruction of healthy cells. The fact that these inflammatory proteins are produced by such different cells in tumours and healthy tissue is therefore an interesting finding.”

Dendritic cells are very rare, whereas macrophages and neutrophils are much more common. Some macrophages are present in most of our organs from embryonic development stages and remain there throughout our lives. Contrary to what was previously thought, these macrophages do not necessarily inhibit inflammation but, stimulated by immunotherapies, can trigger a harmful inflammatory response in the healthy tissue where they reside, thus explaining why toxicity can affect different organs.

Neutralising neutrophils for a double benefit

When macrophages are activated by drugs, they produce inflammatory proteins. These in turn activate neutrophils, which execute the toxic reaction. “This opens the possibility of limiting immunotherapy’s side effects by manipulating neutrophils,” says Mikaël Pittet.

The research team confirmed their discovery by studying the immune reactions of mice whose cell activity was modulated with genetic tools. They were able to identify a loophole that could be exploited to eliminate these side effects. Indeed, neutrophils produce some factors that are important for the development of toxicity, including TNF-α, which could be a therapeutic target. TNF-α inhibitors are already used to modulate the immune response in people with arthritis and could perhaps be useful in the cancer setting to inhibit the toxic effects of neutrophils during immunotherapy. “Furthermore, inhibiting neutrophils could be a more effective way to fight cancer: in addition to triggering a toxic response, some of these cells also promote tumour growth. Thus, by managing to control them, we could have a double beneficial effect: overcome the toxicity in healthy tissues, and limit the growth of cancerous cells,” concludes Mikaël Pittet.

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Published in the Journal of Neuroscience, the finding that dopamine drives plasticity in the auditory pallium of zebra finches lays new groundwork for advancing the understanding of the functions of this neurotransmitter in an area of the brain that encodes complex stimuli.

“People associate dopamine with reward and pleasure,” says lead author Matheus Macedo-Lima, who performed the research in the lab of senior author Luke Remage-Healey as a Ph.D. student in UMass Amherst’s Neuroscience and Behavior graduate program. “It’s a very well-known concept that dopamine is involved in learning. But the knowledge about dopamine in areas related to sensory processing in the brain is limited. We wanted to understand whether dopamine was playing a role in how this brain region learns new sounds or changes with sounds.”

Studying vocal learning in songbirds provides insight into how spoken language is learned, adds behavioral neuroscientist Remage-Healey, professor of psychological and brain sciences. “It’s not just the songbird that comes up with this strategy of binding sounds and meaning using dopamine. There’s something parallel here that we ¬- as humans — are interested in.”

The research team conducted a range of experiments in vitro and in vivo, poking neurons under the microscope and in the brains of live birds that were watching videos and hearing sounds. Ultimately, the scientists obtained anatomical, behavioral and physiological evidence to support their hypothesis about the role of dopamine.

Using antibodies, the researchers showed that dopamine receptors are present in many types of neurons in the songbird auditory brain ¬- they can be inhibitory or excitatory and may also contain an enzyme that produces estrogens. “Dr. Remage-Healey’s research has shown that in the auditory brain of songbirds of both sexes, neurons produce estrogen in social situations, like when listening to birdsong or seeing another bird. We think that dopamine and estrogens might be working together in the sound learning process, but this work focused on dopamine because there was still so much we didn’t know about how dopamine affected the songbird brain,” explains Macedo-Lima, now a postdoctoral associate at the University of Maryland.

Macedo-Lima developed a test, similar to the well-known Pavlov’s dog experiment, in which the birds sat alone in a chamber and were presented with a random sound followed immediately by a silent video of other birds. “We wanted to focus on the association between a meaningless sound — a tone — and the behaviorally relevant thing, which is another bird on video,” he says.

The researchers looked at the birds’ auditory brain regions after this sound-video pairing, using a gene marker known to be expressed when a neuron goes through change or plasticity. “We found this very interesting increase in this gene expression in the left hemisphere, the ventral part of the auditory region, in dopamine receptor-expressing neurons, reflecting the learning process, and paralleling human brain lateralization for speech learning,” Macedo-Lima says.

To show the effect of dopamine on the basic signaling of neurons, the researchers used a whole cell patch clamp technique, controlling and measuring the currents the neurons received. They found in a dish that dopamine activation decreases inhibition and increases excitation.

“This one modulator is tuning the system in a way that ramps down the stop signals and ramps up the go signals,” Remage-Healey explains. “That’s a simple yet powerful control mechanism for how animals are potentially encoding sound. It’s a neurochemical lever that can change how stimuli are registered and passed on in this part of the brain.”

The team then painlessly probed the brain cells of live birds. “What happened when we delivered dopamine was exactly as we were predicting from the whole cell data,” Macedo-Lima says. “We saw that inhibitory neurons fired less when we delivered the dopamine agonist, while the excitatory neurons fired more.”

The same effect occurred when the birds were played birdsong from other songbirds — the excitatory neurons responded more and the inhibitory neurons responded less when dopamine activation occurred. “We were happy to replicate what we saw in a dish in a live animal listening to actual relevant sounds,” Macedo-Lima says.

Dopamine activation also made these neurons unable to adapt to new songs presented to the animal, which strongly corroborates the hypothesis of dopamine’s role in sensory learning. “We currently don’t know how dopamine affects sensory learning in most animals,” Macedo-Lima says, “but this research gives many clues about how this mechanism could work across vertebrates that need to learn complex sounds, such as humans.”

Fossil fuels could be replaced by hydrogen, though, a versatile energy medium that in addition is able to be stored extremely well at low temperatures. “Our idea was therefore to use solar modules to produce climate-neutral hydrogen on site during the Antarctic summer by splitting water into hydrogen and oxygen through electrolysis,” says May, then a postdoc at the Helmholtz-Zentrum Berlin Institute for Solar Fuels. Rehfeld and May applied for funding from the Volkswagen Foundation to investigate whether hydrogen can be generated using sunlight even at sub-zero temperatures, and which method is best suited for this. Low temperatures can considerably reduce the efficiency of electrolysis, though cold actually increases the efficiency of most solar modules.

May and his HZB colleague, Moritz Kölbach, have now empirically compared two different approaches: a conventional setup in which the photovoltaic module is thermally and physically separated from the electrolysis tank, and a newer, thermally coupled setup in which the photovoltaic module is in close contact with the wall of the electrolysis tank, promoting thermal diffusion. To simulate Antarctic conditions, Kölbach obtained a freezer, cut a hole in the door, installed a quartz window, and illuminated the inside of the cabinet with simulated sunlight. He filled the electrolysis container with 30 per cent sulphuric acid (also known as battery acid) that has a freezing point around -35 degrees Celsius and conducts electricity well.

Kölbach then set up the experimental cells, and carried out the series of measurements. During operation, it became apparent that the cell with the thermally coupled PV modules produced comparatively more hydrogen, since the illuminated PV modules pass their waste heat directly to the electrolyser. “We were even able to increase the efficiency by adding additional thermal insulation to the electrolyser. As a result, the electrolyte temperature climbed during illumination from -20 to as high as +13.5 degrees Celsius,” says Kölbach.

The results of this study confirm that thermally coupled systems have potentially higher efficiency than thermally decoupled ones. Whether these advantages can be exploited economically, however, remains to be seen. “Therefore, in the next phase we want to test prototypes under realistic conditions. That will certainly be exciting and we are currently looking for partners for this,” says May.

Locally generated solar hydrogen could be an option for replacing fossil fuels and eliminating the associated pollution danger to the environment and CO₂ emissions, not only at the South Pole, but also in other extremely cold and sparsely populated regions of the world. This could include the high Alps, Canada and Alaska, the Andes, and other mountainous regions like the Himalayas.

“Perhaps solar-generated hydrogen will be economically viable initially in these kinds of remote regions of the world,” says May, recalling the triumphant advance of photovoltaics, which first began supplying power to satellites in space about 60 years ago.

Nitrogen dioxide (NO₂) and fine particulate matter less than 2.5 micra in diameter (PM2.5) are two of the main pollutants related to air pollution and vehicle traffic. PM2.5 particles for example are very fine and easily enter the respiratory tract. “In this work we specifically analysed the effect of maternal exposure to these fine particles and to nitrogen dioxide during pregnancy and the link existing with thyroxine levels in newborn babies. We have been monitoring on a weekly basis, as the development of the fetus varies greatly from one week to the next. So we tried to conduct the most detailed research possible in order to find out which the most sensitive weeks of pregnancy are,” added the UPV/EHU researcher.

So the sample of the INMA (Environment and Childhood) project in Gipuzkoa was analysed. Data on the air pollutants PM2.5 and NO₂, data on TSH and T4 levels from neonatal heels, etc. collected in the project were also used.

According to Amaia Irizar, “the results obtained in this study have revealed the direct relationship between exposure to fine particles during pregnancy and the level of thyroxine in newborns. However, we have not observed a clear link with exposure to nitrogen dioxide.” These results therefore coincide with the limited previous research. “What we have seen in this work,” stressed Irizar, “is that exposure during the first months of pregnancy has a direct influence on the balance of thyroid hormones. These babies tend to have a lower level of thyroxine. As the pregnancy progresses, we found that this relationship gradually diminishes, i.e. the mother’s exposure gradually becomes less important. In late pregnancy, however, this link becomes apparent again, but displays an opposite effect: as the concentration of these fine particles increases, we have seen that the level of thyroid hormones also increases, which has the opposite effect on the balance.” “It is not clear what mechanism lies behind all this. In any case, we have come to the conclusion that the most sensitive periods of pregnancy in terms of atmospheric pollution are the early and late months,” the UPV/EHU researcher stressed.

“The next task would be to study the mechanisms by which these fine particles cause opposing effects in early and late pregnancy. In fact, these particles are nothing more than small spheres made up of carbon, and it is not clear whether the effect these spheres exert is because they pass from the placenta to the baby, whether other components attached to the particles are released once they have entered the body…,” she explained. “We need to continue to investigate whether exposure during pregnancy affects not only thyroid hormones, but also other aspects such as neuropsychological development, growth, obesity, etc.,” explained Amaia Irizar.

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Plants, algae and cyanobacteria convert carbon dioxide and water into biomass and oxygen with the aid of photosynthesis. This process forms the basis of most forms of life on Earth. Global warming is exposing photosynthetic organisms to increasing levels of stress. This reduces growth rates, and in the longer term presents a threat to food supplies for human populations. An international project, in which Ludwig-Maximilians-Universitaet (LMU) in Munich biologist Kärin Nickelsen and his research group played a significant role, has now determined the three-dimensional structure of a protein involved in the formation and maintenance of the membranes in which photosynthesis takes place. The insights provided by the study will facilitate biotechnological efforts to boost the ability of plants to cope with environmental stresses.

The initial steps in photosynthesis take place within the ‘thylakoid’ membranes, which harbor pigment-protein complexes that absorb energy from sunlight. It has been known for decades that, in virtually all photosynthetic organisms, a protein called VIPP1 (which stands for ‘vesicle-inducing protein in plastids’) is indispensable for the assembly of thylakoids. “However, how VIPP1 actually performs this essential function has remained enigmatic up to now,” says Steffen Heinz, a postdoc in Nickelsen’s group and joint first author of the new publication. Thanks to the new study, which was led by the Helmholtz Zentrum München, researchers now know a great deal more.

Assembly of photosynthetic membranes

The team used cryo-electron microscopy to determine the three-dimensional structure of VIPP1 at high resolution. Analysis of this structure, in combination with functional investigation of the protein’s mode of action, demonstrated how small numbers of VIPP1 molecules form short strands, which are interwoven to form a basket-like structure. This then serves as a scaffold for the assembly of the thylakoid membrane, and determines its curvature. Using a related technique known as cryo-electron tomography, the scientists were also able to image VIPP1 membranes in their natural state in algal cells. By introducing site-specific mutations into VIPP1, they showed that the interaction of VIPP1 with thylakoid membranes is vital for the maintenance of their structural integrity under high levels of light stress. This finding demonstrates that the protein not only mediates the assembly of thylakoids, but also plays a role in enabling them to adapt to environmental fluctuations.

The results provide the basis for a better understanding of the mechanisms that underlie the formation and stabilization of thylakoids. They will also open up new opportunities to enhance the ability of green plants to withstand extreme environmental stresses.

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Materials provided by Ludwig-Maximilians-Universität München. Note: Content may be edited for style and length.

During the course of evolution, animals have adapted to the particular demands of their local environments in ways that increased their chances of survival and reproduction. This is also true of diverse aspects of the sensory systems that enable species to perceive their surroundings. In the case of the visual system, these adaptations have shaped features such as the positioning of the eyes and the relative acuity of different regions of the retina.

However, our knowledge of the functional evolution of visual systems in mammals has remained relatively sparse. “In the past 10 or 15 years, the mouse has become the favored model for the investigation of the processing of visual information,” says Professor Laura Busse of the Department of Biology II at Ludwig-Maximilians-Universitaet (LMU) in Munich. “That’s a somewhat surprising development, given that it was previously thought that these rodents primarily sensed the world using their whisker system and smell.” However, color vision in mammals is known to have an effect on the ability to find food, evade predators, and choose mating partners.

“It occurred to us that we don’t really know how mice perceive their natural environment visually,” says Busse, who is a member of the transregional Collaborative Research Center (CRC) 1233 on “Robust Vision.” Here, the term “robust” refers the fact that animals (including humans) are able to draw inferences from limited amounts of visual information, even in environments that are constantly changing. Busse decided to close this gap by studying the visual input and the processing of neuronal signals in mice,” In collaboration with Professor Thomas Euler of Tuebingen University, the Coordinating University of the CRC.

A camera that captures the mouse’s view

Mice are dichromate — in other words, they have two types of cone cells (the photoreceptors that are responsible for color vision) in their retinas. These cells detect electromagnetic radiation in the green and ultraviolet regions of the spectrum, centered on wavelengths of 510 nanometers (nm) and 350 nm, respectively. “We wanted to know what range of color information is available to mice in their natural habitats, and whether the prevalence of these colors can explain the functional characteristics of the neural circuits in the mouse retina,” Busse explains.

Together, the teams in Munich and Tuebingen set out to develop an low-cost, open-source camera which, unlike conventional cameras, was specifically designed to cover the spectral regions in the green and ultraviolet to which the mice retina is sensitive. To facilitate its use in the field, the hand-held camera is equipped with a gimbal, which automatically orients the picture frame, thus avoiding sudden, unintentional shifts in perspective.

The researchers used this camera to image the environment as it would appear to a mouse, at different times of the day, in fields that showed clear signs of their presence. “We knew that the upper hemisphere of the mouse retina, with which they can see the sky, is especially sensitive to UV light,” says Busse. “The lower half of the mouse retina, which is normally oriented towards the ground, shows a higher sensitivity in the green region. The team confirmed that these two spectral ranges closely match the color statistics of the natural environments that are favored by mouse populations. This adaptation could be a result of evolutionary processes — and for example help the animal to perceive birds of prey in the sky — and take evasive action. Experiments using artificial neural nets that mimic the processing characteristics of cone cells in the mouse retina confirm this conjecture.

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“Despite the headlines, there is no scientific evidence that shows that smartphones and digital technology harm our biological cognitive abilities,” says the UC professor of philosophy and psychology who recently co-authored a paper stating such in Nature Human Behaviour.

In the paper, Chemero and colleagues at the University of Toronto’s Rotman School of Management expound on the evolution of the digital age, explaining how smart technology supplements thinking, thus helping us to excel.

“What smartphones and digital technology seem to do instead is to change the ways in which we engage our biological cognitive abilities,” Chemero says, adding “these changes are actually cognitively beneficial.”

For example, he says, your smart phone knows the way to the baseball stadium so that you don’t have to dig out a map or ask for directions, which frees up brain energy to think about something else. The same holds true in a professional setting: “We’re not solving complex mathematical problems with pen and paper or memorizing phone numbers in 2021.”

Computers, tablets and smart phones, he says, function as an auxiliary, serving as tools which are good at memorization, calculation and storing information and presenting information when you need it.

Additionally, smart technology augments decision making skills that we would be hard pressed to accomplish on our own, says the paper’s lead author Lorenzo Cecutti, a PhD candidate at the University of Toronto. Using GPS technology on our phones, he says, can not only help us get there, but lets us choose a route based on traffic conditions. “That would be a challenging task when driving round in a new city.”

Chemero adds: “You put all this technology) together with a naked human brain and you get something that’s smarter…and the result is that we, supplemented by our technology, are actually capable of accomplishing much more complex tasks than we could with our un-supplemented biological abilities.”

While there may be other consequences to smart technology, “making us stupid is not one of them,” says Chemero.

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Materials provided by University of Cincinnati. Original written by Angela Koenig. Note: Content may be edited for style and length.