Why Obese Mothers Tend to Have Children With Susceptibility for Metabolic Diseases? (Biology)

 A Brazilian study published in the journal Molecular Human Reproduction helps understand why obese mothers tend to have children with a propensity to develop metabolic disease during their lifetime, as suggested by previous research.

According to the authors, “transgenerational transmission of metabolic diseases” may be associated with Mfn2 deficiency in the mother’s oocytes (immature eggs). Mfn2 refers to mitofusin-2, a protein involved in the regulation of vascular smooth muscle cell proliferation. It is normally found in the outer membrane of mitochondria, the organelles that supply cells with energy. A deficiency leads to mitochondrial swelling and dysfunction, as well as altering the expression of almost 1,000 genes in female gametes.

“A number of studies have found mitofusin-2 to be an important metabolic regulator. There’s evidence that weight gain leads to a reduction in levels of the protein in muscle and liver cells, both of which play a key role in regulating blood sugar levels. In the case of diabetics, its expression is reduced in these cells,” Marcos Chiaratti, a professor at the Federal University of São Carlos (UFSCar) and principal investigator for the study, which was supported by FAPESP, told Agência FAPESP.

In the recent publication, Chiaratti and his group report the results of experiments with mice genetically modified so as not to express Mfn2 only in oocytes. The Mfn2 deficiency was expected to affect their fertility, but this was not the case. However, their offspring gained more weight than the offspring of control animals and had become diabetic by the age of 9 months, despite being fed a standard diet.

To investigate the molecular mechanisms associated with this abnormal phenomenon, Chiaratti established a collaboration with researchers at the Center for Research on Redox Processes in Biomedicine (Redoxome) and the Obesity and Comorbidities Research Center (OCRC), both of which are Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP. Part of the study was conducted during the master’s research of Bruna Garcia at UFSCar’s Center for Biological and Health Sciences (CCBS), with Chiaratti supervising.

The first step was the identification of the type of dysfunction displayed by Mfn2-deficient oocytes on reaching the stage at which they are ready to be fertilized. The analysis showed a reduced number of mitochondria in these cells and a lower level of ATP (adenosine triphosphate), the molecule that serves as cell fuel.

The researchers also observed that oocyte mitochondria were more aggregated than normal, enlarged to twice the expected size, and further away from the endoplasmic reticulum, an organelle with which they need to interact to import calcium and other substances crucial to their functioning.

According to Chiaratti, one of the known roles of Mfn2 is ensuring that mitochondria stay in contact with the endoplasmic reticulum, a structure that participates in the synthesis and transport of several substances in cells. The results of the study suggest Mfn2 deficiency compromises interaction between the two organelles, impairing the functions of both in oocytes.

“There’s evidence that transgenerational transmission of diseases such as diabetes is associated with mitochondrial dysfunction and endoplasmic reticulum stress in oocytes. Our findings corroborate this hypothesis,” Chiaratti said. “Mfn2 deficiency appears to affect mitochondrial biogenesis [reducing the number of mitochondria] and the capacity of mitochondria to move about in the cytoplasm in order to meet cellular demand for energy.”

The next step consisted of characterizing the Mfn2-deficient oocyte’s transcriptome (the full range of messenger RNA molecules expressed) and comparing it with controls. Using RNA sequencing, the researchers found 517 genes that were less expressed in the genetically modified animals’ oocytes than in controls and 426 genes that were more expressed.

“We then set out to identify the signaling pathways that belonged to these differentially expressed genes. We found pathways associated with the functioning of the endoplasmic reticulum and mitochondria, as well as pathways associated with endocrine processes such as regulation of blood sugar,” Chiaratti said.

Alterations in offspring

Analysis of the offspring of genetically modified females focused on skeletal muscle and liver cells. The aim was to understand why these animals became diabetic even when fed a balanced diet. 

Neither muscle cells nor liver cells were found to be in endoplasmic reticulum stress, a condition characterized by an accumulation of proteins that impairs the organelle’s functioning, and no mitochondrial alterations were found in muscle cells. Liver cell mitochondria were moderately dysfunctional.

Because this alteration was not sufficient to explain the hyperglycemic phenotype of the offspring, the group decided to study insulin signaling in these animals, as insulin produced by the pancreas enables glucose to enter cells and thereby lowers the level of blood sugar.

Their analysis of pancreas cells showed that insulin production was normal, but the level of insulin in the bloodstream was reduced and the signal it normally sends to muscle and liver cells was weak. 

“In these two tissues, insulin causes a biochemical change in the protein Akt [protein kinase B]. The signal sent by insulin makes this molecule become phosphorylated [via addition of phosphate to the protein chain] and this triggers a cascade of biochemical reactions in the cell,” Chiaratti explained.

The results of these analyses, therefore, suggested that the offspring’s muscle and liver tissue received a small amount of insulin, even though the level of insulin production by the pancreas was normal. This raised the hypothesis, to be confirmed in future studies, that insulin was being broken down faster in the organism of these animals.

Next steps

To deepen their understanding of the molecular mechanisms that led to augmented weight gain and hyperglycemia in Mfn2-deficient pups, the researchers plan to repeat the experiment with some modifications. Mfn2-deficient females will be fed a high-calorie diet to exacerbate the effects of the deficiency in their offspring. 

“We also plan to investigate, in animals without any genetic modification, whether a high-calorie diet alone is sufficient to reduce Mfn2 expression and change the way mitochondria function and interact with the reticulum,” Chiaratti said.

The knowledge created by these studies, he added, is expected to permit the development of strategies to manipulate Mfn2 expression in the context of obesity and help prevent transgenerational transmission of metabolic diseases.

For Alicia Kowaltowski, a professor at the University of São Paulo’s Chemistry Institute (IQ-USP), a member of Redoxome and a co-author of the study, the results obtained so far show that a person’s diet and nutritional status influence mitochondrial shape, one of the factors that affect cellular physiology. Proteins that regulate mitochondrial morphology are therefore potential therapeutic targets and should be explored in future research.

“It should be stressed that we didn’t find significant alterations to the mitochondria in liver tissue even though the animals were diabetic. This accords with other studies showing that mitochondrial function in the liver is highly resilient,” Kowaltowski said. “In our view, there must be protection mechanisms in the liver, given its importance to the metabolism. When mitochondrial dysfunction appears in the liver, the reason is that metabolic syndrome has reached an advanced stage of development.”

Infertility and maternal inheritance

Funded by FAPESP via several projects (09/54035-4, 12/50231-6, 17/05899-2, 17/04372-0, 16/11935-9, 16/11942-5, 16/07868-4, 18/06119-3, and 10/51906-1), the study reported in the latest publication is part of a research line that aims to understand how mitochondrial alterations, including DNA mutations, are associated with infertility and transgenerational disease transmission.

“Previous research has shown that mitochondrial dysfunction can compromise egg fertility. We created two animal models with which to investigate this mechanism in more detail: in one we inhibited expression of mitofusin-1 in oocytes, and in the other, we inhibited expression of mitofusin-2,” Chiaratti said.

Mfn1 deficiency made females infertile, as reported in an article published in The Faseb Journal.

“In this earlier study we showed that oocyte-specific Mfn1 deletion altered the expression of 161 genes and affected several processes in oocytes, above all communication with ovarian cells,” Chiaratti said. “In the case of the Mfn2-deficient animals, we observed other alterations in oocytes and offspring, but fertility was not affected. Curiously, the effects of Mfn1 deletion were attenuated in oocytes when Mfn2 was simultaneously inhibited, suggesting that the action of Mfn1 occurs after that of Mfn2.”

The article “Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis” can be retrieved from: academic.oup.com/molehr/advance-article-abstract/doi/10.1093/molehr/gaaa071/5942688.

Featured image: The phenomenon may be associated with a deficiency of the protein mitofusin-2 in the mother’s eggs, which affects the shape and functioning of mitochondria. The finding was based on experiments with mice conducted at the Federal University of São Carlos and reported in the journal Molecular Human Reproduction (this image of a mitofusin-2 deficient egg shows mitochondria [stained green] to be fewer, more aggregated, and swollen than in controls / Marcos Chiaratti)

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Provided by FAPESP

LSD May Offer Viable Treatment for Certain Mental Disorders (Psychiatry)

McGill study a step in understanding the mechanism of psychedelics’ impact on brain and potential for therapeutic use.

Researchers from McGill University have discovered, for the first time, one of the possible mechanisms that contributes to the ability of lysergic acid diethylamide (LSD) to increase social interaction. The findings, which could help unlock potential therapeutic applications in treating certain psychiatric diseases, including anxiety and alcohol use disorders, are published in the journal PNAS.

Psychedelic drugs, including LSD, were popular in the 1970s and have been gaining popularity over the past decade, with reports of young professionals claiming to regularly take small non-hallucinogenic micro-doses of LSD to boost their productivity and creativity and to increase their empathy. The mechanism of action of LSD on the brain, however, has remained a mystery.

Studies in mice provide clues

To conduct their study, the researchers administered a low dose of LSD to mice over a period of seven days, resulting in an observable increase in the sociability of the mice. “This increased sociability occurs because the LSD activates the serotonin 5-HT_2A receptors and the AMPA receptors — which is a glutamate receptor, the main brain excitatory neurotransmitters — in the prefrontal cortex and also activates a cellular protein called mTORC 1,” explains Danilo De Gregorio, PharmD, PhD, who is a postdoctoral fellow in the Neurobiological Psychiatry Unit at McGill and the study’s first author. “These three factors, taken together, promote social interaction in mice, which is the equivalent of empathy and social behaviour in humans.”

The researchers note that the main outcome of their study is the ability to describe, at least in rodents, the underlying mechanism for the behavioural effect that results in LSD increasing feelings of empathy, including a greater connection to the world and sense of being part of a large community. “The fact that LSD binds the 5-HT_2A receptor was previously known. The novelty of this research is to have identified that the prosocial effects of LSD activate the 5-HT₂ receptors, which in-turn activate the excitatory synapses of the AMPA receptor as well as the protein complex mTORC1, which has been demonstrated to be dysregulated in diseases with social deficits such as autism spectrum disorder,” as specified by Prof. Nahum Sonenberg, Professor at the Department of Biochemistry of McGill University, world renowned expert in the molecular biology of diseases and co-lead author of the study.

Using the cutting-edge technique of optogenetics, a technique where genes for light-sensitive proteins are introduced into specific types of brain cells in order to monitor and control their activity precisely using light signals, the researchers observed that when the excitatory transmission in the prefrontal cortex is de-activated, the prosocial effect of LSD was nullified, highlighting the importance of this brain region on the modulation of the behavioural effects of LSD.

Moving forward to apply the findings to humans

Having found that LSD increases social interaction in mice, the researchers are hoping to continue their work and to test the ability of LSD to treat mutant mice displaying the behavioural deficits similar to those seen in human pathologies including autism spectrum disorders and social anxiety disorders. The hope is to eventually explore whether micro-doses of LSD or some novel derivates might have a similar effect in humans and whether it could also be a viable and safe therapeutic option.

“Social interaction is a fundamental characteristic of human behaviour,” notes the co-lead author Dr. Gabriella Gobbi, Professor in the Department of Psychiatry at McGill and psychiatrist at the McGill University Health Centre. “These hallucinogenic compounds, which, at low doses, are able to increase sociability may help to better understand the pharmacology and neurobiology of social behavior and, ultimately, to develop and discover novel and safer drugs for mental disorders.”

Featured image credit: gettyimages

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Reference: “Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission,” by D. De Gregorio, N. Sonenberg, G. Gobbi, et al, was published in PNAS on January 25, 2020. Doi: 10.1073/pnas.2020705118

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Provided by McGill University

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About McGill University

Founded in Montreal, Quebec, in 1821, McGill University is Canada’s top ranked medical doctoral university. McGill is consistently ranked as one of the top universities, both nationally and internationally. It is a world-renowned institution of higher learning with research activities spanning two campuses, 11 faculties, 13 professional schools, 300 programs of study and over 40,000 students, including more than 10,200 graduate students. McGill attracts students from over 150 countries around the world, its 12,800 international students making up 31% of the student body. Over half of McGill students claim a first language other than English, including approximately 19% of our students who say French is their mother tongue.

Extreme Black Holes Have Hair That can be Combed (Astronomy)

Black holes are considered amongst the most mysterious objects in the universe. Part of their intrigue arises from the fact that they are actually amongst the simplest solutions to Einstein’s field equations of general relativity. In fact, black holes can be fully characterized by only three physical quantities: their mass, spin and charge. Since they have no additional “hairy” attributes to distinguish them, black holes are said to have “no hair”: Black holes of the same mass, spin, and charge are exactly identical to each other.

Dr. Lior Burko of Theiss Research in collaboration with Professor Gaurav Khanna of the University of Massachusetts Dartmouth and the University of Rhode Island alongside his former student Dr. Subir Sabharwal discovered that a special kind of black hole violates black hole uniqueness, the so-called “no hair” theorem. Specifically, the team studied extremal black holes — holes that are “saturated” with the maximum charge or spin they can possibly carry. They found that there is a quantity that can be constructed from the spacetime curvature at the black hole horizon that is conserved, and measurable by a distant observer. Since this quantity depends on how the black hole was formed, and not just on the three classical attributes, it violates black hole uniqueness.

This quantity constitutes “gravitational hair” and potentially measurable by recent and upcoming gravitational wave observatories like LIGO and LISA. The structure of this new hair follows the development of a similar quantity that was found by Angelopoulos, Aretakis, and Gajic in the context of a simpler “toy” model using a scalar field and spherical black holes, and extends it to gravitational perturbations of rotating ones.

“This new result is surprising,” said Burko, “because the black hole uniqueness theorems are well established, and in particular their extension to extreme black holes. There has to be an assumption of the theorems that is not satisfied, to explain how the theorems do not apply in this case.” Indeed, the team followed on previous work by Aretakis, that found that even though external perturbations of extreme black holes decay as they do also for regular black holes, along the event horizon certain perturbation fields evolve in time indefinitely. “The uniqueness theorems assume time independence. But the Aretakis phenomenon explicitly violates time independence along the event horizon. This is the loophole through which the hair can pop out and be combed at a great distance by a gravitational wave observatory,” said Burko. Unlike other work that found hair in black hole scalarization, Burko noted that “in this work we were working with the vacuum Einstein theory, without additional dynamical fields that modify the theory and which may violate the Strong Equivalence Principle.”

The team used very intensive numerical simulations to generate their results. The simulations involved using dozens of the highest-end Nvidia graphics-processing-units (GPUs) with over 5,000 cores each, in parallel. “Each of these GPUs can perform as many as 7 trillion calculations per second; however, even with such computational capacity the simulations look many weeks to complete,” said Khanna.

Given the breakthrough nature of this work, it was published on 1/26/2021 in one of the top peer-reviewed physics journals, Physical Review D as a prestigious Letter. The published version may be found online at this location: DOI 10.1103/PhysRevD.103.L021502.

The research was partially funded by the National Science Foundation and the Office of Naval Research. Computational resources of UMass Dartmouth’s Center for Scientific Computing & Visualization Research (CSCVR) were utilized for the research work. The CSCVR promotes the mission of UMass Dartmouth by providing undergraduate and graduate students with high quality discovery-based educational experiences that transcend the traditional boundaries of academic field or department, and foster collaborative research in the computational sciences within the University and with researchers at other universities, National Labs, and industry. Khanna serves as the Director of the Center.

Featured image: Artist’s conception of a rotating black hole accreting matter via an accretion disk and emitting a jet. © NASA/JPL-Caltech

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Reference: Lior M. Burko, Gaurav Khanna, and Subir Sabharwal, “Scalar and gravitational hair for extreme Kerr black holes”, Phys. Rev. D 103, L021502 – Published 26 January 2021. https://doi.org/10.1103/PhysRevD.103.L021502

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Provided by Theiss Research

New study: Malaria Tricks the Brain’s Defence System (Medicine)

Malaria is one of the most common causes of death in children in Africa and is triggered by a small parasite that lives in the blood. When the parasite builds up in the blood vessels of the brain, it develops into one of the most dangerous forms of the disease, cerebral malaria. So far, it has been the understanding that the malaria parasite was not able to penetrate the actual brain tissue, but now researchers from the University of Copenhagen have found malaria parasites can do that and have mapped the mechanism they utilise.

Every year, more than 400,000 people die from malaria, the majority are children under the age of five years old, who die from a disease which affects more than 200 million people a year.

The most serious form of the disease is cerebral malaria which may cause severe neurological consequences and, in the worst-case scenario, result in death. The precise mechanism behind cerebral malaria has remained a mystery – until now, says a research group from the Department of Immunology and Microbiology at the University of Copenhagen.

‘In our study, we show that a certain type of the malaria parasite can cross the blood-brain barrier by utilising a mechanism that is also used by immune cells in special cases. It is a major breakthrough in the understanding of cerebral malaria, and it partly explains the disease process seen in brain infections’, says Professor Anja Ramstedt Jensen who, together with her colleague, Assistant Professor Yvonne Adams, has headed the study.

Malaria mimics immune cells

The blood-brain barrier is the guarding barrier between the brain´s blood vessels and the cells and other components that make up brain tissue. The barrier ensures that only certain molecules are allowed to pass through to the brain cells. It prevents harmful substances and microorganisms from crossing, but, in some cases, it allows the white blood cells which are an important part of our immune system to pass through.

‘The malaria parasite takes up residence in red blood cells. However, since red blood cells cannot cross the blood-brain barrier, it has so far been our understanding that malaria parasites could not enter into brain tissue. Now we can show that the parasite is able to mimic the mechanism that the immune system’s white blood cells use to cross the barrier, and we now know that this helps to explain the disease mechanism behind cerebral malaria’, says Anja Ramstedt Jensen.

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The blood-brain barrier

The barrier separates the brain tissue from the blood and is of great importance in maintaining a constant chemical composition in the brain, thus ensuring the best conditions for the function of the brain cells. It acts as a kind of border control that decides which molecules may enter into the brain. Water and oxygen can get through, as can other substances such as alcohol and coffee.

In fact, the barrier does its job so well that it is difficult to medicate in the brain. Thus, the vast majority of all drugs tested in connection with central nervous system disorders may not be allowed to cross the blood-brain barrier.

In response to cerebral malaria, the brain swells up. As the brain is encircled by the skull, it increases the pressure inside the brain, and the elevated pressure blocks the blood supply to the brain. The swelling of the brain can also prevent fluid from leaving the brain, which contributes to further swelling and, in some cases, to the death of the person.

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To investigate the mechanism behind cerebral malaria, the researchers have created a 3D model of the blood-brain barrier consisting of, among other things, brain cells which they have grown in cell culture. The method has so far been used in other contexts to study which drugs and peptides can cross the blood-brain barrier. But this is the first time the method has been used to study infections.

‘This is completely new knowledge within malaria research. Previously, we have only been able to study how red blood cells with the malaria parasite bind to brain cells, but not whether they can penetrate  brain cells’, says Assistant Professor Yvonne Adams.

Based on this new method, the researchers are now in the process of further studying the molecular details that explain how malaria parasites penetrate the so-called endothelial cells, which are the cells in the blood-brain barrier that allow or reject access of molecules to our brain tissue.

‘In addition, we are expanding our studies and the application of the method to other diseases such as Lyme disease, Borrelia, which is the most common cause of bacterial brain infection in Denmark and, among other things, causes meningitis and other forms of inflammation in the central nervous system’, says Anja Ramstedt Jensen.

Read the study ‘P. falciparum erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood-brain barrier in cerebral malaria’ here. The published study is supported by, among others, the Lundbeck Foundation.

Featured image credit: Colourbox

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Provided by University of Copenhagen

Myeloid Immune Cells in the Blood Tied to Severe COVID-19 (Medicine)

Individual variations in how the immune system responds to SARS-CoV-2 appear to impact the severity of disease. Researchers at Karolinska Institutet in Sweden have now been able to show that patients with severe COVID-19 have significantly elevated levels of a certain type of immune cells in their blood, called myeloid-derived suppressor cells. The study published in the Journal of Clinical Investigation may bring an increased understanding of how early immune responses impact disease severity.

Most individuals with COVID-19 develop mild to moderate symptoms and recover without needing hospital treatment. In severe cases, however, COVID-19 can lead to respiratory failure or even death. It is not yet known why the severity of disease varies so much between patients.

Researchers at Karolinska Institutet, Karolinska University Hospital, Stemirna Therapeutics in Shanghai, and Stanford University in the United States have now studied one type of immune cell, monocytic myeloid-derived suppressor cells, or M-MDSC, and their potential role in COVID-19.

Dampens T cell activity

T cells are part of the immune system and play an important part in the body’s protection against viral infections such as COVID-19. M-MDSCs have been shown to increase in other inflammatory conditions, and their suppressive effect on T cell activity has been established. The role of M-MDSC in respiratory infections, however, is largely unknown. Since low levels of T cells are a hallmark of COVID-19, it is of interest to understand the role of M-MDSCs in this disease.

The study consisted of 147 patients with mild to fatal COVID-19 who were sampled repeatedly from blood and the respiratory tract. These were then compared with patients with influenza and healthy individuals.

Unbalanced immune system

The results show that patients with severe COVID-19 have significantly elevated levels of M-MDSCs in blood compared with milder cases and healthy individuals. COVID-19 patients had fewer T cells in blood than healthy subjects, and they showed signs of impaired function.

The analysis also showed that the levels of M-MDSCs early in the course of disease seemed to reflect subsequent disease severity.

Anna Smed Sörensen, associate professor at the Department of Medicine, Solna, Karolinska Institutet. © Ulf Sirborn

“Our results help increase the understanding of what causes severe COVID-19 and is an important piece of the puzzle in understanding the connection between the early, innate immune system, which includes M-MDSC, and the later, adaptive immune system, which includes T cells. There is also a strong clinical connection, as you could potentially use the results to find new biomarkers for severe illness”, says Anna Smed Sorensen, associate professor at the Department of Medicine, Solna, Karolinska Institutet, and the study’s last author.

An inherent limitation of the study is the number of patients and amount of sample material that could be collected, why each sample was used as efficiently as possible.

“The next step in our research is to further study the connection between different parts of the immune system, such as M-MDSC, T cells, and antibodies”, says Anna Smed Sorensen.

The study was funded by the Swedish Research Council, the Swedish Heart-Lung Foundation, Bill & Melinda Gates Foundation, the Knut and Alice Wallenberg Foundation, and Karolinska Institutet. There are no reported conflicts of interest.

Featured image: Medical staff in protective glove holds hand over patients hand © gettyimage

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Reference: Sara Falck-Jones, Sindhu Vangeti, Meng Yu, Ryan Falck-Jones, Alberto Cagigi, Isabella Badolati, Bjorn Osterberg, Maximilian Julius Lautenbach, Eric Ahlberg, Ang Lin, Rico Lepzien, Inga Szurgot, Klara Lenart, Fredrika Hellgren, Holden Maecker, Jorgen Salde, Jan Albert, Niclas Johansson, Max Bell, Karin Lore, Anna Farnert, and Anna Smed Sörensen,  “Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity”, Journal of Clinical Investigation, 25 January 2021, doi: 10.1172/JCI44734.

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Provided by Karolinska Institutet

Vaccine Shows Potential Against Deadly Leptospirosis Bacteria (Medicine)

A potential vaccine protects hamsters and mice against death caused by multiple Leptospira species, and prevents kidney colonisation in mice.

Scientists have designed a single-dose universal vaccine that could protect against the many forms of leptospirosis bacteria, according to a study published today in eLife.

An effective vaccine would help prevent the life-threatening conditions caused by leptospirosis, such as Weil’s disease and lung haemorrhage, which are fatal in 10% and 50% of cases, respectively.

Leptospirosis is caused by a diverse group of spirochetes called leptospires. A broad range of mammals, including rats, harbour the bacteria in their kidneys and release them into the environment through their urine. Humans and animals can then get infected after coming into contact with contaminated water or soil. In addition to having a major impact on the health of vulnerable human populations, leptospirosis is an economically important animal health problem, making it a significant One Health challenge. This means that collaborative efforts are needed across disciplines and sectors to improve public health outcomes against leptospirosis infection.

The Leptospira family of bacteria is made up of 64 species with 300 different varieties (called serovars). This makes developing a vaccine challenging, because researchers need to find a common feature of the bacteria that will trigger an immune response.

“We have recently identified a novel protein called FcpA in the flagella of Leptospira which enables it to move and penetrate human and animal tissues,” explains first author Elsio Wunder Jr, Associate Research Scientist in Epidemiology (Microbial Diseases) at Yale School of Public Health, Yale University, New Haven, US. “With this study, we wanted to see whether using engineered Leptospira that lacks a functional FcpA molecule has the potential for a vaccine that could provide major public health benefit.”

The mutated FcpA Leptospira was tested as an attenuated vaccine – a live vaccine that cannot cause disease. After the vaccine was given to hamsters and mice, it disseminated throughout the body before being cleared within seven days in the hamsters and after two weeks in the mice. No traces of the mutated Leptospira could be detected in kidney tissue or blood after this time point, showing that the attenuated vaccine is cleared by the immune system before it results in disease or death.

To test whether the vaccine candidate could protect against all types of Leptospira infection, they tested a single dose of the mutant Leptospira and compared this against heat-killed Leptospira to see whether they could prevent infection and disease by a range of similar and different serovars. Immunisation with the heat-killed vaccine gave partial protection against similar serovars but not against different serovars of Leptospira. By contrast, the attenuated vaccine (mutated Leptospira) provided cross-protection against serovars belonging to three different species of Leptospira, which encompass the majority of serovars of importance to human and animal health.

Further analysis of the mice and hamsters after vaccination showed that they generated antibodies that recognised a wide range of proteins across the different species of Leptospira. Moreover, by studying the antibody response in detail, the team identified 41 different proteins that could be targets for future vaccines. The majority of these proteins (70%) looked similar across all 13 disease-causing species of Leptospira studied, suggesting they are likely to be important to the microbes’ survival and would make effective future vaccine candidates.

“In this proof-of-concept study, we have shown that a universal leptospirosis vaccine candidate can prevent both death and kidney colonisation in animal models,” concludes author Albert Ko, Department Chair and Professor of Epidemiology (Microbial Diseases) at Yale School of Public Health. “These findings take us one step closer to achieving the holy grail for the field, which is an effective vaccine that protects against the many Leptospira species and can be deployed as a broad solution to the human and animal health challenge caused by leptospirosis.”

Featured image: A microscopy image of Leptospira bacteria. Image credit: Wunder et al. (CC BY 4.0)

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Reference: Elsio A Wunder et al., “A live attenuated-vaccine model confers cross-protective immunity against different species of the Leptospira genus, Microbiology and Infectious Disease, 2021. DOI: 10.7554/eLife.64166

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Provided by eLife

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About eLife

eLife is a non-profit organisation created by funders and led by researchers. Our mission is to accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours. We aim to publish work of the highest standards and importance in all areas of biology and medicine, including Microbiology and Infectious Disease, while exploring creative new ways to improve how research is assessed and published. eLife receives financial support and strategic guidance from the Howard Hughes Medical Institute, the Knut and Alice Wallenberg Foundation, the Max Planck Society and Wellcome. Learn more at https://elifesciences.org/about.

To read the latest Microbiology and Infectious Disease research published in eLife, visit https://elifesciences.org/subjects/microbiology-infectious-disease.

Scientists Developed Energy Saving Ceramic Phosphors for High Power LED Systems (Material Science)

Materials scientists of Far Eastern Federal University (FEFU), in collaboration with an international research team, have advanced the design of composite ceramic materials (Ce3+:YAG-Al2O3), i.e. solid-state light converters (phosphors) that can be applied in-ground and aerospace technologies. The LED systems based on the developed materials to save 20-30 percent more energy compared to commercial analogues. A related article was published in Materials Characterization.

Over 15% of the total global electricity production or about $ 450 billion annually spent on lighting. According to the photonics development roadmap run in Russia, the development of LED technology with an efficiency of more than 150 lm/W will allow to release up to 30% of electricity by 2025.

Based on the developed ceramic light converters, it is possible to produce both compact energy-efficient white light-emitting diodes (wLEDs) and high-power (high brightness) systems. The new material is in demand for many photonic applications from portable projectors and endoscopes to laser TVs with a diagonal of more than 100 inches, lighting devices for auto and aircraft construction, megastructures, etc.

“The consumption of white LEDs is more than half of the total consumption of high brightness LEDs. Some peculiarities of the technology for the production of organic phosphors for modern commercial white LEDs lead to the quick aging of the light-emitting diode that loses brightness and quality of color rendering. We get around the problem by creating completely inorganic light converters in the form of composite ceramics based on yttrium aluminum garnet, activated by cerium ions Ce3+:YAG, and a thermally stable phase of aluminum oxide Al2O3”, says Anastasia Vornovskikh, a Junior Researcher at the REC for “Advanced Ceramic Materials” of the FEFU Polytechnic Institute (school, PI).

The new materials are characterized by high values of thermal strength and thermal conductivity, endure high pumping power, and generate bright white light without obvious thermal quenching of the photoluminescence intensity. This makes it possible to reduce the operating temperature of the LED device down to 120-70°C, more than 2 times in comparison with commercial samples of Ce3+:YAG.

“We synthesized materials by vacuum reactive sintering of initial oxide powders of aluminum, yttrium, cerium, and gadolinium. Particular attention we paid to the identification of the quantitative relationship between the main scattering centers that are residual pores and Al2O3 crystallites and the spectroscopic properties of ceramic phosphors. Our light converters meet all the requirements for new generation wLEDs. They have a long lifespan, high luminous efficacy and color rendering index while maintaining the requirements for the environmental friendliness and material dimensions”, says project manager Denis Kosyanov, Director of the REC for “Advanced Ceramic Materials”, of the Industrial Safety Department of FEFU PI.

In the study took part researchers from Far Eastern Federal University (FEFU); Shanghai Institute of Ceramics, the Shanghai Technological Institute, the University of the Chinese Academy of Sciences; Institute of Chemistry of the Far Eastern Branch of the Russian Academy of Sciences; Institute of Solid State Chemistry and Mechanochemistry of the Siberian Branch of the Russian Academy of Sciences.

This work was financially supported by the Russian Science Foundation (Project No. 20-73-10242).

Featured image: The microstructure of a composite ceramic phosphor, and the appearance of an LED device based on © Denis Kosyanov, FEFU

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Reference: D.Yu. Kosyanov, Xin Liu, A.A. Vornovskikh, A.A. Kosianova, A.M. Zakharenko, A.P. Zavjalov, O.O. Shichalin, V.Yu. Mayorov, V.G. Kuryavyi, Xinglu Qian, Jun Zou, Jiang Li, Al2O3-Ce:YAG and Al2O3-Ce:(Y,Gd)AG composite ceramics for high brightness lighting: Effect of microstructure, Materials Characterization, Volume 172, 2021, 110883, ISSN 1044-5803, https://doi.org/10.1016/j.matchar.2021.110883. (http://www.sciencedirect.com/science/article/pii/S1044580321000139)

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Provided by Far Eastern Federal University

Children Rely on What They Hear When Detecting Emotions (Psychology)

Children determine emotion through hearing rather than seeing, our researchers have found.

Children determine emotion through hearing rather than seeing, our researchers have found.

First-of-its-kind study

In a first-of-its-kind study, our Department of Psychology looked at how children pick up on the emotions of a situation.

They found that whilst adults prioritised what they see, young children overwhelmingly prioritised what they could hear, known as ‘auditory dominance’.

The findings could benefit both education professionals and parents currently managing home learning, by increasing their understanding of how young children pick up on what is going on around them.

It could also provide new avenues to understanding emotional recognition in children with developmental challenges such as autism.

Age and emotional assessment

Volunteers in three age categories (seven and under, eight to 11, and 18+) were shown pictures of humans, with faces blurred, and played human voices, which conveyed happy and fearful and sad and angry emotions.

The pictures and sounds were presented both on their own, and in corresponding and contrasting combinations, and the volunteers were asked what the over-riding emotion was in each.

The team found that adults based their emotional assessment on what they could see whereas young children relied on what they could hear.

Our researchers now plan to investigate whether young children still rely on what they can hear when they can see human facial expressions and when human voices are replaced with music conveying similar emotions.

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Reference: Paddy Ross, Beth Atkins, Laura Allison, Holly Simpson, Catherine Duffell, Matthew Williams, Olga Ermolina, Children cannot ignore what they hear: Incongruent emotional information leads to an auditory dominance in children, Journal of Experimental Child Psychology, Volume 204, 2021, 105068, ISSN 0022-0965, https://doi.org/10.1016/j.jecp.2020.105068. (http://www.sciencedirect.com/science/article/pii/S0022096520305221)

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Provided by Durham University

Researchers Discovers New Control Mechanism in the Innate Immune System (Biology)

Although the protein ITIH4 is found in large amounts in the blood, its function has so far been unknown. By combining many different techniques, researchers from Aarhus University have discovered that ITIH4 inhibits proteases in the innate immune system via an unknown mechanism. The research results have just been published in the prestigious scientific journal Science Advances.

Proteases are enzymes that cleave other proteins. Most often, proteases occur in cascade networks, where a particular event triggers a chain reaction in which several proteases cleave and thereby activate each other. Most well known is probably the coagulation cascade, which causes clotting of our blood when a vessel is punctured.

But a similar network of proteases called the complement system is found in our blood and tissues. Activation of the complement system leads to the elimination of disease-causing organisms, cancer cells, and our own dying cells. To prevent the complement system from attacking our healthy cells, it is kept under close control by proteins which inactivate the proteases after a short time; these control proteins are called protease inhibitors.

At the Department of Biomedicine at Aarhus University, Professor Steffen Thiel and PhD student Rasmus Pihl wanted to investigate which other proteins in our blood the so-called MASP proteases from the complement cascade interact with. With the help of the mass spectrometry group at the Department of Molecular Biology and Genetics at Aarhus University, led by Professor Jan J. Enghild, they found to their surprise that two MASP proteases formed a strong complex with the ITIH4 protein.

ITIH4 forms a complex with the MASP-1 and MASP-2 enzymes

“I was highly surprised when I saw the first data from our partners, showing that ITIH4 could form a complex with the MASP-1 and MASP-2 enzymes. At Biomedicine, we have been studying these two proteases for 25 years, and ITIH4 has simply never been on the radar. But it made good sense, as proteins similar to ITIH4 act as inhibitors of other proteases,” says Rasmus Pihl.

Rasmus and Steffen now began a systematic study of how ITIH4 affects MASP-1 and MASP-2. It turned out that when ITIH4 formed a complex with the MASP-1 and MASP-2 enzymes, these could still cleave small proteins, while large proteins could not be cleaved when ITIH4 inhibited MASP-1 and MASP-2.

Their colleagues Jan J. Enghild and Gregers R. Andersen at the Department of Molecular Biology and Genetics nearly fell out of their chair when they learned about their discovery.

Since the 1980s, researchers at the department have characterized another protease inhibitor called A2M exactly with this property. Had their colleagues at Biomedicine now discover that ITIH4 functions similar to A2M?

To characterize in detail how ITIH4 inhibits the MASP proteases, Rasmus Pihl isolated both free ITIH4 and ITIH4 bound to the MASP-1 protease. By the use of X-ray small-angle scattering and electron microscopy, these samples were studied by postdoc Rasmus Kjeldsen Jensen and Professor Gregers Rom Andersen at Molecular Biology and Genetics. They showed that ITIH4 makes contact with the MASP-1 protease via a so-called von Willebrand domain, which matched nicely with the results from the Department of Biomedicine. This is a completely new mechanism for inhibiting proteases, and entirely different from the way A2M inhibits proteases.

“There is very little knowledge about ITIH4, but it is known that under various pathological conditions, the protein can be cleaved. Our results show that such a cleavage is absolutely necessary for the way ITIH4 can function as an enzyme inhibitor,” explains Professor Steffen Thiel.”

Gregers Rom Andersen explains: “By using cryo-electron microscopy, we now try to understand in detail how ITIH4 inhibits MASP-1 and MASP-2 via this new inhibition mechanism. We already know that when ITIH4 is cleaved, it forms a complex with both MASP-1 and another ITIH4 molecule. We are very excited to see how it takes place.”

At one point, Winston Churchill expressed: “Men occasionally stumble over the truth, but most of them pick themselves up and hurry off as if nothing ever happened. “As a researcher, it is absolutely necessary to maintain curiosity. It is deeply fascinating to work with proteins and mechanisms that are completely new and undescribed. This also means that we do not know where we end up in terms of describing whether ITIH4 has a significance in connection with clinical situations,” says Steffen Thiel.

The new results have led to a grant from the Novo Nordisk Foundation to continue the collaboration between the two departments.

Featured image: Researchers from Aarhus University have discovered that ITIH4 inhibits proteases in the innate immune system via an unknown mechanism. Figure: Rasmus Kjeldsen Jensen.

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Reference: Rasmus Pihl, Rasmus K. Jensen, C. Poulsen, Lisbeth Jensen, Annette G. Hansen, Ida B. Thøgersen, József Dobó, Péter Gál, Gregers R. Andersen, Jan J. Enghild and Steffen Thiel, “ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism”, Science Advances, 2021. DOI: 10.1126/sciadv.aba7381

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Provided by Aarhus University