The fossils, belonging to an arthropod known as Leanchoilia, confirm the presence — predicted by earlier studies in genetics and developmental biology of insect and spider embryos — of an extreme frontal domain of the brain that is not segmented and is invisible in modern adult arthropods. Despite being invisible, this frontal domain gives rise to several crucial neural centers in the adult arthropod brain, including stem cells that eventually provide centers involved in decision-making and memory. This frontal domain was hypothesized to be distinct from the forebrain, midbrain and hindbrain seen in living arthropods, and it was given the name prosocerebrum, with “proso” meaning “front.”

Described in a paper published today in the journal Current Biology, the fossils provide the first evidence of the existence of this discrete prosocerebral brain region, which has a legacy that shows up during the embryonic development of modern arthropods, according to paper lead author Nicholas Strausfeld, a Regents Professor of Neuroscience at the University of Arizona.

“The extraordinary fossils we describe are unlike anything that has been seen before,” Strausfeld said. “Two nervous systems, already unique because they are identically preserved, show that half a billion years ago this most anterior brain region was present and structurally distinct before the evolutionary appearance of the three segmental ganglia that denote the fore-, mid- and hindbrain.”

The term ganglion refers to a system of networks forming a nerve center that occurs in each segment of the nervous system of an arthropod. In living arthropods, the three ganglia that mark the three-part brain condensed together to form a solid mass, obscuring their evolutionary origin as segmented structures.

Fossils of Brain Tissue are Extremely Rare

Discovered in deposits of the Kaili formation — a geological formation in the Guizhou province of southwest China — the fossilized remains of Leanchoilia date back to the Cambrian period, about 508 million years ago. The Kaili fossils occur in sedimentary rock that has high concentrations of iron, the presence of which probably helped preserve soft tissue, which subsequently was replaced by carbon deposits.

“The Kaili fossils open a window for us to glimpse the body plan evolution of animals that lived more than half a billion years ago,” said the paper’s first author, Tian Lan of the Guizhou Research Center for Palaeobiology at Guizhou University in China. “For the first time, we now know that arthropod fossils of the Kaili formation have the potential to preserve neural tissue that show us the primitive brain of the early stem arthropod existing at the dawn of the animal world.”

“Nervous systems, as other soft tissues, are difficult to fossilize,” added co-author Pedro Martinez of the Universitat de Barcelona and Institut Catalá in Barcelona, Spain. “This makes the study of the early evolution of neural systems a challenging task.”

The fossils also shed new light on the evolutionary origin of two separate visual systems in arthropod evolution: pairs of front-facing eyes or sideward looking eyes, the descendants of which are still present in species living today.

Many arthropods, including insects and crustaceans, have a distinct bilateral pair of faceted compound eyes and another set of less obvious eyes — with more primitive architecture — known as nauplius eyes, or ocelli. These are structurally similar to the principal eyes of spiders and scorpions. These simpler eyes correspond to the prosocerebrum’s forward eyes in Leanchoilia, in line with evidence obtained by previous studies analyzing gene expression patterns during embryonic development of living arthropods.

Leanchoilia‘s sideward eyes, on the other hand, relate to the protocerebrum, which is the segmental ganglion defining the arthropod forebrain, lying just behind the prosocerebrum. In living arthropods, the protocerebrum provides the compound eyes of insects and crustaceans, or the lateral single-lens eyes of arachnids, centipedes and millipedes. The visual centers serving those eyes also belong to the brain’s protocerebral region.

Strausfeld explained that in living arthropods, the protocerebrum, or forebrain, has incorporated — in a way, swallowed up — the ancient centers provided by the prosocerebrum, so that it is no longer discernible as a distinct anatomical entity.

The fossils are so well-preserved that they demonstrate that in addition to frontward eyes, the prosocerebrum has also given rise to ganglia associated with the labrum, or “upper lip,” of modern arthropods. The fossils also confirm an earlier hypothesis suggesting that the labrum must have originally evolved from the grasping appendages of Radiodonta, a group of stem-arthropods that were top predators during the Cambrian period.

“When compared with other, similar fossil material belonging to more advanced lineages, the organization of the Leanchoilia brain demonstrates that the ganglionic arrangement of the early brain underwent condensation and fusion of its components, which explains why in living species the prosocerebrum cannot be individually distinguished,” Strausfeld said.

Implications for Brain Evolution in Vertebrates

In addition to closing a century-old gap in the understanding of arthropod brain evolution, the findings have important implications for the early evolution of vertebrate brains, Strausfeld said.

Although simple, fishlike animals existed at the same time as these now-fossilized arthropods, there are no convincing fossils of their brains and, thus, neither fossil evidence nor anatomical evidence for a prosocerebrum in vertebrates. Yet, modern studies show that genes defining the fore- mid- and hindbrains of, for example, mice correspond to genes defining the three ganglionic divisions of the arthropod brain. And in vertebrates, certain crucial centers involved in decision making and in learning and memory have some genetic correspondences with the higher centers in the arthropod brain, which originated in the ancient arthropod prosocerebrum.

Thus, it is plausible that even earlier than the Cambrian period, possibly even before the evolution of segmentally organized body plans, the common ancestor of both vertebrates and invertebrates possessed basic circuits for simple cognition and decision making. And while an ancient prosocerebral-like brain might have been present in the very early ancestors of vertebrates, no such fossil has even suggested evidence for a discrete, nonsegmental domain.

“Nevertheless, one can reasonably speculate that vertebrates have embedded in their ‘modern’ brains parts of an ancient, non-segmented brain that has so far only been demonstrable in an early arthropod, such as Leanchoilia,” Strausfeld said.

Additional co-authors on the study are Yuanlong Zhao of the Guizhou Research Center for Palaeobiology at Guizhou University in Guiyang, China; Fangchen Zhao of the State Key Laboratory of Palaeobiology and Stratigraphy of the Chinese Academy of Sciences in Nanjing, China; and You He of Shanghai Synchrotron Radiation Facility.

Glial cells are support cells located throughout the brain and spinal cord. When those cells become cancerous, the resulting tumor is called a glioma. In dogs, gliomas are the second most common type of tumor in the central nervous system and represent about 35% of all intracranial cancers. Median survival time for dogs with glioma treated with radiation therapy ranges from nine to 14 months, which is similar to the 14 month median survival time for humans treated with a combination of surgery, radiation and chemotherapy.

There are three types of canine glioma: oligodendroglioma, astrocytoma or undefined glioma. Each of these subtypes can be further classified as low or high-grade based on certain microscopic features. Although glioma subtype and grade affect survival and treatment choice in humans, it is currently unknown whether the same is true for dogs.

Immunotherapy harnesses the power of the body’s immune system to attack cancer. Though immunotherapy has shown promise in certain types of cancers, it hasn’t been successful in glioma in humans, possibly because gliomas have been shown to suppress the immune system in order to facilitate tumor growth. Researchers are trying to better understand the interaction between glioma and the immune system with hopes of improving therapeutic outcomes.

“If we want to pursue immunotherapy for glioma, we first need to understand how these tumors interact with the immune system,” says Gregory Krane, first author of the research and a veterinary pathologist who recently received his Ph.D. from North Carolina State University. “There are many shared features between canine and human glioma, which makes researching the immune system in canine glioma a good approach to addressing questions about this cancer in both humans and dogs.”

The multi-institutional research team examined 73 different gliomas obtained from veterinary patients seen at the NC State College of Veterinary Medicine between 2006 and 2018. Utilizing immunohistochemical tagging and computerized image analysis, the team identified the numbers of each type of immune cell in each tumor: B lymphocytes, T lymphocytes, regulatory T lymphocytes (Tregs) and macrophages. The team found higher numbers of Tregs and polarized macrophages in high- versus low-grade tumors, but no differences for other immune cells between different tumor types or grades.

“Tregs inhibit aspects of the immune response,” Krane says. “In healthy individuals, this prevents autoimmune disease. But cancers can recruit and activate Tregs to prevent the immune system from attacking the tumor. We found that Tregs were more abundant in high-grade gliomas than in low-grade gliomas. We hypothesize that Tregs may be involved in glioma-mediated immunosuppression, although that will require further research.”

The research team also counted the number of macrophages in each tumor, which can be polarized to either end of a spectrum referred to as M1 or M2 polarization. In a general sense, M1-polarized macrophages are pro-inflammatory and anti-tumor, and M2-polarized macrophages are the opposite. They found that the macrophage population in high-grade gliomas tended to be polarized towards the M2 phenotype.

“These macrophage polarization data can expand the glioma immunosuppression hypothesis by providing another mechanism by which gliomas may suppress the immune system in the dog,” Krane says.

Krane is hopeful that this study may lead to a better understanding of how gliomas affect the immune system, and eventually to improved immunotherapies for glioma. “Using the dog as a preclinical model for understanding the immune response to glioma could lead to treatments that will help both dogs and people,” Krane says. “Though further work is needed, our data provide some support to utilize canine patients with glioma to evaluate therapies targeting Tregs or macrophage polarization designed for use in humans.”

The research was published online in July 2021 in Veterinary Pathology and was supported by the National Institute of Environmental Health Sciences’ National Toxicology Program (NIEHS/NTP), NC State’s College of Veterinary Medicine, and Charles River Laboratories. Christopher Mariani, associate professor of neurology at NC State and principal investigator of NC State’s Comparative Neuroimmunology and Neuro-oncology Laboratory, is corresponding author. Other NC State co-authors were associate professors of pathology David Malarkey and Debra Tokarz, and veterinary student Britani Rainess. Researchers from NIEHS/NTP, Charles River Laboratories, the University of Alabama at Birmingham, Cornell University and Integrated Laboratory Systems coauthored the work.

Story Source:

Materials provided by North Carolina State University. Original written by Tracey Peake. Note: Content may be edited for style and length.

The condition, which is now termed TBK1 deficiency, was previously known to scientists but its name, cause and treatment were identified for the first time in the study published August 6 in Cell.

The scientists reported that the absence of the protein, known as TBK1 (TANK-binding kinase 1), renders cells vulnerable to a jarring form of programmed cell death in response to TNF, but that this genetic defect can be effectively and quickly addressed by therapeutic agents that block the source of the inflammation.

Homozygous mutations in TBK1, which occur when copies of the aberrant gene encoding the protein are passed on by both parents, are extremely rare. Based on past studies in mouse models and human cell cultures, researchers assumed that these mutations would leave individuals susceptible to a wide range of viral infections. They found instead that none of the four people in the cohort they studied, ages 7 to 32, showed signs of inadequate antiviral immunity. Rather, they all suffered from a systemic autoinflammatory condition that resulted from a dysregulated response to TNF, an important protein involved in controlling inflammation and cell death.

“TBK1 signaling activates the body’s antiviral mechanisms to fight off infection and block different stages of viral replication, as well as control TNF-mediated inflammation,” says lead author Justin Taft, PhD, an investigator in the Department of Microbiology, the Precision Immunology Institute, and the Center for Inborn Errors of Immunity at the Icahn School of Medicine at Mount Sinai. “But if a mutation prevents expression of the TBK1 gene or disrupts its function, then cells become overly sensitive to TNF. And that can trigger a disproportionate amount of cell death, which sets off a violent cascade of debris from dying cells that inflames surrounding tissue and fuels the inflammation.”

By treating TBK1-deficient individuals with anti-TNF therapeutics, the Mount Sinai-led team confirmed its suspicions about the underlying biology of the genetically driven condition. “We have essentially defined a new disease and its associated mechanisms of autoinflammation, which previously were managed with steroid treatments, non-steroidal anti-inflammatory drugs, or other non-specific therapeutics clinicians deemed worth trying,” says Dusan Bogunovic, PhD, Director of the Center for Inborn Errors of Immunity; Associate Professor of Oncological Sciences, Microbiology, and Pediatrics; member of the Precision Immunology Institute and The Mindich Child Health and Development Institute; and senior author of the study. “We were able to target the condition directly and effectively with TNF inhibitors once we knew the causative factors of the inflammation. And the clinical improvement was quick and substantial.”

For Dr. Taft, the work of the global team of researchers underscores the power of the increasingly vital field of personalized medicine. “We started with four individuals who were known to have a homozygous TBK1 mutation, and did extensive lab work to determine how the defect could induce this autoinflammatory reaction,” says Dr. Taft. “And from the genetics we uncovered not only a plausible mechanism of the disease and new information around TBK1 biology, but identified a disease-specific treatment that significantly improves the autoinflammatory condition.”

In addition to Mount Sinai, the collaborative research effort included Erasmus University Medical Center in the Netherlands, Mayo Clinic, the National Human Genomic Research Institute, Imperial College London, SRCC Children’s Hospital and Jaslok and Breach Candy Hospitals in Mumbai, India, and Hacettepe University in Ankara, Turkey.

Devised by NTU researchers, the method produces a compound known as ‘urea’, which is a natural product found in the urine of mammals, and an essential compound for fertilisers that is mass-produced industrially to increase crop yields.

However, the current Haber-Bosch process used to make urea is energy-intensive, requiring temperatures of 500 degrees Celsius and pressures of two hundred times sea-level atmospheric pressure. It creates significant CO₂ emissions, contributing to approximately 2 per cent of global energy annually.

Seeking a more sustainable and energy-efficient method, the team found a way to greatly improve an existing alternative approach to urea production known as electrocatalysis — using electricity to drive chemical reactions in a solution.

Using the nanomaterial indium hydroxide as a catalyst, the researchers reacted nitrate and carbon dioxide and found that the process formed urea five times more efficiently than previously reported attempts using electrocatalysis, specifically by causing the chemical reaction to take place in a ‘highly selective’ manner.

Co-lead author of the study, Professor Alex Yan from the NTU School of Materials Science and Engineering (MSE) said, “Our method essentially manipulates the chemical reaction process to become ‘highly selective’. By picking a better catalyst, we helped the nitrate ions and carbon dioxide molecules to optimally position themselves to facilitate urea formation, while suppressing the creation of unnecessary by-products like hydrogen, leading to higher efficiency and better urea yields.”

The study findings are published in the peer-reviewed scientific journal Nature Sustainability in July, and the alternative urea production method has been patented by NTU.

This new method to produce urea may inspire the future design of sustainable chemistry approaches and contribute to ‘greener’ agricultural practices to feed the world’s growing population, say the research team.

The study reflects the university’s commitment to address humanity’s grand challenges on sustainability as part of the NTU 2025 strategic plan, which seeks to accelerate the translation of research discoveries into innovations that mitigate our impact on the environment.

Greener, simpler, and competitive with industrial methods

As a proof of concept, the scientists tested the efficiency of their devised method in the lab and found that the approach achieved a urea yield of 53.4 per cent, which is competitive with the current Haber-Bosch industrial method, that was first demonstrated in 1910.

The Haber-Bosch, a two-step thermal process, is fossil fuel reliant and can only happen at specific high temperatures, and high-pressure conditions. First, nitrogen and hydrogen are combined to make ammonia. Carbon dioxide is then bonded with it to make urea. By comparison, the new NTU approach is more environmentally friendly and simpler. It uses nitrate — a compound with bonds that require less energy to break — carbon dioxide, and hydrogen to directly trigger urea formation under room temperature.

The new method is simple enough to be adopted at both large and small scales, say the research team. The electrocatalytic device could be easily operated by farmers to generate their own urea for fertilisers. The method could also one day be powered entirely by renewable energy.

First author of the research, Dr Lyu Chade, Research Fellow from the NTU School of MSE said, “With advances in solar technology, we may potentially use sunlight to power the electrocatalysis process in future, which can further help lower global emissions.”

As the next steps, the research team is aiming to achieve even higher yield results and to refine the catalytic selectivity, by exploring catalysts that would trigger faster reactions. They also plan to find a way to power the process using solar energy and to create a prototype device to demonstrate scaled up urea production.

The international research team includes researchers from the University of Texas at Austin, University of Science and Technology of China and Harbin Institute of Technology, China.

“We met the challenge by creating all-new swabs, which were ready and clinically tested in just three weeks,” said Ramy Arnaout, M.D., D.Phil., Associate Professor of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, and Associate Director of the Clinical Microbiology Laboratories, Beth Israel Deaconess Medical Center (BIDMC).

“Handling crises successfully requires a different set of skills than the everyday,” said Dr. Arnaout. “Competition and secrecy are out. Cooperation and openness are in. Resolving the swab crisis was a case study in these and other valuable lessons.”

As the first wave of COVID-19 broke out across the United States, BIDMC, which had the largest in-house COVID-19 testing center in Boston, found themselves with only a week’s supply of swabs. “More manufacturing was the only lasting solution,” Dr. Arnaout said. He and his colleagues began reverse engineering swabs, to determine if they could make them from scratch.

Swabs must be engineered to be neither too stiff, nor too flexible, and must be individually packaged and sterile. BIDMC needed around ten thousand a week; the country needed roughly ten million.

The first week, group members floated, shot down, resurrected, and repurposed various ideas, said Dr. Arnaout. Ultimately, the team saw two options: to find a scalable means to assemble swabs, or else to “find a way to make a stripped-down swab in a single go, without the need for assembly.” 3D printing had “advantages in speed of development and in the variety of structures it can make.”

Dr. Arnaout had previously demonstrated that open and collaborative crowdsourcing is a viable route to solving complex computational problems, specifically his work in computational immunology. He put this lesson to work in the COVID crisis.

“We navigated our… networks, letting manufacturers know about the swab crisis and what we needed from them to solve it,” said Arnaout. “We set up a free publicly viewable knowledge base online in the form of a GitHub repository — a type of website usually used by software engineers to collaborate on coding projects — to share everything we knew with everyone who might want to know it. This was critical for lowering the activation energy for anyone who wanted to join the effort… By the end of the first week, prototypes were rolling in.”

Over the course of the second week, the team tested more than 150 prototypes. “We were giving manufacturers feedback and suggestions one day and receiving new prototypes the next,” Dr. Arnaout said. “We put our protocols and results online.”

The team spoke often with BIDMC’s Institutional Review Board, “whose help and quick feedback were indispensable for cutting through red tape,” Dr. Arnaout said. “We put our IRB-approved protocol online as well.” BIDMC’s technology ventures office assured the team that the evaluation and feedback they were providing to manufacturers would not constitute intellectual property, thereby avoiding any haggling over ownership, which could have wasted precious time.”

By the fourth week, the team had validated four prototypes for clinical use. By summer’s end, “millions of the swabs our coalition helped design, vet, and mass-produce had been sold and used for COVID-19 testing” across the United States and in Europe, Dr. Arnaout wrote.

That experience suggested five lessons:

1. Define the mission — “a simple, clear, and concrete unifying goal for the entire team,” said Dr. Arnaout.
2. Establish norms for behavior. At BIDMC, that took place “mostly via conversations, repetition of the main message and personal example,” said Dr. Arnaout. “Conversations often began or ended with an explicit acknowledgment of the temptation to go it alone… and a reminder that we were not going to give in to such temptation.”
3. Leverage expertise. “At BIDMC, the clinical trials office handled paperwork that the investigators would have handled themselves under normal circumstances.”
4. Practice open and clear communication, “by eliminating the friction of gatekeeping access to information,” said Dr. Arnaout.
5. Stay positive.

“Perhaps we all can take the opportunity afforded by this trying time to improve how we meet our everyday challenges,” said Dr. Arnaout. “By doing so, we might find ourselves further along, more capable, and better prepared for when the next crisis inevitably hits.”