Human pluripotent stem cells (PSCs) are a useful tool for researchers investigating how cells specialise to make every tissue of our body. They come in two different states, primed and naïve. Both types of PSC can self-renew and differentiate into new cell types but they have distinct functions and molecular characteristics.

Group leader Peter Rugg-Gunn explained the importance of these cells: “Human PSCs in the naïve state replicate the key molecular and cellular characteristics of cells in a pre-implantation stage embryo. Importantly, when naïve PSCs are encouraged to self-organise in particular conditions, they form structures that resemble an early blastocyst stage of development. By growing these cells in the lab, we can learn about the key events that happen during human development, and they have potential uses in personalised medicine. But we need to create high-quality, stable stem cell populations to be able to conduct our experiments.”

Pluripotent stem cells are formed either from embryos or using Nobel Prize-winning methods to remove cell identity from specialised cells. The majority of reprogramming experiments generate primed PSCs, which are more developmentally advanced than naïve PSCs. Naïve PSCs can be collected directly from human pre-implantation embryos, or more commonly researchers expose primed PSCs to conditions that induces them to become naïve PSCs. Existing methods for reprogramming were inefficient and slow, preventing researchers’ from quickly producing the numbers of high-quality stem cells they needed.

Adam Bendall, PhD student and a lead researcher on the study, said: “Very little was known about what genetic and epigenetic factors are required for naïve cell reprogramming, and this knowledge gap limited the design of reprogramming conditions.”

The low efficiency of naïve reprogramming suggests the presence of barriers that limit cells in reaching the naïve state. Adam and his colleagues honed in on these barriers by performing a large-scale genetic screen to identify genes that hinder and help reprogramming. They were able to identify a large number of genes that have a crucial role in naïve PSC programming that had not been previously linked to the process.

The team focused on one epigenetic complex in particular, the PRC1.3 complex, that regulates gene expression without altering the underlying DNA sequence, and which they found to be essential for the formation of naïve PSCs. Without this complex, the cells undergoing reprogramming become a completely different type of cell rather than naïve PSCs. This suggests that the activity of PRC1.3 could encourage more cells to reprogram properly, in effect lowering the barrier.

After identifying factors that promote reprogramming, the researchers also looked at factors that impede reprogramming, exemplified in their study by an epigenetic protein called HDAC2. Dr Amanda Collier, first author on the paper, explained: “Excitingly, when we inhibited one of these factors using selective chemicals, then naïve PSC reprogramming occurred more efficiently and rapidly. We’re able to look at it from both sides; we can remove the barriers and introduce the factors that push cells towards state change.”

Not only does this research improve scientists’ ability to produce human naïve PSCs, it provides details on the molecular events that occur during the cell state transition itself, some of which are conserved in developmental regulation in human embryos.

The Rugg-Gunn lab are putting together the pieces of a bigger puzzle — the best understanding of the formation and control of naïve stem cells. Their previous research has identified molecular factors that help to maintain cells in a naïve stage. Group leader, Peter Rugg-Gunn said: “By building up our tools for manipulating pluripotent stem cells, we can spend more time asking important questions about the pre-implantation embryo. In the longer term, further improvements in working with naïve PSCs might open up the possibility for using these cells in personalised disease models or cell therapies, although this will require more research on how to differentiate naïve PSCs into specialised cell types.”

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Materials provided by Babraham Institute. Note: Content may be edited for style and length.

Anyone who enjoys reading thrillers knows: Before thieves break into a mansion, they like to toss a juicy chop over the fence, in which they have hidden a few sleeping pills. When the watchdogs get down to their second dinner, they succumb to deep slumber shortly thereafter. The jewels of the lady of the house change hands much more unperturbed after that.

Tumor cells often proceed in a very similar way: They cast out sleeping pills that paralyze the immune system. More specifically, they surround themselves with a cloud of adenosine, an important endogenous messenger. In this way, they disable the body’s own “killer cells,” which would otherwise cause the cancer cells to die.

This is because the adenosine molecules bind to tiny antennae on the surface of the immune cells, the A2A receptors (the abbreviation stands for “type 2A adenosine receptors”). This knocks out the defensive troops, so to speak. Researchers around the globe are therefore looking for molecules that can block the A2A receptor and prevent the paralyzing effect of adenosine.

Bombardment with X-rays

“Our study should make this search a lot easier,” explains Prof. Dr. Christa Müller of the Pharmaceutical Institute of the University of Bonn. “We have added novel variants of a known inhibitor, a substance called preladenant, to the A2A receptor. Then we created crystals from the receptor-inhibitor complexes — it’s the first time in the world that this has been achieved with preladenant-like substances.”

Crystallization made it possible to elucidate the structure of the complex. “To do this, we bombard the compound with X-rays,” explains Tobias Claff, who performed the main part of the experiments. “The crystal diffracts the rays. The way it does this then allows us to deduce the spatial structure of the complex — right down to the arrangement of individual atoms and their interactions.”

In this way, the researchers were able to show to which points of the A2A receptor preladenant binds. With this knowledge, it is now possible to specifically modify the inhibitor to give it better properties. In addition to having the strongest possible effect, drugs should for example not be broken down too quickly. They also need to be able to reach the place where they are supposed to do their work — in this case, the brain. “Our study will make it much easier to optimize the substance,” Claff says with optimism.

A2A belongs to a group of receptors that regulate key functions in the body. They span the membrane of cells. The part of them that sits on the outside of the membrane serves as a sensor, receiving molecular signals like an antenna. When it does, it triggers specific reactions with its part that protrudes into the cell. This then activates certain genes, for example.

Dye bound to the inhibitory molecule

“These receptors are immensely important because of their central position,” says Christa Müller, who is also a member of the Transdisciplinary Research Areas (TRA) “Building Blocks of Matter” and “Life and Health.” “Many of them, however, are unfortunately relatively unstable. This is unfavorable for X-ray structural analyses — crystallization takes days, sometimes even weeks.” The researchers therefore specifically modified the A2A receptor at a single point, making it considerably more stable.

Additionally, they succeeded in attaching a dye to the preladenant with a kind of molecular string. “This allows us to control where in the tissue preladenant attaches to the A2A receptor,” Müller says. At the same time, the length and flexibility of the nanostring ensures that the inhibitor is not obstructed from binding to the receptor.

Both advances could also serve as models for work with other receptors that belong to the same group. “The methods we have developed in Bonn in recent years will allow us to elucidate the structure of such and other cell membrane proteins in the future,” the pharmacist is convinced. “There aren’t many research facilities that can do this kind of structural analysis of extremely complex molecules.”

Participating institutions and funding:

In addition to the University of Bonn, the Centre for Structural Systems Biology (CSSB) and Forschungszentrum Jülich were involved. The study was funded by the German Research Foundation and the Federal Ministry of Education and Research.

Fermi surfaces in metals are a boundary between energy states that are occupied and unoccupied by electrons. Fermi surfaces are normally closed contours forming shapes such as spheres, ovoids, etc. Electrons at the Fermi surface control many properties of materials such as electrical and thermal conductivity, optical properties, etc. In extremely rare occasions, the Fermi surface contains disconnected segments that are known as Fermi arcs and often are associated with exotic states like superconductivity.

Adam Kaminski, leader of the research team, explained that newly discovered Fermi arcs are the result of electron band splitting, which results from the magnetic order of Nd atoms that make up 50% of the sample. However, the electron splitting that the team observed in NdBi was not typical band splitting behavior.

There are two established types of band splitting, Zeeman and Rashba. In both cases the bands retain their original shape after splitting. The band splitting that the research team observed resulted in two bands of different shapes. As the temperature of the sample decreased, the separation between these bands increased and the band shapes changed, indicating a change in fermion mass.

“This splitting is very, very unusual, because not only is the separation between those bands increasing, but they also change the curvature,” Kaminski said. “This is very different from anything else that people have observed to date.”

The previously known cases of Fermi arcs in Weyl semimetals persist because they are caused by the crystal structure of the material which is difficult to control. However, the Fermi arcs that the team discovered in NdBi are induced by magnetic ordering of the Nd atoms in the sample. This order can be readily changed by applying a magnetic field, and possibly by changing the Nd ion for another rare earth ion such as Cerium, Praseodymium, or Samarium (Ce, Pr, or Sm). Since Ames Lab is a world leader in rare earth research, such changes in composition can be easily explored.

“This new type of Fermi arcs appears whenever the sample becomes antiferromagnetic. So when the sample develops magnetic order, these arcs just appear seemingly out of nowhere,” said Kaminski.

According to Kaminski, another important characteristic of these new Fermi arcs is that they have what is called spin texture. In normal metals, each electronic state is occupied by two electrons, one with a spin up, one with a spin down, so there is no net spin. The newly discovered Fermi arcs have single orientation of spin at each of their points. Since they exist only in a magnetically ordered state, the arcs can be switched on and off very quickly by applying a magnetic pulse, for example from an ultrafast laser.

“Having such a spin decoration or spin texture is important because one of the quests in electronics is to move away from the charge-based electronics. Everything that you use now is based on moving electrons in wires and that causes dissipation,” Kaminski said.

The ability to control the spin of electrons relates to a new branch of information technology called spintronics, which is based on electron spin rather than on moving charges along wires.

“Instead of moving a charge, we either flip the orientation of the spin or cause the propagation of the spin along the wire,” Kaminski explained. “These spin changes technically should not dissipate energy, so it doesn’t cost a lot of energy to store information as spin or to move information as spin.”

Kaminski emphasized the importance of this finding to the field, but he said there is still a lot of work to be done before these findings can be used in new technology.

Crystal growth and characterization were supported by Center for the Advancement of Topological Semimetals (CATS), an Energy Frontier Research Center funded by the U.S. DOE, Office of Basic Energy Sciences.

The new discovery could accelerate the widespread use of hydrogen fuel cells, which hold great promise as efficient, clean energy sources for vehicles and other applications.

It’s one of a string of discoveries for the Héctor D. Abruña lab in their ongoing search for active, inexpensive, durable catalysts for use in alkaline fuel cells.

“This finding makes progress toward using efficient, clean hydrogen fuel cells in place of fossil fuels,” said Abruña, professor in the department of chemistry and chemical biology at Cornell University.

The results published March 21 in “A Completely Precious-Metal-Free Alkaline Fuel Cell With Enhanced Performance Using a Carbon-Coated Nickel Anode,” in the Proceedings of the National Academy of Sciences.

Expensive precious metals, such as platinum, are currently required in hydrogen fuel cells to efficiently catalyze the reactions they employ to produce electricity. Although alkaline polymer electrolyte membrane fuel cells (APEMFCs) enable the use nonprecious metal electrocatalysts, they lack the necessary performance and durability to replace precious metal-based systems.

A fuel cell produces electricity through the hydrogen oxidation reaction (HOR) and an oxygen reduction reaction (OOR). Platinum, in particular, is a model catalyst for both reactions because it catalyzes them efficiently, and is durable in the acidic environment of a PEM fuel cell, Abruña said.

But what about other materials?

Recent experiments with nonprecious-metal HOR electrocatalysts needed to overcome two major challenges, the researchers wrote: low intrinsic activity from too strong a hydrogen binding energy, and poor durability due to rapid passivation from metal oxide formation.

To overcome these challenges, the researchers designed a nickel-based electrocatalyst with a 2 nanometer shell made of nitrogen-doped carbon.

Their hydrogen fuel cell has an anode (where hydrogen is oxidized) catalyst consisting of a solid nickel core surrounded by the carbon shell. When paired with a cobalt-manganese cathode (where oxygen is reduced), the resulting completely precious-metal-free hydrogen fuel cell outputs more than 200 milliwatts per square centimeter.

The presence of nickel oxide species on the surface of the nickel electrode slows the hydrogen oxidation reaction dramatically, Abruña said. The nitrogen-doped carbon coating serves as a protection layer and enhances the HOR kinetics, making the reaction quicker and much more efficient.

In addition, the presence of the graphene coating on the nickel electrode prevents the formation of nickel oxides — resulting in electrodes with dramatically enhanced lifetimes. These electrodes are also much more tolerant to carbon monoxide, which rapidly poisons platinum.

“The use of this novel anode would dramatically lower prices enabling the application of alkaline fuel cells in a wide variety of areas,” Abruña said.

In February, Abruña and colleagues found that a cobalt nitride catalyst is nearly as efficient as platinum in catalyzing the oxygen reduction reaction.

Funding for this research was provided by the Center for Alkaline-Based Energy Solutions, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Basic Energy Sciences, and the Zhuang research group at Wuhan University, China, supported by the National Natural Science Foundation of China.

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Materials provided by Cornell University. Original written by Kate Blackwood, courtesy of the Cornell Chronicle. Note: Content may be edited for style and length.

In the new study, researchers combined diffusion MRI data from the Human Connectome Project with histological cross-sections of the corpus callosum, the major tract that connects the left and right sides of the brain. The Human Connectome maps the strength of all connections in the brain but does not provide the actual number of axons, while the histological cross-sections allow estimates for how many axons are packed into a given volume. Combining the connection strengths with the axon densities yielded estimates for the number of axons in the cerebral cortex.

The analysis indicated that there are almost 2.5 billion long-range axons traversing the cerebral cortex. However, despite this large number, they found that the numbers connecting different functional brain regions were quite low. For example, among the estimated 130 million axons in the arcuate fasciculus tract, only about 1 to 2 million (less than 2%) directly connected Broca’s and Wernicke’s areas, a connection which is necessary for normal language ability. The model predicts that other long connections, like those from the hippocampus to the frontal cortex that are needed for memory retrieval, are actually made in multiple steps. The findings will thus improve models of cognition, especially processes that rely on connections between distal regions of the brain.

“A major unsolved problem is how the human cortex integrates information processing by its 16 billion neurons across its surface to unify awareness,” Rosen adds. “Our finding that cortical areas are sparsely connected implies that this integration is accomplished either via linkage of the dense local connections or by rare, extraordinarily privileged long-range axons.”

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