Structure and functional binding epitopes of VISTA

V-domain Ig Suppressor of T-cell Activation (VISTA) is an immune checkpoint protein involved in the regulation of T cell activity. Checkpoint proteins are overexpressed by cancer cells or surrounding immune cells and prevent anti-tumor activity by co-opting natural regulation mechanisms to escape immune clearance. Compared to healthy tissues, VISTA is upregulated on tumor infiltrating leukocytes, including high expression on myeloid-derived suppressor cells (MDSCs). Through VISTA signaling, these inhibitory immune cells prevent effective antigen presentation and indirectly promote tumor growth. VISTA is implicated in a number of human cancers including skin (melanoma), prostate, colon, pancreatic, ovarian, endome­trial, and non-small cell lung. VISTA is a known member of the B7 protein family but the mechanism of action is still unclear as VISTA has been shown to function as both a ligand1,2 and a receptor3.  In the model of VISTA as a receptor, the proposed ligand of interaction is V-set and immunoglobulin domain containing 3 (VSIG3)4,5.

>Read more on the SSRL website

Image: Structure of human VISTA with extended C-C’ loop (blue), mapped VSTB/VSIG3 binding epitope (red), and disulfide bonds (yellow).

The role of ‘charge stripes’ in superconducting materials

The studies could lead to a new understanding of how high-temperature superconductors operate.

High-temperature superconductors, which carry electricity with zero resistance at much higher temperatures than conventional superconducting materials, have generated a lot of excitement since their discovery more than 30 years ago because of their potential for revolutionizing technologies such as maglev trains and long-distance power lines. But scientists still don’t understand how they work.
One piece of the puzzle is the fact that charge density waves – static stripes of higher and lower electron density running through a material – have been found in one of the major families of high-temperature superconductors, the copper-based cuprates. But do these charge stripes enhance superconductivity, suppress it or play some other role?
In independent studies, two research teams report important advances in understanding how charge stripes might interact with superconductivity. Both studies were carried out with X-rays at the Department of Energy’s SLAC National Accelerator Laboratory.

>Read more on the LCLS at SLAC website

Image: This cutaway view shows stripes of higher and lower electron density – “charge stripes” – within a copper-based superconducting material. Experiments with SLAC’s X-ray laser directly observed how those stripes fluctuate when hit with a pulse of light, a step toward understanding how they interact with high-temperature superconductivity.
Credit: Greg Stewart/SLAC National Accelerator Laboratory

Winning the fight against influenza

Annual influenza epidemics and episodic pandemics continue to cause widespread illness and mortality. The World Health Organization estimates that annual influenza epidemics cause around 3–5 million cases of severe illness and up to 650,000 deaths worldwide. Seasonal influenza vaccination still remains the best strategy to prevent infection, but the vaccines that are available now offer a very limited breadth of protection. Human broadly neutralizing antibodies (bnAbs) that bind to the hemagglutinin (HA) stem region provide hope for a universal vaccine (Figure 1a)1,2. Binding of these bnAbs prevents the pH-induced conformational changes that are required for viral fusion in the endosomal compartments of target cells in the respiratory tract and, hence, viral entry in our cells.

>Read more on the SSRL at SLAC website

Image: Complex of Influenza virus HA with (a) Fab CR6261, (b) llama single domain antibody SD36, and (c) JNJ4796.

In a first, researchers identify reddish coloring in an ancient fossil mouse

X-rays reveal an extinct mouse was dressed in brown to reddish fur on its back and sides and had a tiny white tummy.

Researchers have for the first time detected chemical traces of red pigment in an ancient fossil – an exceptionally well-preserved mouse, not unlike today’s field mice, that roamed the fields of what is now the German village of Willershausen around 3 million years ago.
The study revealed that the extinct creature, affectionately nicknamed “mighty mouse” by the authors, was dressed in brown to reddish fur on its back and sides and had a tiny white tummy. The results were published today inNature Communications.
The international collaboration, led by researchers at the University of Manchester in the U.K., used X-ray spectroscopy and multiple imaging techniques to detect the delicate chemical signature of pigments in this long-extinct mouse.

>Read more on the SSRL at SLAC Lab website

Image: In this image showing the fossil chemistry of an ancient mouse, blue represents calcium in the bones, green is the element zinc which has been shown to be important in the biochemistry of red pigment and red is a particular type of organic sulfur. This type of sulfur is enriched in red pigment. When combined, regions rich in both zinc and sulfur appear yellow on this image, showing that the fur on this animal was rich in the chemical compounds that are most probably derived from the original red pigments produced by the mouse. (10.1038/s41467-019-10087-2)

Doubling the DNA alphabet

Implications for life in the universe and DNA storage

Life on Earth is dictated by the DNA alphabet comprised of only four DNA bases or letters: A, T, G and C. It has long been of interest to understand whether there is something very special about the four letters that comprise DNA and whether this is the only code that could support life. At a basic level, this question can be addressed by examining an expanded alphabet and determining the properties of DNA including additional synthetic letters. This study impacts our current understanding of terrestrial DNA and suggests that extraterrestrial life forms could have evolved using a different genetic code than found here on Earth. The work has immediate applications in synthetic biology for the creation of new molecules and greatly expands the ability to store information in DNA.

Now, in breakthrough work, funded by NASA, NSF and NIGMS, Dr. Steven Benner at the Foundation for Applied Molecular Evolution, in collaboration with Dr. Millie Georgiadis at the Indiana University School of Medicine, and colleagues at biotechnology companies and other universities, have provided evidence that the standard DNA code can be expanded to include eight letters forming “hachimoji DNA” (“hachi” eight and “moji” letter in Japanese) using four novel synthetic nucleobases (B, S, P and Z) in addition to A, T, C and G and still retain critical features of natural DNA1,2. Structurally, hachimoji DNA can adopt a standard double helical form of DNA and retain Watson-Crick complementary base pairing, which allows the expanded DNA to be faithfully replicated and transcribed by polymerases to produce hachimoji DNA copies and hachimoji RNA. These properties are essential for a genetic system that can support life.

>Read more on the Stanford Synchrotron Radiation Lightsource (SSRL) at SLAC website

Image: Crystal structure of a double helix built from eight hachimoji building blocks, G (green), A (red), C (dark blue), T (yellow), B (cyan), S (pink), P (purple), and Z (orange). The first four building blocks are found in human DNA; the last four are synthetic, and possibly present in alien life. Each strand of the double helix has the sequence CTTAPCBTASGZTAAG. Notable is the geometric regularity of the pairs, a regularity that is needed for evolution.

Cause of cathode degradation identified for nickel-rich materials

Combination of research methods reveals causes of capacity fading, giving scientists better insight to design advanced batteries for electric vehicles

A team of scientists including researchers at the U.S. Department of Energy’s (DOE) Brookhaven National Laboratory and SLAC National Accelerator Laboratory have identified the causes of degradation in a cathode material for lithium-ion batteries, as well as possible remedies. Their findings, published on Mar. 7 in Advanced Functional Materials, could lead to the development of more affordable and better performing batteries for electric vehicles.

Searching for high-performance cathode materials
For electric vehicles to deliver the same reliability as gas vehicles they need lightweight yet powerful batteries. Lithium-ion batteries are the most common type of battery found in electric vehicles today, but their high cost and limited lifetimes are limitations to the widespread deployment of electric vehicles. To overcome these challenges, scientists at many of DOE’s national labs are researching ways to improve the traditional lithium-ion battery.

>Read more on the NSLS-II at Brookhaven Lab website

Image: Members of the Brookhaven team are shown at NSLS-II’s ISS beamline, where part of the research was conducted. Pictured from front to back are Eli Stavitski, Xiao-Qing Yang, Xuelong Wang, and Enyuan Hu.

Mechanism of thiopurine resistance in acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is an aggressive lymphoid malignancy that is currently the leading cause of cancer in pediatric patients1. Despite intensified chemotherapy regimens, the cure rates of ALL only approaches 40%2. Specific mutations in the cytosolic 5’-nucleotidase II (NT5C2) gene are present in about 20% of relapsed pediatric T-ALL and 3-10% of relapsed B-precursor ALL cases3,4.

NT5C2 is a cytosolic nucleotidase that maintains intracellular nucleotide pool levels by exporting excess purine nucleotides out of the cell5.  NT5C2 can also dephosphorylate and inactivate the metabolites of the 6-thioguanine (6-TG) and 6-mercaptopurine (6-MP) commonly used to treat ALL6. Thus, relapse associated activating mutations in NT5C2 confer resistance to 6-MP and 6-TG chemotherapy. Upon allosteric activation, a disordered region of NT5C2 adopts a helical configuration (helix A) and facilitates substrate binding and catalysis (Fig. 1a)7.  Mutations in this regulatory region of NT5C2 have been modeled to strongly activate NT5C2.  However, the majority of NT5C2 mutations associated with relapsed ALL do not occur in this region.
To better understand the mechanisms by which these gain-of function NT5C2 mutations lead to increased nucleotidase activity, Dieck, Tzoneva, Forouhar and colleagues investigated additional regulatory elements that may control NT5C2 activation.  They collected crystallographic data for several mutant NT5C2 homotetramers at SSRL (NT5C2-537X D52N/D407A in active state (BL9-2), NT5C2-Q523X D52N in basal state and in active state (BL14-1) and full-length NT5C2 R39Q/D52N in basal state (BL12-2)) and used the structural information as a guide in the understanding of the mechanistic details.

>Read more on the Stanford Synchrotron Radiation Lightsource website

Figure (a) A ribbon diagram of the active structure of NT5C2 WT, in which the allosteric helix A (αA) is shown in dark purple. The N and C termini amino acids (S4 and S488), and the termini amino acids (L402 and R421) of the disordered region in the arm segment are also labeled. Panels b and c shows ribbon and surface (for subunit B) depictions of basal (b) and active dimers (c) of WT.

Structural basis of neurosteroid anesthetic action on GABAA receptors

Type A γ-aminobutyric acid receptors (GABAARs) control neuronal excitability1. They are targets for the treatment of neurological diseases and disorders and also for general anesthetics. The underlying mechanisms of these drugs’ action on GABAARs remain to be determined.
One of the mechanisms is to potentiate function of GABAARs via binding to the transmembrane domain (TMD)2. Ample experimental evidence suggests that the TMD of GABAARs harbors sites for the primary actions of general anesthetics and neurosteroids. The TMD plays an essential role in functional transitions among the resting, activated, and desensitized states of these Cl-conducting channels.
Alphaxalone (5α-pregnan-3α-ol-11,20 dione) is a potent neurosteroid anesthetic. The anxiolytic, anticonvulsant, analgesic, and sedative-hypnotic effects of alphaxalone have been linked to its potentiation of GABA-evoked currents and direct activation of GABAARs3. However, the data about the alphaxalone binding site in GABAARs and the underlying structural basis of alphaxalone’s action are sparse.

>Read more on the Stanford Synchrotron Radiation Lightsource at SLAC

Figure: Alphaxalone-induced structural changes at the bottom of the TMD (a) Bottom view of overlaid TM1-TM2 structures of the apo (orange) and alphaxalone-bound (cyan) α1GABAAR chimera. (b) Side view of overlaid structures of apo (principal subunit – gold; complementary subunit – orange) and alphaxalone-bound (principal subunit – blue; complementary subunit – cyan) α1GABAAR chimera. For clarity, only TM2 and TM3 are shown in the principal subunit and only TM1 and TM2 are shown in the complementary subunit. The arrow highlights structural perturbations originating from the alphaxalone binding site near W246 through the TM1-TM2 linker to the pore-lining residues P253 (-2′) and V257 (2′). (c) The 2FO-FC electron density maps (blue mesh, contoured at 1 σ) covering TM1-TM2 in the apo (left) and alphaxalone-bound (right) α1GABAAR chimera. The sidechains are shown only for residues W246 to V257 (2′).

Untangling a strange phenomenon in lithium-ion batteries

New research offers the first complete picture of why a promising approach of stuffing more lithium into battery cathodes leads to their failure.

A better understanding of this could be the key to smaller phone batteries and electric cars that drive farther between charges.
The lithium-ion batteries that power electric vehicles and phones charge and discharge by ferrying lithium ions back and forth between two electrodes, an anode and a cathode. The more lithium ions the electrodes are able to absorb and release, the more energy the battery can store.
One issue plaguing today’s commercial battery materials is that they are only able to release about half of the lithium ions they contain. A promising solution is to cram cathodes with extra lithium ions, allowing them to store more energy in the same amount of space. But for some reason, every new charge and discharge cycle slowly strips these lithium-rich cathodes of their voltage and capacity.
A new study provides a comprehensive model of this process, identifying what gives rise to it and how it ultimately leads to the battery’s downfall. Led by researchers from Stanford University and the Department of Energy’s SLAC National Accelerator Laboratory and Lawrence Berkeley National Laboratory, it was published today in Nature Materials.

>Read more on the Stanford Synchrotron Radiation Lightsource (SSRL)

Image: A mysterious process called oxygen oxidation strips electrons from oxygen atoms in lithium-rich battery cathodes and degrades their performance, shown at left. Better understanding this property and controlling its effects could lead to better performing electric vehicles.
Credit: Gregory Stewart/SLAC National Accelerator Laboratory)

Copper mobilization and immobilization

… along an organic matter and redox gradient- insights from a mofette site.

The metal copper (Cu) is known to be an essential trace element for many organisms but it is also considered a severe contaminant at higher concentrations. Especially in soils with changing redox conditions, Cu binding mechanisms and, thus, Cu mobility are hard to predict. The metal is known to have a high affinity to soil organic matter (SOM), i.e., it can either be sequestered by adsorption to solid-phase organic matter or mobilized by complexation with dissolved organic matter. Under reducing conditions, Cu(II) can also be reduced to Cu(I) via biotic and abiotic processes and precipitate in the form of sulfidic minerals.
>Read more on the SSRL website
Image: Picture of the investigated mofette site (left) and Cu sorption isotherms determined for mofette, transitions, and reference soil in a Cu spike experiment (right).
Credit: Reprinted with permission from Mehlhorn et al. 2018, ES&T, DOI: 10.1021/acs.est.8b02668, Copyright 2018 American Chemical Society

Visualising shared-ligand intermediates of metal exchange

Visualized by Rapid Freeze Quench and Selenium EXAFS of Se-Labeled Metallochaperones. A Paradigm for Studying Copper-Mediated Host-Pathogen Interactions.

Mammalian hosts defend against invading pathogens via the import of toxic concentrations of copper into the phagolysosome. To combat this host-defense strategy, gram negative pathogens respond via sophisticated copper export systems which are able to neutralize the copper onslaught2. Chemical mechanisms of metal exchange between protein components of metal exporters are thus important factors in understanding pathogenic virulence and are believed to occur via formation of intermediates in which the metal is coordinated by ligands derived from each partner.  However, since these ligand sets are often similar (or even identical), following the kinetics of transfer has been challenging, and has required the development of sophisticated spectroscopic approaches.

>Read more on the SSRL website

Image: Middle: Se EXAFS Fourier transforms at increasing time points for the reaction of SeM-labeled apo-CusF with unlabeled Cu(I)-loaded CusB.  Left and right: in silico models of the proposed protein-protein interface and shared-ligand intermediate.

Single atoms can make more efficient catalysts

Detailed observations of iridium atoms at work could help make catalysts that drive chemical reactions smaller, cheaper and more efficient.

Catalysts are chemical matchmakers: They bring other chemicals close together, increasing the chance that they’ll react with each other and produce something people want, like fuel or fertilizer.

Since some of the best catalyst materials are also quite expensive, like the platinum in a car’s catalytic converter, scientists have been looking for ways to shrink the amount they have to use.

Now scientists have their first direct, detailed look at how a single atom catalyzes a chemical reaction. The reaction is the same one that strips poisonous carbon monoxide out of car exhaust, and individual atoms of iridium did the job up to 25 times more efficiently than the iridium nanoparticles containing 50 to 100 atoms that are used today.

>Read more on the SSRL at SLAC website

Image: Scientists used a combination of four techniques, represented here by four incoming beams, to reveal in unprecedented detail how a single atom of iridium catalyzes a chemical reaction.
Credit: Greg Stewart/SLAC National Accelerator Laboratory

Lattice Coupling conspires in the correlated cuprate high-Tc superconductivity

For the cuprate high temperature superconductivity (high-Tc) research over the past three decades, the biggest challenge is to identify the relevant low energy degrees of freedom that are critical to formulating the correct theoretical model for high-Tc superconductivity. The main difficulty lies in the closeness between various relevant energy scales. For low energy processes that are comparable to the superconducting gap energy ∆sc, there are the spin exchange energy J, the lattice vibration (phonon) energy Ωph, and the van Hove singularity energy E(π,0). However, anomalous isotope effects on Tc and superfluid density in the cuprates cannot be captured by traditional phonon-mediated superconductivity theories. Historically, a purely electronic Hamiltonian – the Hubbard model – was widely regarded to encapsulate all the core physics of the high-Tc phenomena.

In a recent paper published in Science, scientists from Stanford University and from Stanford Institute for Materials and Energy Sciences (SIMES), in collaboration with material scientists from Japan and theoreticians from Japan, the Netherlands, and Berkeley, reinstated the substantial role of the lattice vibration in the cuprate high-Tc superconductivity – however, in a subtle way that is highly intertwined with the electronic correlations. They finely straddled 18 differently hole-doped high-Tc compound Bi2Sr2CaCu2O8+δ within 8% change of hole carrier concentration, a doping range where Tc evolves from 47 K to 95 K through a putative quantum critical point, around which the electronic correlation effect experiences a sudden change. Then systematic experiments were carried out using the angle-resolved photoemission spectroscopy (ARPES) facility at SSRL Beam Line 5-4. Here, the high-resolution ARPES end station provided critical information of both the superconducting gap and the electron-lattice coupling.

>Read more on the Stanford Synchrotron Radiation Lightsource website

Image: Intertwined growth of the superconductivity and the electron-phonon coupling tuned by the hole concentration. The red line is an illustration of the Tc in Bi-2212 (Tcmax = 95 K). The blue shade and line represent the single-layer Bi-2201 system, where the coupling to the B1g mode is weak and T max is only 38 K. The yellow ball represents the optimally doped tri-layer Bi-2223 where Tcmax is 108 K. The top-right inset shows the intertwined relation between the pseudogap and the EPC under strong electronic correlation. The Madelung potential and the lattice stacking along the c-axis are schematically depicted for the single- layer, bi-layer and tri-layer systems. The dark grey blocks represent the CuO2n- plane, and the light grey blocks represent the charge reservoir layers (Ca2+, SrO, BiO+). The orange dots mark the CuO2n- planes that experience to the first order a non-zero out-of-plane electric field.
Credit: Science, doi: 10.1126/science.aar3394

X-rays uncover a hidden property that leads to failure in a lithium-ion battery material

Experiments at SLAC and Berkeley Lab uproot long-held assumptions and will inform future battery design.

Over the past three decades, lithium-ion batteries, rechargeable batteries that move lithium ions back and forth to charge and discharge, have enabled smaller devices that juice up faster and last longer.
Now, X-ray experiments at the Department of Energy’s SLAC National Accelerator Laboratory and Lawrence Berkeley National Laboratory have revealed that the pathways lithium ions take through a common battery material are more complex than previously thought. The results correct more than two decades worth of assumptions about the material and will help improve battery design, potentially leading to a new generation of lithium-ion batteries.

An international team of researchers, led by William Chueh, a faculty scientist at SLAC’s Stanford Institute for Materials & Energy Sciences and a Stanford materials science professor, published these findings today in Nature Materials.
“Before, it was kind of like a black box,” said Martin Bazant, a professor at the Massachusetts Institute of Technology and another leader of the study. “You could see that the material worked pretty well and certain additives seemed to help, but you couldn’t tell exactly where the lithium ions go in every step of the process. You could only try to develop a theory and work backwards from measurements. With new instruments and measurement techniques, we’re starting to have a more rigorous scientific understanding of how these things actually work.”

>Read more on the SLAC website

Image: When lithium ions flow into the battery’s solid electrode – illustrated here in hexagonal slices – the lithium can rearrange itself, causing the ions to clump together into hot spots that end up shortening the battery lifetime.
Credit: Stanford University/3Dgraphic

Direct Observation of the Kinetics of Gas–Solid Reactions

… using in-situ kinetic and spectroscopic techniques.

Copper oxide is a widely used adsorptive material that removes trace amounts of H2S from various process streams via chemical reaction to form copper sulfide. At room temperature the thermodynamics favor a near complete conversion of CuO to copper sulfide in the presence of H2S. However, in application, the extent of conversion of the CuO to copper sulfide during reaction can be influenced by many factors, including the initial crystalline state of the CuO, and the rate at which solid products accumulate on the reactive surfaces or within pores of the CuO particles. This incomplete utilization of CuO is problematic for industrial applications because it typically leads to oversized equipment and/or frequent process shutdowns. Developing fundamental insight at the atomic scale for this reaction could overcome these limitations by providing a rational basis for the design of new materials and by leading to predictive models that allow for current materials to be operated toward their thermodynamic limits. Thus, experiments that combine reaction kinetic testing while also simultaneously capturing chemical and structural changes in the solid phase at multiple length scales are necessary to elucidate the fundamentals of these reactions at various length scales.

Previous studies were successful in semi-quantitatively relating properties of materials to performance in fixed-bed systems, however, differences in performance were often attributed to physical properties at the >10 mm scale (e.g., surface area, pore volume, bulk density). The effects of molecular scale material characteristics (e.g., microscopic shape, metal oxide crystallite size, and surface composition) were rarely investigated, thus, it is difficult to extend the conclusions from these studies across a broad range of conditions and materials.

>Read more on the SSRL at SLAC website

Image (extract): (A) CuO and CuS concentration maps derived from XANES analysis of TXM images of individual CuO particle during reaction with 1000 ppm H2S. (B) Fractional conversion versus time (derived from linear combination fitting of Cu K-edge XANES) of fixed beds of CuO particles consisting of 2 different crystallite sizes (red circles are 2.8 nm and blue squares are 28 nm) and of individual CuO particles. See the entire figure here.

Empowering multicomponent cathode materials for sodium ion batteries

…by exploring three-dimensional compositional heterogeneities

Energy storage devices have revolutionized the modern electronics industry by enabling the widespread application of portable electronic devices. Moreover, these storage devices also have the potential to reduce the dependence on fossil fuels by implementing electric vehicles in the market. To date, lithium ion batteries have dominated the market because of the high energy density delivered by them. However, one should look into the sustenance of such devices because Li is not one of the most abundant metals on Earth’s crust. Thus, developing an alternative to lithium ion batteries has become one of the key issues to ensure the sustainable future of energy storage devices. Sodium ion batteries provide one such alternative. Out of all the components of a battery, cathode materials play one of the key roles in determining the overall performance of such batteries. Unfortunately, sodium-ion batteries have been lagging behind their lithium ion counterpart in terms of performance. Thus, new design strategies must be undertaken in order to improve the performance of cathode materials for sodium ion batteries.

>Read more on the SSRL at SLAC website

Image (extract): Three-dimensional elemental associations of pristine Na0.9Cu0.2Fe0.28Mn0.52O2 studied through transmission x-ray tomography. a) Visualizing the surface elemental associations at different angles with different colors corresponding to different association, and b) 2D cross-sectional association maps showing the bulk elemental associations. [Energy Environ. Sci., DOI: 10.1039/C8EE00309B (2018)] See entire figure here.