Toward a blueprint for anti-influenza drugs

The structures provide an atomic-level blueprint from which to design more effective anti-influenza drugs that can overcome growing drug resistance.

Influenza virus infection is a perennial problem. According to the Centers for Disease Control and Prevention, the 2017-18 flu season saw high levels of emergency-department visits for influenza-like illness, high influenza-related hospitalization rates, and elevated and geographically widespread influenza activity for an extended period.

Although yearly vaccinations can reduce the number of flu infections, these vaccines are able to target only a subset of viral strains—there is, as yet, no “universal vaccine.” As a result, there is still a need for antiviral drugs to treat the illness after infection has occurred. This is especially important for groups of people who can experience serious complications from the flu, such as those with respiratory diseases or immune disorders. In recent years, however, resistance to certain classes of antiviral drugs has become a problem.

>Read more on the Advanced Light Source website

Image: Molecular dynamics simulation of a drug molecule, amantadine (cyan sticks), in the M2 proton channel. The drug’s ammonium group (blue tip) mimics hydronium, stabilizing the drug molecule in a position to block the channel.

Tunable ferromagnetism in a 2D material at room temperature

Breakthroughs in next-generation spintronic logic and memory devices could hinge on our ability to control spin behavior in two-dimensional materials—stacks of ultrathin layers held together by relatively weak electrostatic (van der Waals) forces. The reduced dimensionality of these so-called “van der Waals materials” often leads to tunable electronic and magnetic properties, including intrinsic ferromagnetism. However, it remains a challenge to tune this ferromagnetism (e.g. spin orientation, magnetic domain phase, and magnetic long-range order) at ambient temperatures.

In this work, researchers performed a study of Fe3GeTe2, a van der Waals material that consists of Fe3Ge layers alternating with two Te layers. The material’s magnetic properties were characterized using a variety of techniques, including x-ray absorption spectroscopy (XAS) with x-ray magnetic circular dichroism (XMCD) contrast at Beamline 6.3.1 and photoemission electron microscopy (PEEM) at Beamline 11.0.1.

>Read more on the Advanced Light Source (ALS) at LBNL website

Image: PEEM images for unpatterned and patterned Fe3GeTe2 samples at 110 K and 300 K. The unpatterned samples formed stripe domains at 110 K, which disappeared at 300 K. The patterned samples formed out-of-plane stripe domains at 110 K and transitioned to in-plane vortex states at 300 K, demonstrating control over magnetism at room temperature and beyond.

Researchers create most complete high-res atomic movie of photosynthesis to date

In a major step forward, SLAC’s X-ray laser captures all four stable states of the process that produces the oxygen we breathe, as well as fleeting steps in between. The work opens doors to understanding the past and creating a greener future.

Despite its role in shaping life as we know it, many aspects of photosynthesis remain a mystery. An international collaboration between scientists at SLAC National Accelerator Laboratory, Lawrence Berkeley National Laboratory and several other institutions is working to change that. The researchers used SLAC’s Linac Coherent Light Source (LCLS) X-ray laser to capture the most complete and highest-resolution picture to date of Photosystem II, a key protein complex in plants, algae and cyanobacteria responsible for splitting water and producing the oxygen we breathe. The results were published in Nature today.

Explosion of life

When Earth formed about 4.5 billion years ago, the planet’s landscape was almost nothing like what it is today. Junko Yano, one of the authors of the study and a senior scientist at Berkeley Lab, describes it as “hellish.” Meteors sizzled through a carbon dioxide-rich atmosphere and volcanoes flooded the surface with magmatic seas.
Over the next 2.5 billion years, water vapor accumulating in the air started to rain down and form oceans where the very first life appeared in the form of single-celled organisms. But it wasn’t until one of those specks of life mutated and developed the ability to harness light from the sun and turn it into energy, releasing oxygen molecules from water in the process, that Earth started to evolve into the planet it is today. This process, oxygenic photosynthesis, is considered one of nature’s crown jewels and has remained relatively unchanged in the more than 2 billion years since it emerged.

>Read more on the SLAC website (for LCLS)
>Read also the article on the Berkeley website (for ALS)

Image: Using SLAC’s X-ray laser, researchers have captured the most complete high-res atomic movie to date of Photosystem II, a key protein complex in plants, algae and cyanobacteria responsible for splitting water and producing the oxygen we breathe.
Credit: Gregory Stewart, SLAC National Accelerator Laboratory)

Expanding the infrared nanospectroscopy window

The ability to investigate heterogeneous materials at nanometer scales and far-infrared energies will benefit a wide range of fields, from condensed matter physics to biology.

Scientific studies require tools that match the natural length and energy scales of the phenomena under investigation. For many questions in biology, quantum materials, and electronics, this means nanometer spatial resolution combined with far-infrared energies. For example, scientists might want to study collective electron oscillations in quantum materials for optoelectronic circuits, or the characteristic vibration modes of protein molecules in biological systems.

A recently developed infrared technique—synchrotron infrared nanospectroscopy (SINS)—combines broadband synchrotron light with atomic-force microscopes to enable infrared imaging and spectroscopy at the nanoscale. However, the technique could only be used in a narrow range of the electromagnetic spectrum that excluded far-infrared wavelengths, due to a scarcity of suitable light sources and detectors for that range. In this work, researchers extended SINS to far-infrared wavelengths, opening up a whole new experimental regime.

> Read more on the Advanced Lightsource at Berkeley Lab website

Image: Left: Nanoscale images of SiO2 hole array, obtained using atomic-force microscopy (AFM, top) and synchrotron infrared nanospectroscopy (SINS, bottom), demonstrating SINS contrast between patterned SiO2 and underlying Si substrate with ~30 nm spatial resolution (inset). Scale bar = 200 nm. Right: SINS broadband spectroscopic data for SiO2, taken along dotted line in images at left, showing amplitude (top) and phase (bottom) information from asymmetric  Si–O stretching (1200 cm–1) and bending (460 cm–1) modes. The lower-energy bending mode had previously been inaccessible with this technique.

Targeting bacteria that cause meningitis and sepsis

The work provides molecular-level information about how the antibody confers broad immunity against a variable target and suggests strategies for further improvement of available vaccines.

Our central nervous systems (brain and spinal cord) are surrounded by three membranes called “meninges.” Meningitis is caused by the swelling of these membranes, resulting in headache, fever, and neck stiffness. Most cases of meningitis in the United States are the result of viral infections and are relatively mild. However, meningitis caused by bacterial infection, if left untreated, can be deadly or lead to serious complications, including hearing loss and neurologic damage.

The bacterium responsible for meningitis (Neisseria meningitidis) can also infect the bloodstream, causing another life-threatening condition known as sepsis. N. meningitidis is spread through close contact (coughing or kissing) or lengthy contact (e.g. in dorm rooms or military barracks). In this work, researchers were interested in understanding how humans develop immunity to bacterial meningitis and sepsis, collectively known as meningococcal disease, by vaccination with a new protein-based vaccine.

>Read more on the Advanced Light Source website

Image: The work provides molecular-level information about how the antibody confers broad immunity against a variable target and suggests strategies for further improvement of available vaccines.

2018 ALS User Meeting Highlights

Past, present, and future converged at the ALS User Meeting, held October 2–4, 2018. About 480 registrants helped celebrate the 25th anniversary of first light at the ALS and the announcement of CD-1 approval for the ALS Upgrade project (ALS-U), a major federal milestone. Users’ Executive Committee (UEC) Chair Will Chueh kicked things off by acknowledging the organizers—UEC members Jennifer Ciezak-Jenkins, Alex Frañó, and Michael Jacobs—and thanking the ALS for its support. He also explained the organizing principle behind the program: to engage student and young-scientist users and strengthen interactions between users in general. Jeff Neaton, Berkeley Lab’s Associate Laboratory Director for Energy Sciences, then extended an official welcome to attendees. He noted that it’s been an exciting year for the ALS, which gained a new director, Steve Kevan, in addition to CD-1 approval for ALS-U.

>Read more on the Advanced Light Source website

Image: Plenary session, Day 1.
Credit: Peter DaSilva/Berkeley Lab

New clues to cut through the mystery of Titan’s atmospheric haze

A team including Berkeley Lab scientists homes in on a ‘missing link’ in Titan’s one-of-a-kind chemistry.

Saturn’s largest moon, Titan, is unique among all moons in our solar system for its dense and nitrogen-rich atmosphere that also contains hydrocarbons and other compounds, and the story behind the formation of this rich chemical mix has been the source of some scientific debate.
Now, a research collaboration involving scientists in the Chemical Sciences Division at the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) has zeroed in on a low-temperature chemical mechanism that may have driven the formation of multiple-ringed molecules – the precursors to more complex chemistry now found in the moon’s brown-orange haze layer.
The study, co-led by Ralf Kaiser at the University of Hawaii at Manoa and published in the Oct. 8 edition of the journal Nature Astronomy, runs counter to theories that high-temperature reaction mechanisms are required to produce the chemical makeup that satellite missions have observed in Titan’s atmosphere.

>Read more on the Advanced Light Source/Berkeley Lab website

Image: The atmospheric haze of Titan, Saturn’s largest moon (pictured here along Saturn’s midsection), is captured in this natural-color image (box at left). A study that involved experiments at Berkeley Lab’s Advanced Light Source has provided new clues about the chemical steps that may have produced this haze.
Credits: NASA Jet Propulsion Laboratory, Space Science Institute, Caltech

Advanced Light Source upgrade project moves forward

An upgrade of Berkeley Lab’s X-ray facility clears next stage in federal approval process.

The Advanced Light Source (ALS), a scientific user facility at the Department of Energy’s (DOE) Lawrence Berkeley National Laboratory (Berkeley Lab), has received federal approval to proceed with preliminary design, planning and R&D work for a major upgrade project that will boost the brightness of its X-ray beams at least a hundredfold.

The upgrade will give the ALS, which this year celebrates its 25th anniversary, brighter beams with a more ordered structure – like evenly spaced ripples in a pond – that will better reveal nanoscale details in complex chemical reactions and in new materials, expanding the envelope for scientific exploration.
“This upgrade will make it possible for Berkeley Lab to be the leader in soft X-ray research for another 25 years, and for the ALS to remain at the center of this Laboratory for that time,” said Berkeley Lab Director Mike Witherell.

Steve Kevan, ALS Director, added, “The upgrade will transform the ALS. It will expand our scientific frontiers, enabling studies of materials and phenomena that are at the edge of our understanding today. And it will renew the ALS’s innovative spirit, attracting the best researchers from around the world to our facility to conduct their experiments in collaboration with our scientists.”

>Read more on the Advanced Light Source website

Image: A computer rendering providing a top view of the ALS and shows equipment that will be installed during the ALS-U project.
Credit: Berkeley Lab

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

Structure reveals mechanism behind periodic paralysis

The results suggest possible drug designs that could provide relief to patients with a genetic disorder that causes them to be overcome suddenly with profound muscle weakness.

A rare genetic disorder called hypokalemic periodic paralysis (hypoPP) causes sudden, profound muscle weakness in people who occasionally exhibit low levels of potassium in their blood, or hypokalemia. When a patient is hypokalemic, hypoPP affects the function of the muscles responsible for skeletal movement. The disease has been known to stem from mutations in certain membrane proteins that channel and regulate the flow of sodium into cells. Exactly how the mutation affects the proteins’ function, however, was not known.

In earlier work, researchers from the Catterall Lab at the University of Washington had solved the structure of a sodium channel called NavAb from a prokaryote (single-celled organism). As a next step, the group decided to see if NavAb could serve as a model for studying the mutations that cause hypoPP in humans (eukaryotes), with the goal of finding a way to prevent or treat this disorder.

A leak in the pipe?

In a resting state, muscle-cell membranes keep potassium ions and sodium ions separated, inside and outside the cell, respectively, creating a voltage across the membrane. A chemical signal from a nerve cell sets off a cascade of events that results in sodium ions flowing into the cell, changing the membrane potential and and ultimately triggering muscle contraction.

>Read more on the Advanced Light Source website

Image: Three states of the voltage-sensing domain (VSD) of a membrane-channel protein. In the normal state, the water-accessible space (magenta) does not extend through the channel, preventing sodium (gray spheres) from passing through. In the disease state, a clear passage allows sodium to leak through, resulting in muscle paralysis. In the “rescued” state, the binding of guanidinium (blue and yellow spheres) effectively closes the channel and blocks sodium leakage. The red sphere represents the location of the disease-causing mutation. The side-chain sticks represent the voltage sensors of the sodium channel.

Infrared beams show cell types in a different light

Berkeley Lab scientists developing new system to identify cell differences.

By shining highly focused infrared light on living cells, scientists at the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) hope to unmask individual cell identities, and to diagnose whether the cells are diseased or healthy.
They will use their technique to produce detailed, color-based maps of individual cells and collections of cells – in microscopic and eventually nanoscale detail – that will be analyzed using machine-learning techniques to automatically sort out cell characteristics.

Using microscopic color maps to unlock cell identity

Their focus is on developing a rapid way to easily identify cell types, and features within cells, to aid in biological and medical research by providing a way to probe living cells in their native environment without harming the cells or requiring obtrusive cell-labeling techniques.
“This is totally noninvasive,” said Cynthia McMurray, a biochemist and senior scientist in Berkeley Lab’s Molecular Biophysics and Integrated Bioimaging (MBIB) Division who is leading this new imaging effort with Michael Martin, a physicist and senior staff scientist at Berkeley Lab’s Advanced Light Source (ALS).
The ALS has dozens of beamlines that produce beams of intensely focused light, from infrared to X-rays, for a broad range of experiments.

>Read more on the Advanced Light Source website

Image: From left to right: Aris Polyzos, Edward Barnard, and Lila Lovergne, pictured here at Berkeley Lab’s Advanced Light Source, are part of a research team that is developing a cell-identification technique based on infrared imaging and machine learning.
Credit: Marilyn Chung/Berkeley Lab

Graphene-Based Catalyst Improves Peroxide Production

Hydrogen peroxide is an important commodity chemical with a growing demand in many areas, including the electronics industry, wastewater treatment, and paper recycling.

Hydrogen peroxide (H2O2) is a common household chemical, well known for its effectiveness at whitening and disinfecting. It’s also a valuable commodity chemical used to etch circuit boards, treat wastewater, and bleach paper and pulp—a market expected to grow as demand for recycled paper products increases.

Compared to chlorine-based bleaches, hydrogen peroxide is more environmentally benign: the only degradation product of its use is water. However, it’s currently produced through a multistep chemical reaction that consumes significant amounts of energy, generates substantial waste, and requires a catalyst of palladium—a rare and expensive metal. Furthermore, the transport and storage of bulk hydrogen peroxide can be hazardous, making local, on-demand production highly desirable.

Better living through electrochemistry

Scientists seek a way to generate hydrogen peroxide electrochemically—by a much simpler process called the oxygen reduction reaction (ORR). This reaction takes oxygen from the air and combines it with water and two electrons to produce H2O2. If this reaction could be efficiently catalyzed, it could enable the disinfection of water at remote locations, or during disaster recovery, using hydrogen peroxide made from local air and water. For this work, the researchers focused on hydrogen peroxide synthesis in alkaline environments, where the reaction bath can be used directly, such as for bleaching or the treatment of acidic waste streams.

>Read more on the Advanced Light Source website

Image: The production of hydrogen peroxide (H2O2) from oxygen (O2) was efficiently catalyzed by graphene oxide, a form of graphene characterized by various oxygen defects that act as centers for catalytic activity. Depicted are two types of defects: one in which an oxygen atom bridges two carbon atoms above the graphene plane, and one where oxygen atoms replace carbon atoms within the graphene plane.

A designed material untangles long-standing puzzle

This approach could lead to new materials with emergent physics and unique electronic properties, supporting broader research efforts to revolutionize modern electronics.

When atoms or molecules assemble to form bulk matter, new properties (such as conductivity and ferromagnetism) that didn’t exist in the constituent parts can emerge from the whole. Similarly, stacking atomically thin layers into nanostructures (heterostructures) can give rise to a rich variety of emergent phases not found in bulk materials.

Materials that exhibit emergent phenomena (“quantum materials”) often feature multiple phases with simultaneous phase transitions. A great deal of effort is currently being expended to disentangle such transitions, to discover what drives them and to ultimately harness them in new materials with desired functionalities. Most of these efforts have relied on external perturbations (light, pressure, etc.) to decouple the transitions. In this work, researchers found a way to do this intrinsically, through layer-by-layer design of stacking sequences with mismatched periodicities.

>Read more on the Advanced Light Source website

Image: (a) Rare-earth (RE) nickelates (RENiO3) host multiple types of entangled orderings. This illustration depicts a magnetic ordering (spin directions indicated by yellow arrows) and a charge ordering (a checkerboard of two nickel oxidation states, indicated by sphere size and color) in bulk RENiO3 (RE and O atoms omitted for clarity). 
Please find the entire image here.

Open and shut: pain signals in nerve cells

Our daily function depends on signals traveling between nerve cells (neurons) along fine-tuned pathways. Central nervous system neurons contain acid-sensing ion channel 1a (ASIC1a), a protein important in sensing pain and forming memories of fear. An ion channel lodged in the cell membrane that provides a pathway for sodium ions to enter the cell, ASIC1a opens and closes in response to changes in extracellular proton concentrations. When protons accumulate outside the neuron, the channel opens, allowing sodium ions to flow into the cell, depolarizing the cell membrane and generating an electrical signal. The channel eventually becomes desensitized to protons and the gate closes. Scientists have visualized both the open and desensitized channel structures, but the third structure, which forms when the protons dissipate and the channel closes, remained elusive. Using protein crystallography at the ALS, researchers finally visualized the closed channel.

>Read more on the Advanced Light Source website

Animation: As the proton concentration increases or decreases, the gated channel ASIC1a toggles between open and closed positions, controlling the timing of signals traveling through the cell membrane of one neuron en route to the next.

Structures reveal new target for malaria vaccine

The discovery paves the way for the development of a more effective and practical human vaccine for malaria, a disease responsible for half a million deaths worldwide each year.

Malaria kills about 445,000 people a year, mostly young children in sub-Saharan Africa, and sickens more than 200 million. It’s caused by a parasite, Plasmodium falciparum (Pf), and is spread to humans through the bite of an infected Anopheles mosquito.

The parasite’s complex life cycle and rapid mutations have long challenged vaccine developers. Only one experimental vaccine, known as RTS,S, has progressed to a Phase 3 clinical trial (testing on large groups of people for efficacy and safety). To elicit an immune response, this vaccine uses a fragment of circumsporozoite protein (CSP), which covers the malaria parasite in its native conformation. However, the trial results showed that RTS,S is only moderately effective, protecting about one-third of the young children who received it over a period of four years.

>Read more on the Advanced Light Source website.

Image (a) Left: Surface representation of CIS43 (light chain in tan and heavy chain in light blue), with peptide 21 shown as sticks (purple). Right: A 90° rotation of the representation. See entire image here.

Berkeley Lab researchers receive DOE Early Career Research Awards

Six scientists at Lawrence Berkeley National Laboratory (Berkeley Lab) have been selected by the U.S. Department of Energy’s (DOE’s) Office of Science to receive significant funding for research through its Early Career Research Program.

The program, now in its ninth year, is designed to bolster the nation’s scientific workforce by providing support to exceptional researchers during the crucial early career years, when many scientists do their most formative work. The six Berkeley Lab recipients are among a total of 84 recipients selected this year, including 30 from DOE’s national laboratories. This year’s awards bring to 35 the total number of Berkeley Lab scientists who have received Early Career Research Program awards since 2010.

“We are grateful that DOE has chosen to recognize these six young Berkeley Lab scientists,” said Berkeley Lab Director Mike Witherell. “Our Lab takes very seriously the responsibility to train the next generation of scientists and engineers. Each of their proposed projects not only represents cutting-edge science but will also contribute to our understanding of the world and a sustainable future.“

The scientists are each expected to receive grants of up to $2.5 million over five years to cover year-round salary plus research expenses.

>Read more on the Advanced Light Source website

Image: Ethan Crumlin is a staff scientist at the Advanced Light Source (ALS), a DOE Office of Science User Facility at Berkeley Lab, who specializes in studies of chemistry at the interfaces between solids, liquids, and gases.