Cells are biological wonders. Throughout billions of years of existence on Earth, these tiny units of life have evolved to collaborate at the smallest levels in promoting, preserving and protecting the organism they comprise. Among these functions is the transport of lipids and other biomacromolecules between cells via membrane adhesion and fusion -- processes that occur in many biological functions, including waste transport, egg fertilization and digestion. At the University of California, Santa Barbara, chemical engineers have developed a way to directly observe both the forces present and the behavior that occurs during cell hemifusion, a process by which only the outer layers of the lipid bilayer of cell membranes merge. While many different techniques have been used to observe membrane hemifusion, simultaneous measurements of membrane thickness and interaction forces present a greater challenge, according to Dong Woog Lee, lead author of a paper that appears in the journal ("Real-time intermembrane force measurements and imaging of lipid domain morphology during hemifusion"). 
An artist's concept of cell hemifusion. (Illustration by Peter Allen) 'It is hard to simultaneously image hemifusion and measure membrane thickness and interaction forces due to the technical limitations,' he said. However, by combining the capabilities of the Surface Forces Apparatus (SFA) -- a device that can measure the tiny forces generated by the interaction of two surfaces at the sub-nano scale -- and simultaneous imaging using a fluorescence microscope, the researchers were able to see in real time how the cell membranes rearrange in order to connect and open a fusion conduit between them. The SFA was developed in Professor Jacob Israelachvili's Interfacial Sciences Lab at UCSB. Israelachvili is a faculty member in the Department of Chemical Engineering at UCSB. To capture real time data on the behavior of cell membranes during hemifusion, the researchers pressed together two supported lipid bilayers on the opposing surfaces of the SFA. These bilayers consisted of lipid domains -- collections of lipids that in non-fusion circumstances are organized in more or less regularly occurring or mixed arrangements within the cell membrane. 'We monitored these lipid domains to see how they reorganize and relocate during hemifusion,' said Lee. The SFA measured the forces and distances between the two membrane surfaces as they were pushed together, visualized at the Ångstrom (one-tenth of a nanometer) level. Meanwhile, fluorescent imaging made it possible to see the action as the more ordered-phase (more solid) domains reorganized and allowed the more disordered-phase (more fluid) domains to concentrate at the point of contact. 'This is the first time observing fluorescent images during a hemifusion process simultaneously with how the combined thickness of the two bilayers evolve to form a single layer,' said Lee. This rearrangement of the domains, he added, lowers the amount of energy needed during the many processes that require membrane fusion. At higher pressures, according to the study, the extra energy activates faster hemifusion of the lipid layers. Lipid domains have been seen in many biological cell membranes, and have been linked to various diseases such as multiple sclerosis, Alzheimer's disease and lung diseases. According to the researchers, this novel device could be used to diagnose, provide a marker for, or study dynamic transformations in situations involving lipid domains in pathological membranes. The fundamental insights provided by this device could also prove useful for other materials in which dynamic changes occur between membranes, including surfactant monolayers and bilayers, biomolecules, colloidal particles, surfactant-coated nanoparticles and smart materials.
read more "Seeing the action involved in cell membrane hemifusion"
An artist's concept of cell hemifusion. (Illustration by Peter Allen) 'It is hard to simultaneously image hemifusion and measure membrane thickness and interaction forces due to the technical limitations,' he said. However, by combining the capabilities of the Surface Forces Apparatus (SFA) -- a device that can measure the tiny forces generated by the interaction of two surfaces at the sub-nano scale -- and simultaneous imaging using a fluorescence microscope, the researchers were able to see in real time how the cell membranes rearrange in order to connect and open a fusion conduit between them. The SFA was developed in Professor Jacob Israelachvili's Interfacial Sciences Lab at UCSB. Israelachvili is a faculty member in the Department of Chemical Engineering at UCSB. To capture real time data on the behavior of cell membranes during hemifusion, the researchers pressed together two supported lipid bilayers on the opposing surfaces of the SFA. These bilayers consisted of lipid domains -- collections of lipids that in non-fusion circumstances are organized in more or less regularly occurring or mixed arrangements within the cell membrane. 'We monitored these lipid domains to see how they reorganize and relocate during hemifusion,' said Lee. The SFA measured the forces and distances between the two membrane surfaces as they were pushed together, visualized at the Ångstrom (one-tenth of a nanometer) level. Meanwhile, fluorescent imaging made it possible to see the action as the more ordered-phase (more solid) domains reorganized and allowed the more disordered-phase (more fluid) domains to concentrate at the point of contact. 'This is the first time observing fluorescent images during a hemifusion process simultaneously with how the combined thickness of the two bilayers evolve to form a single layer,' said Lee. This rearrangement of the domains, he added, lowers the amount of energy needed during the many processes that require membrane fusion. At higher pressures, according to the study, the extra energy activates faster hemifusion of the lipid layers. Lipid domains have been seen in many biological cell membranes, and have been linked to various diseases such as multiple sclerosis, Alzheimer's disease and lung diseases. According to the researchers, this novel device could be used to diagnose, provide a marker for, or study dynamic transformations in situations involving lipid domains in pathological membranes. The fundamental insights provided by this device could also prove useful for other materials in which dynamic changes occur between membranes, including surfactant monolayers and bilayers, biomolecules, colloidal particles, surfactant-coated nanoparticles and smart materials.
Polymeric nanoimaging agents carrying attached MRI tracer are able to pass through the blood–brain barrier (BBB) and specifically target cancer cells for efficient imaging. A qualitative/quantitative “MRI virtual biopsy” method is based on a nanoconjugate carrying MRI contrast agent gadolinium-DOTA and antibodies recognizing tumor-specific markers and extravasating through the BBB. In newly developed double tumor xenogeneic mouse models of brain metastasis this noninvasive method allowed differential diagnosis of HER2- and EGFR-expressing brain tumors. (© ACS) Ljubimova, director of the Nanomedicine Research Center in the Department of Neurosurgery and director of the Nanomedicine Program at the Samuel Oschin Comprehensive Cancer Institute, has received a $2.5 million grant from the National Institutes of Health to continue the research. The drug delivery system and its component parts, together called a nanobioconjugate or nanodrug, is in an emerging class of molecular drugs designed to slow or stop cancers by blocking them in multiple ways within the brain. The drug is about 20 to 30 nanometers in size – a fraction of a human hair, which is 80,000 to 100,000 nanometers wide. Cedars-Sinai scientists began developing the “platform” of the drug delivery system about a decade ago. The nanodrug can have a variety of chemical and biological “modules” attached. “Each component serves a specialized function, such as seeking out cancer cells and binding to them, permeating the walls of blood vessels and tumor cells, or dismantling molecular mechanisms that promote tumor growth,” said Eggehard Holler, PhD, professor of neurosurgery and director of nanodrug synthesis at Cedars-Sinai. The new delivery system plays two roles: diagnosing brain tumors by identifying cells that have spread to the brain from other organs, and then fighting the cancer with precise, individualized tumor treatment. Researchers can determine tumor type by attaching a tracer visible on an MRI. If the tracer accumulates in the tumor, it will be visible on MRI. With the cancer’s molecular makeup identified through this virtual biopsy, researches can load the “delivery system” with cancer-targeting components that specifically attack the molecular structure. To show that the virtual biopsies could distinguish one cancer cell type from another, the researchers devised what is believed to be a unique method, implanting different kinds of breast and lung cancers into laboratory mice to represent metastatic disease – with one type of cancer implanted on each side of the brain. Lung and breast cancers are those that most often spread to the brain. The researchers used the nano delivery system to identify and attack the cancers. In each instance, animals that received treatment lived significantly longer than those in control groups. “Several drugs are quite effective in treating different types of breast cancers, lung cancer, lymphoma and other cancers at their original sites, but they are ineffective against cancers that spread to the brain because they are not able to cross the blood-brain barrier that protects the brain from toxins in the blood,” said Keith Black, MD, chair of the Department of Neurosurgery, director of the Maxine Dunitz Neurosurgical Institute, director of the Johnnie L. Cochran, Jr., Brain Tumor Center and the Ruth and Lawrence Harvey Chair in Neuroscience. “The nanodrug is engineered to cross this barrier with its payload intact, so drugs that are effective outside the brain may be effective inside as well,” Black added. Ljubimova, Black and Holler led the study and contributed equally to the article. Rameshwar Patil, PhD, a project scientist in Ljubimova’s laboratory, is first author. Researchers from Cedars-Sinai’s Department of Neurosurgery, Department of Biomedical Sciences, Department of Imaging, and the Samuel Oschin Comprehensive Cancer Institute contributed to the study with colleagues from the University of Southern California and Arrogene Inc., a biotech company associated with Cedars-Sinai.
Zhigang Gui (left), Laurent Bellaiche Gui used supercomputers at Oak Ridge National Laboratory to perform large-scale computations to determine the electrical properties of electrical vortices in ferroelectric materials, which generate an electric field when their shape is changed. An electrical vortex occurs when the electric dipoles arrange themselves in an unusual swirling movement, Bellaiche said. In this ferroelectric system, electrical vortices are created and determined by the temperature of the material, Bellaiche said. The simulations also revealed that the existence of an electrical vortex increases the band gap – the major factor determining a material’s conductivity – in this material, which offers insight to the controversial issue about the origin of the conductivity of electrical vortices. “By changing temperature we are changing the band alignment,” Gui said. “Imagine having the same system having two different band alignments, which can lead to different applications. When decreasing temperature, our systems can transform from a Type-I band alignment, which favors light-emitting devices, to a Type-II band alignment, which favors sensors in semiconductor industries.”