Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer's Disease.

To elucidate the role of Tau isoforms and post-translational modification (PTM) stoichiometry in Alzheimer's disease (AD), we generated a high-resolution quantitative proteomics map of 95 PTMs on multiple isoforms of Tau isolated from postmortem human tissue from 49 AD and 42 control subjects. Although Tau PTM maps reveal heterogeneity across subjects, a subset of PTMs display high occupancy and frequency for AD, suggesting importance in disease. Unsupervised analyses indicate that PTMs occur in an ordered manner, leading to Tau aggregation. The processive addition and minimal set of PTMs associated with seeding activity was further defined by analysis of size-fractionated Tau. To summarize, features in the Tau protein critical for disease intervention at different stages of disease are identified, including enrichment of 0N and 4R isoforms, underrepresentation of the C terminus, an increase in negative charge in the proline-rich region (PRR), and a decrease in positive charge in the microtubule binding domain (MBD).

Ice-Binding Proteins and Their Function.

Ice-binding proteins (IBPs) are a diverse class of proteins that assist organism survival in the presence of ice in cold climates. They have different origins in many organisms, including bacteria, fungi, algae, diatoms, plants, insects, and fish. This review covers the gamut of IBP structures and functions and the common features they use to bind ice. We discuss mechanisms by which IBPs adsorb to ice and interfere with its growth, evidence for their irreversible association with ice, and methods for enhancing the activity of IBPs. The applications of IBPs in the food industry, in cryopreservation, and in other technologies are vast, and we chart out some possibilities.

A peptide-binding domain shared with an Antarctic bacterium facilitates Vibrio cholerae human cell binding and intestinal colonization.

Vibrio cholerae, the causative agent of the disease cholera, is responsible for multiple pandemics. V. cholerae binds to and colonizes the gastrointestinal tract within the human host, as well as various surfaces in the marine environment (e.g., zooplankton) during interepidemic periods. A large adhesin, the Flagellar Regulated Hemagglutinin A (FrhA), enhances binding to erythrocytes and epithelial cells and enhances intestinal colonization. We identified a peptide-binding domain (PBD) within FrhA that mediates hemagglutination, binding to epithelial cells, intestinal colonization, and facilitates biofilm formation. Intriguingly, this domain is also found in the ice-binding protein of the Antarctic bacterium Marinomonas primoryensis, where it mediates binding to diatoms. Peptide inhibitors of the M. primoryensis PBD inhibit V. cholerae binding to human cells as well as to diatoms and inhibit biofilm formation. Moreover, the M. primoryensis PBD inserted into FrhA allows V. cholerae to bind human cells and colonize the intestine and also enhances biofilm formation, demonstrating the interchangeability of the PBD from these bacteria. Importantly, peptide inhibitors of PBD reduce V. cholerae intestinal colonization in infant mice. These studies demonstrate how V. cholerae uses a PBD shared with a diatom-binding Antarctic bacterium to facilitate intestinal colonization in humans and biofilm formation in the environment.

Controlled Self-Assembly of Nanoscale Superstructures in Phase-Change Ge-Sb-Te Nanowires.

Controlled growth of semiconductor nanowires with atomic precision offers the potential to tune the material properties for integration into scalable functional devices. Despite significant progress in understanding the nanowire growth mechanism, definitive control over atomic positions of its constituents, structure, and morphology via self-assembly remains challenging. Here, we demonstrate an exquisite control over synthesis of cation-ordered nanoscale superstructures in Ge-Sb-Te nanowires with the ability to deterministically vary the nanowire growth direction, crystal facets, and periodicity of cation ordering by tuning the relative precursor flux during synthesis. Furthermore, the role of anisotropy on material properties in cation-ordered nanowire superstructures is illustrated by fabricating phase-change memory (PCM) devices, which show significantly different growth direction dependent amorphization current density. This level of control in synthesizing chemically ordered nanoscale superstructures holds potential to precisely modulate fundamental material properties such as the electronic and thermal transport, which may have implications for PCM, thermoelectrics, and other nanoelectronic devices.

Adhesin domains responsible for binding bacteria to surfaces they colonize project outwards from companion split domains.

Bacterial adhesins attach their hosts to surfaces that the bacteria will colonize. This surface adhesion occurs through specific ligand-binding domains located towards the distal end of the long adhesin molecules. However, recognizing which of the many adhesin domains are structural and which are ligand binding has been difficult up to now. Here we have used the protein structure modeling program AlphaFold2 to predict structures for these giant 0.2- to 1.5-megadalton proteins. Crystal structures previously solved for several adhesin regions are in good agreement with the models. Whereas most adhesin domains are linked in a linear fashion through their N- and C-terminal ends, ligand-binding domains can be recognized by budding out from a companion core domain so that their ligand-binding sites are projected away from the axis of the adhesin for maximal exposure to their targets. These companion domains are "split" in their continuity by projecting the ligand-binding domain outwards. The "split domains" are mostly ß-sandwich extender modules, but other domains like a ß-solenoid can serve the same function. Bioinformatic analyses of Gram-negative bacterial sequences revealed wide variety ligand-binding domains are used in their Repeats-in-Toxin adhesins. The ligands for many of these domains have yet to be identified but known ligands include various cell-surface glycans, proteins, and even ice. Recognizing the ligands to which the adhesins bind could lead to ways of blocking colonization by bacterial pathogens. Engineering different ligand-binding domains into an adhesin has the potential to change the surfaces to which bacteria bind.

Horizontal Gene Transfer in Vertebrates: A Fishy Tale.

The recent assembly of the herring genome suggests this fish acquired its antifreeze protein gene by horizontal transfer and then passed a copy on to the smelt. The direction of gene transfer is confirmed by some accompanying transposable elements and by the breakage of gene synteny.

CD57 defines a novel cancer stem cell that drive invasion of diffuse pediatric-type high grade gliomas.

BACKGROUND: Diffuse invasion remains a primary cause of treatment failure in pediatric high-grade glioma (pHGG). Identifying cellular driver(s) of pHGG invasion is needed for anti-invasion therapies. METHODS: Ten highly invasive patient-derived orthotopic xenograft (PDOX) models of pHGG were subjected to isolation of matching pairs of invasive (HGGINV) and tumor core (HGGTC) cells. RESULTS: pHGGINV cells were intrinsically more invasive than their matching pHGGTC cells. CSC profiling revealed co-positivity of CD133 and CD57 and identified CD57+CD133- cells as the most abundant CSCs in the invasive front. In addition to discovering a new order of self-renewal capacities, i.e., CD57+CD133- > CD57+CD133+ > CD57-CD133+ > CD57-CD133- cells, we showed that CSC hierarchy was impacted by their spatial locations, and the highest self-renewal capacities were found in CD57+CD133- cells in the HGGINV front (HGGINV/CD57+CD133- cells) mediated by NANOG and SHH over-expression. Direct implantation of CD57+ (CD57+/CD133- and CD57+/CD133+) cells into mouse brains reconstituted diffusely invasion, while depleting CD57+ cells (i.e., CD57-CD133+) abrogated pHGG invasion. CONCLUSION: We revealed significantly increased invasive capacities in HGGINV cells, confirmed CD57 as a novel glioma stem cell marker, identified CD57+CD133- and CD57+CD133+ cells as a new cellular driver of pHGG invasion and suggested a new dual-mode hierarchy of HGG stem cells.

A transgenic mouse model of Down syndrome acute lymphoblastic leukemia identifies targetable vulnerabilities.

Not available.

Protein inclusion into ice can dissociate subunits.

An antifreeze protein's inclusion into ice can be used to purify it from other proteins and solutes. Domains that are covalently attached to the antifreeze protein are also drawn into the ice such that the ice-binding portion of the fusion protein can be used as an affinity tag. Here we have explored the use of ice-affinity tags on multi-subunit proteins. When an ice-binding protein was attached as a tag to multisubunit complexes a substantial portion of each multimer dissociated during overgrowth by the ice. The protein subunit attached to the affinity tag was enriched in the ice and the other subunit was appreciably excluded. We suggest that step growth of the advancing ice front generates shearing forces on the bound complex that can disrupt non-covalent protein-protein interactions. This will effectively limit the use of ice-affinity tags to single subunit proteins.

Resonant domain-wall-enhanced tunable microwave ferroelectrics.

Ordering of ferroelectric polarization1 and its trajectory in response to an electric field2 are essential for the operation of non-volatile memories3, transducers4 and electro-optic devices5. However, for voltage control of capacitance and frequency agility in telecommunication devices, domain walls have long been thought to be a hindrance because they lead to high dielectric loss and hysteresis in the device response to an applied electric field6. To avoid these effects, tunable dielectrics are often operated under piezoelectric resonance conditions, relying on operation well above the ferroelectric Curie temperature7, where tunability is compromised. Therefore, there is an unavoidable trade-off between the requirements of high tunability and low loss in tunable dielectric devices, which leads to severe limitations on their figure of merit. Here we show that domain structure can in fact be exploited to obtain ultralow loss and exceptional frequency selectivity without piezoelectric resonance. We use intrinsically tunable materials with properties that are defined not only by their chemical composition, but also by the proximity and accessibility of thermodynamically predicted strain-induced, ferroelectric domain-wall variants8. The resulting gigahertz microwave tunability and dielectric loss are better than those of the best film devices by one to two orders of magnitude and comparable to those of bulk single crystals. The measured quality factors exceed the theoretically predicted zero-field intrinsic limit owing to domain-wall fluctuations, rather than field-induced piezoelectric oscillations, which are usually associated with resonance. Resonant frequency tuning across the entire L, S and C microwave bands (1-8 gigahertz) is achieved in an individual device-a range about 100 times larger than that of the best intrinsically tunable material. These results point to a rich phase space of possible nanometre-scale domain structures that can be used to surmount current limitations, and demonstrate a promising strategy for obtaining ultrahigh frequency agility and low-loss microwave devices.