SWI is valuable for characterization of intracranial hemorrhage and mineralization but has long acquisition times. We compared a highly accelerated wave-controlled aliasing in parallel imaging ...(CAIPI) SWI sequence with 2 commonly used alternatives, standard SWI and T2*-weighted gradient recalled-echo (T2*W GRE), for routine clinical brain imaging at 3T.
A total of 246 consecutive adult patients were prospectively evaluated using a conventional SWI or T2*W GRE sequence and an optimized wave-CAIPI SWI sequence, which was 3-5 times faster than the standard sequence. Two blinded radiologists scored each sequence for the presence of hemorrhage, the number of microhemorrhages, and severity of motion artifacts. Wave-CAIPI SWI was then evaluated in head-to-head comparison with the conventional sequences for visualization of pathology, artifacts, and overall diagnostic quality. Forced-choice comparisons were used for all scores. Wave-CAIPI SWI was tested for superiority relative to T2*W GRE and for noninferiority relative to standard SWI using a 15% noninferiority margin.
Compared with T2*W GRE, wave-CAIPI SWI detected hemorrhages in more cases (
< .001) and detected more microhemorrhages (
< .001). Wave-CAIPI SWI was superior to T2*W GRE for visualization of pathology, artifacts, and overall diagnostic quality (all
< .001). Compared with standard SWI, wave-CAIPI SWI showed no difference in the presence or number of hemorrhages identified. Wave-CAIPI SWI was noninferior to standard SWI for the visualization of pathology (
< .001), artifacts (
< .01), and overall diagnostic quality (
< .01). Motion was less severe with wave-CAIPI SWI than with standard SWI (
< .01).
Wave-CAIPI SWI provided superior visualization of pathology and overall diagnostic quality compared with T2*W GRE and was noninferior to standard SWI with reduced scan times and reduced motion artifacts.
This study is a framework proposal for understanding the antimicrobacterial effect of both α-Ag2WO4 microcrystals (AWO) synthesized using a microwave hydrothermal (MH) method and α-Ag2WO4 ...microcrystals with Ag metallic nanofilaments (AWO:Ag) obtained by irradiation employing an electron beam to combat against planktonic cells of methicillin-resistant Staphylococcus aureus (MRSA). These samples were characterized by X-ray diffraction (XRD), FT-Raman spectroscopy, ultraviolet visible (UV–vis) measurements, field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), and high resolution transmission electron microscopy (HRTEM). The results reveal that both AWO and AWO:Ag solutions have bacteriostatic and bactericidal effects, but the irradiated sample is more efficient; i.e., a 4-fold of the MRSA planktonic cells as compared to the nonirradiated sample was observed. In addition, first principles calculations were performed to obtain structural and electronic properties of AWO and metallic Ag, which provides strong quantitative support for an antimicrobacterial mechanism based on the enhancement of electron transfer processes between α-Ag2WO4 and Ag nanoparticles.
Each year, 10 million people worldwide survive the neurologic injury associated with a stroke. Importantly, stroke survivors have more than twice the risk of subsequently developing dementia compared ...with people who have never had a stroke. The link between stroke and the later development of dementia is not understood. There are reports of oligoclonal bands in the CSF of stroke patients, suggesting that in some people a B-lymphocyte response to stroke may occur in the CNS. Therefore, we tested the hypothesis that a B-lymphocyte response to stroke could contribute to the onset of dementia. We discovered that, in mouse models, activated B-lymphocytes infiltrate infarcted tissue in the weeks after stroke. B-lymphocytes undergo isotype switching, and IgM, IgG, and IgA antibodies are found in the neuropil adjacent to the lesion. Concurrently, mice develop delayed deficits in LTP and cognition. Genetic deficiency, and the pharmacologic ablation of B-lymphocytes using an anti-CD20 antibody, prevents the appearance of delayed cognitive deficits. Furthermore, immunostaining of human postmortem tissue revealed that a B-lymphocyte response to stroke also occurs in the brain of some people with stroke and dementia. These data suggest that some stroke patients may develop a B-lymphocyte response to stroke that contributes to dementia, and is potentially treatable with FDA-approved drugs that target B cells.
•Ferromagnetism preserved at the interface between Fe and granular Sb2Te3 deposited by MOCVD.•Preferential Fe–Te bonding in Fe/Sb2Te3 heterostructures.•Identification of a possible general bonding ...mechanism between Fe and chalcogenide-based TI.•Insight on rapid thermal annealing to improve the Fe/Sb2Te3 interface quality.
Interfacing topological insulators (TI) with ferromagnetic (FM) layers is a promising route towards the next generation of ultra-low power spintronic devices based on charge-to-spin current conversion. Here, we present the Fe/Sb2Te3 interface structure, its chemical composition and magnetic properties. Thin films (30 nm) of the topological insulator Sb2Te3 were synthesized by Metal Organic Chemical Vapor Deposition (MOCVD) at room temperature on Si/SiO2 substrates, then capped with a 54Fe(10 nm)/57Fe(1 nm) bilayer by Pulsed Laser Deposition (PLD) to allow interface-sensitive Conversion Electron Mössbauer Spectroscopy (CEMS). X-ray diffraction (XRD) showed the polycrystalline nature of both the Fe and Sb2Te3 layers. X-ray reflectivity (XRR) identified a non-trivial layered structure with the presence of an intermixed layer at the Fe/Sb2Te3 interface. Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) confirmed the partial elemental interdiffusion between the Fe and Sb2Te3 layers. Interface-sensitive CEMS evidenced that about a half of the 1-nm-thick 57Fe layer in contact with Sb2Te3 coordinates ferromagnetically, whereas the remaining paramagnetic fraction preferentially bonds with Te. The Fe/Sb2Te3 system was shown to have a far from sharp interface, exhibiting a marked chemical reactivity already at room temperature. The tendency of Fe to preferentially bond with the chalcogenide element of topological insulators has been previously observed for the interface with Bi2Se3 and Bi2Te3, thus suggesting a possible universal behavior at the interface between Fe and chalcogenide-based TI.
Chondroitin sulfate proteoglycans (CSPGs) are a family of extracellular matrix molecules with various functions in regulating tissue morphogenesis, cell division, and axon guidance. A number of CSPGs ...are highly upregulated by reactive glial scar tissues after injuries and form a strong barrier for axonal regeneration in the adult vertebrate CNS. Although CSPGs may negatively regulate axonal growth via binding and altering activity of other growth-regulating factors, the molecular mechanisms by which CSPGs restrict axonal elongation are not well understood. Here, we identified a novel receptor mechanism whereby CSPGs inhibit axonal growth via interactions with neuronal transmembrane leukocyte common antigen-related phosphatase (LAR). CSPGs bind LAR with high affinity in transfected COS-7 cells and coimmunoprecipitate with LAR expressed in various tissues including the brain and spinal cord. CSPG stimulation enhances activity of LAR phosphatase in vitro. Deletion of LAR in knock-out mice or blockade of LAR with sequence-selective peptides significantly overcomes neurite growth restrictions of CSPGs in neuronal cultures. Intracellularly, CSPG-LAR interaction mediates axonal growth inhibition of neurons partially via inactivating Akt and activating RhoA signals. Systemic treatments with LAR-targeting peptides in mice with thoracic spinal cord transection injuries induce significant axon growth of descending serotonergic fibers in the vicinity of the lesion and beyond in the caudal spinal cord and promote locomotor functional recovery. Identification of LAR as a novel CSPG functional receptor provides a therapeutic basis for enhancing axonal regeneration and functional recovery after CNS injuries in adult mammals.
A compendium of different types of abiotic chemical syntheses identifies a consensus set of 10 “prebiotic” α-amino acids. Before the emergence of biosynthetic pathways, this set is the most plausible ...resource for protein formation (i.e., proteogenesis) within the overall process of abiogenesis. An essential unsolved question regarding this prebiotic set is whether it defines a “foldable set”—that is, does it contain sufficient chemical information to permit cooperatively folding polypeptides? If so, what (if any) characteristic properties might such polypeptides exhibit? To investigate these questions, two “primitive” versions of an extant protein fold (the β-trefoil) were produced by top-down symmetric deconstruction, resulting in a reduced alphabet size of 12 or 13 amino acids and a percentage of prebiotic amino acids approaching 80%. These proteins show a substantial acidification of pI and require high salt concentrations for cooperative folding. The results suggest that the prebiotic amino acids do comprise a foldable set within the halophile environment.
The ubiquity of phospho-ligands suggests that phosphate binding emerged at the earliest stage of protein evolution. To evaluate this hypothesis and unravel its details, we identified all ...phosphate-binding protein lineages in the Evolutionary Classification of Protein Domains database. We found at least 250 independent evolutionary lineages that bind small molecule cofactors and metabolites with phosphate moieties. For many lineages, phosphate binding emerged later as a niche functionality, but for the oldest protein lineages, phosphate binding was the founding function. Across some 4 billion y of protein evolution, side-chain binding, in which the phosphate moiety does not interact with the backbone at all, emerged most frequently. However, in the oldest lineages, and most characteristically in αβα sandwich enzyme domains, N-helix binding sites dominate, where the phosphate moiety sits atop the N terminus of an α-helix. This discrepancy is explained by the observation that N-helix binding is uniquely realized by short, contiguous sequences with reduced amino acid diversity, foremost Gly, Ser, and Thr. The latter two amino acids preferentially interact with both the backbone amide and the side-chain hydroxyl (bidentate interaction) to promote binding by short sequences. We conclude that the first αβα sandwich domains emerged from shorter and simpler polypeptides that bound phospho-ligands via N-helix sites.
De novo emergence demands a transition from disordered polypeptides into structured proteins with well-defined functions. However, can polypeptides confer functions of evolutionary relevance, and how ...might such polypeptides evolve into modern proteins? The earliest proteins present an even greater challenge, as they were likely based on abiotic, spontaneously synthesized amino acids. Here we asked whether a primordial function, such as nucleic acid binding, could emerge with ornithine, a basic amino acid that forms abiotically yet is absent in modern-day proteins. We combined ancestral sequence reconstruction and empiric deconstruction to unravel a gradual evolutionary trajectory leading from a polypeptide to a ubiquitous nucleic acid-binding protein. Intermediates along this trajectory comprise sequence-duplicated functional proteins built from 10 amino acid types, with ornithine as the only basic amino acid. Ornithine side chains were further modified into arginine by an abiotic chemical reaction, improving both structure and function. Along this trajectory, function evolved from phase separation with RNA (coacervates) to avid and specific double-stranded DNA binding. Our results suggest that phase-separating polypeptides may have been an evolutionary resource for the emergence of early proteins, and that ornithine, together with its postsynthesis modification to arginine, could have been the earliest basic amino acids.
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► A consensus set of 10 pre-biotic α-amino acids is identified from diverse abiotic sources. ► The properties of the pre-biotic set of amino acids suggest that it likely comprises a ...“foldable” set. ► Proteogenesis appears most compatible with an acidophilic/halophilic environment.
“Proteogenesis” (the origin of proteins) is a likely key event in the unsolved problem of biogenesis (the origin of life). The raw material for the very first proteins comprised the available amino acids produced and accumulated upon the early earth via abiotic chemical and physical processes. A broad consensus is emerging that this pre-biotic set likely comprised Ala, Asp, Glu, Gly, Ile, Leu, Pro, Ser, Thr, and Val. A key question in proteogenesis is whether such abiotically-produced amino acids comprise a “foldable” set. Current knowledge of protein folding identifies properties of complexity, secondary structure propensity, hydrophobic–hydrophilic patterning, core-packing potential, among others, as necessary elements of foldability. None of these requirements excludes the pre-biotic set of amino acids from being a foldable set. Moreover, nucleophile and metal ion/mineral binding capabilities also appear present in the pre-biotic set. Properties of the pre-biotic set, however, likely restrict foldability to the acidophilic/halophilic environment.
Alzheimer's disease (AD) is associated with memory impairment and altered peripheral metabolism. Mounting evidence indicates that abnormal signaling in a brain-periphery metabolic axis plays a role ...in AD pathophysiology. The activation of pro-inflammatory pathways in the brain, including the interleukin-6 (IL-6) pathway, comprises a potential point of convergence between memory dysfunction and metabolic alterations in AD that remains to be better explored. Using T2-weighted magnetic resonance imaging (MRI), we observed signs of probable inflammation in the hypothalamus and in the hippocampus of AD patients when compared to cognitively healthy control subjects. Pathological examination of post-mortem AD hypothalamus revealed the presence of hyperphosphorylated tau and tangle-like structures, as well as parenchymal and vascular amyloid deposits surrounded by astrocytes. T2 hyperintensities on MRI positively correlated with plasma IL-6, and both correlated inversely with cognitive performance and hypothalamic/hippocampal volumes in AD patients. Increased IL-6 and suppressor of cytokine signaling 3 (SOCS3) were observed in post-mortem AD brains. Moreover, activation of the IL-6 pathway was observed in the hypothalamus and hippocampus of AD mice. Neutralization of IL-6 and inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling in the brains of AD mouse models alleviated memory impairment and peripheral glucose intolerance, and normalized plasma IL-6 levels. Collectively, these results point to IL-6 as a link between cognitive impairment and peripheral metabolic alterations in AD. Targeting pro-inflammatory IL-6 signaling may be a strategy to alleviate memory impairment and metabolic alterations in the disease.
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