In acute stroke with proximal artery occlusion, FLAIR vascular hyperintensities observed beyond the boundaries of the cortical lesion on DWI (newly defined "FLAIR vascular hyperintensity-DWI ...mismatch") may be a marker of tissue at risk of infarction. Our aim was to compare the occurrence of FLAIR vascular hyperintensity-DWI mismatch relative to that of perfusion-weighted imaging-DWI mismatch in patients with proximal MCA occlusion before IV thrombolysis.
In 141 consecutive patients with proximal MCA occlusion, 2 independent observers analyzed FLAIR images for the presence of FLAIR vascular hyperintensity-DWI mismatch before IV thrombolysis. PWI-DWI mismatch was defined as Volumehypoperfusion > 1.8 × VolumeDWI, with Volumehypoperfusion > 6 seconds on time to maximum value of the residue function maps in the 94 patients with available PWI. The presence of FLAIR vascular hyperintensity-DWI mismatch, PWI-DWI mismatch, and infarct growth on 24-hour follow-up DWI was compared.
A FLAIR vascular hyperintensity-DWI mismatch was present in 102/141 (72%) patients, with an excellent interobserver reliability (κ = 0.91), and a PWI-DWI mismatch, in 61 of the 94 (65%) patients with available PWI. FLAIR vascular hyperintensity-DWI mismatch predicted PWI-DWI mismatch with a sensitivity of 92% (95% CI, 85%-99%) and a specificity of 64% (95% CI, 47%-80%). Patients with FLAIR vascular hyperintensity-DWI mismatch had smaller initial DWI lesion and larger infarct growth (P < .001) than patients without FLAIR vascular hyperintensity-DWI mismatch, even though their final infarcts remained smaller (P < .001).
Albeit being moderately specific, probably due to inclusion of oligemic tissue, the FLAIR vascular hyperintensity-DWI mismatch identifies large PWI-DWI mismatch with high sensitivity.
Defensins and cathelicidins are the two major families of mammalian anti‐microbial proteins. They contribute to host, innate, anti‐microbial defense by disrupting the integrity of the bacterial cell ...membrane. However, several members of the mammalian anti‐microbial proteins including defensins and cathelicidins have been shown recently to have chemotactic effects on host cells. Human neutrophil α‐defensins are chemotactic for resting, naïve CD45RA/CD4 T cells, CD8 T cells, and immature dendritic cells. Human β‐defensins are also chemotactic for immature dendritic cells but induce the migration of memory CD45RO/CD4 T cells. In contrast, cathelicidin/LL‐37 is chemotactic for neutrophils, monocytes, and T cells but not for dendritic cells. Thus, these anti‐microbial peptides have distinct, host‐target cell spectra. The chemotactic activities of human β‐defensins and cathelicidin/LL‐37 are mediated by human CC chemokine receptor 6 and formyl peptide receptor‐like 1, respectively. The capacities of defensins and cathelicidins to mobilize various types of phagocytic leukocytes, immature dendritic cells, and lymphocytes, together with their other effects such as stimulating IL‐8 production and mast cell degranulation, provide evidence for their participation in alerting, mobilizing, and amplifying innate and adaptive anti‐microbial immunity of the host.
In nature, sophisticated functional materials are created through hierarchical self-assembly of simple nanoscale motifs. In the laboratory, much progress has been made in the controlled assembly of ...molecules into one-, two- and three-dimensional artificial nanostructures, but bridging from the nanoscale to the macroscale to create useful macroscopic materials remains a challenge. Here we show a scalable self-assembly approach to making free-standing films from amyloid protein fibrils. The films were well ordered and highly rigid, with a Young's modulus of up to 5-7 GPa, which is comparable to the highest values for proteinaceous materials found in nature. We show that the self-organizing protein scaffolds can align otherwise unstructured components (such as fluorophores) within the macroscopic films. Multiscale self-assembly that relies on highly specific biomolecular interactions is an attractive path for realizing new multifunctional materials built from the bottom up.
Alpha-synuclein (αS) is causally involved in the development of Parkinson disease (PD); however, its role in normal vertebrate physiology has remained unknown. Recent studies demonstrate that αS is ...induced by noroviral infection in the enteric nervous system of children and protects mice against lethal neurotropic viral infection. Additionally, αS is a potent chemotactic activator of phagocytes. In this report, using both wild-type and αS knockout mice, we show that αS is a critical mediator of inflammatory and immune responses. αS is required for the development of a normal inflammatory response to bacterial peptidoglycan introduced into the peritoneal cavity as well as antigen-specific and T cell responses following intraperitoneal immunization. Furthermore, we show that neural cells are the sources of αS required for immune competence. Our report supports the hypothesis that αS accumulates within the nervous system of PD individuals because of an inflammatory/immune response.
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•Peritoneal inflammation triggers αS production by neurons that innervate peritoneum•αS activates APCs by triggering TLR4 and promotes innate and adaptive immune responses•Neuronal αS is required for the induction of peritonitis and immune responses•αS-triggered immune responses may contribute to PD development and/or progression
Alam et al. show that αS produced by the neurons of the gastrointestinal system is critical for the manifestation of peritoneal inflammation and systemic antigen-specific immune responses, which may in turn, promote neuronal αS accumulation and contribute to the development and/or progression of Parkinson disease.
Beta-defensins play a dual role during immune response. Their direct antimicrobial properties contribute to the local innate immune response by combating microbial invasions. Furthermore, previous ...studies revealed the capacity of certain beta-defensin family members to chemoattract immature dendritic cells and CD45RO+ CD4+ T cells through chemokine receptor CCR6. However, because beta-defensins also chemoattract macrophages and monocytes, which do not express CCR6, efforts have been made to identify other receptors for these polypeptides. In this study, we demonstrate the capacity of human beta-defensin (hBD)2 and 3 and their mouse orthologs, beta-defensin 4 and 14, to interact with CCR2, a chemokine receptor expressed on monocytes, macrophages, and neutrophils. These beta-defensins, fused to the Fc region of human IgG1, showed binding to CCR2-transfected HEK293 cells, as revealed by flow cytometry. The beta-defensin fusion proteins also induced CCR2-specific chemotaxis of transfected HEK293 cells, human peripheral blood monocytes, and mouse peritoneal exudate cells in a dose-dependent manner. Preincubation of human monocytes with CCL2/MCP-1, the chemokine ligand for CCR2, abolished migration induced by beta-defensins. Conversely, preincubation with hBD2:Ig or hBD3:Ig inhibited MCP-1 induced migration. Peritoneal exudate cells from CCR2-deficient mice failed to migrate toward these fusion proteins. In conclusion, the beta-defensins used in this study contribute to the innate and adaptive immune response in their role as chemoattractants. Our data indicate that hBD2 and hBD3, together with their mouse orthologs (beta-defensin 4 and 14), are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner.
This review provides an historical account of the discovery and development of cytokines. Cytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and ...mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell growth, differentiation, cell death, angiogenesis, and development and repair processes aimed at the restoration of homeostasis. Although cytokines are occasionally produced constitutively, they are usually produced by virtually every nucleated cell type in response to injurious stimuli. Cytokines act on cells expressing complementary receptors. Cytokines have been assigned to various family groups based on the structural homologies of their receptors. This review shows how cytokine research evolved from phenomenological to molecular stages and from a focus on ligands to characterization of cytokine receptors. The advent of molecular biology, monoclonal antibodies, and microsequencing made it possible to obtain pure recombinant cytokine preparation for experimental and therapeutic applications. The development of targeted gene deletions revealed many cytokines to have unexpected pathophysiological functions. The identification of "virokines," homologues that mimic cytokine ligands and receptors, has provided impetus to the founding of biotechnology companies aimed at developing cytokine agonists and antagonists for therapeutic applications. The discipline of cytokinology is now endowed with several journals, multiple annual meetings, and many devoted investigators. The explosion in cytokine information over the past 40 years has been enormous and full of surprises. If past be prologue, with the advent of genomics and proteomics the future should witness even greater progress.
The acquired enamel pellicle is an oral, fluid-derived protein layer that forms on the tooth surface. It is a biologically and clinically important integument that protects teeth against enamel ...demineralization, and abrasion. Tooth surfaces are exposed to different proteinaceous microenvironments depending on the enamel location. For instance, tooth surfaces close to the gingival sulcus contact serum proteins that emanate via this sulcus, which may impact pellicle composition locally. The aims of this study were to define the major salivary and serum components that adsorb to hydroxyapatite, to study competition among them, and to obtain preliminary evidence in an in vivo saliva/serum pellicle model. Hydroxyapatite powder was incubated with saliva and serum, and the proteins that adsorbed were identified by mass spectrometry. To study competition, saliva and serum proteins were labeled with CyDyes, mixed in various proportions, and incubated with hydroxyapatite. In vivo competition was assessed using a split-mouth design, with half the buccal tooth surfaces coated with serum and the other half with saliva. After exposure to the oral environment for 0 min, 30 min and 2 h, the pellicles were analyzed by SDS-PAGE. In pure saliva- or serum-derived pellicles, 82 and 84 proteins were identified, respectively. When present concomitantly, salivary protein adsorbers effectively competed with serum protein adsorbers for the hydroxyapatite surface. Specifically, acidic proline-rich protein, cystatin, statherin and protein S100-A9 proteins competed off apolipoproteins, complement C4-A, haptoglobin, transthyretin and serotransferrin. In vivo evidence further supported the replacement of serum proteins by salivary proteins. In conclusion, although significant numbers of serum proteins emanate from the gingival sulcus, their ability to participate in dental pellicle formation is likely reduced in the presence of strong salivary protein adsorbers. The functional properties of the acquired enamel pellicle will therefore be mostly dictated by the salivary component.
Alpha-synuclein (αS) is a nerve cell protein associated with Parkinson disease (PD). Accumulation of αS within the enteric nervous system (ENS) and its traffic from the gut to the brain are ...implicated in the pathogenesis and progression of PD. αS has no known function in humans and the reason for its accumulation within the ENS is unknown. Several recent studies conducted in rodents have linked αS to immune cell activation in the central nervous system. We hypothesized that αS in the ENS might play a role in the innate immune defenses of the human gastrointestinal (GI) tract.
We immunostained endoscopic biopsies for αS from children with documented gastric and duodenal inflammation and intestinal allograft recipients who contracted norovirus. To determine whether αS exhibited immune-modulatory activity, we examined whether human αS induced leukocyte migration and dendritic cell maturation.
We showed that the expression of αS in the enteric neurites of the upper GI tract of pediatric patients positively correlated with the degree of acute and chronic inflammation in the intestinal wall. In intestinal allograft subjects who were closely monitored for infection, expression of αS was induced during norovirus infection. We also demonstrated that both monomeric and oligomeric αS have potent chemoattractant activity, causing the migration of neutrophils and monocytes dependent on the presence of the integrin subunit, CD11b, and that both forms of αS stimulate dendritic cell maturation.
These findings strongly suggest that αS is expressed within the human ENS to direct intestinal inflammation and implicates common GI infections in the pathogenesis of PD.
Objectives
Saliva contains biomarkers for systemic as well as oral diseases. This study was undertaken to assess the variability in the sources of such biomarkers (plasma, cells) and attempted to ...identify saliva deterioration markers in order to improve saliva diagnostic outcomes.
Materials and Methods
Inter‐ and intrasubject variations in salivary gingival crevicular fluid levels were determined by measuring salivary albumin and transferrin levels. The purity of collected glandular secretions was determined by bacterial culture, and the variability in epithelial cell numbers by cell counting and optical density measurement. Saliva sample deterioration markers were identified by RP‐HPLC and LC‐ESI‐MS/MS.
Results
Tenfold variations were observed in plasma‐derived albumin and transferrin levels, emphasizing the need for biomarker normalization with respect to plasma contributions to saliva. Epithelial cell levels varied 50‐fold in samples collected before and after a meal. Salivary fungal levels varied within subjects and among subjects from 0 to >1,000 colony‐forming units per milliliter. In saliva samples incubated for various time intervals at 37°C, five peptides were identified that steadily increased in intensity over time and which could be explored as “deterioration markers.”
Conclusion
Taking saliva characteristics appropriately into account will help realize the promise that this body fluid is suitable to be exploited for reliable healthcare monitoring and surveillance.
The Khatyrka meteorite contains both icosahedral and decagonal quasicrystals. In our previous studies, icosahedral quasicrystals have been synthesized and recovered from shock experiments at the ...interface between CuAl
and stainless steel 304 alloys. In this study, we report a new shock recovery experiment aimed at synthesizing decagonal quasicrystals similar to decagonite, natural Al
Ni
Fe
. Aluminum 2024 and permalloy 80 alloys were stacked together and shocked in a stainless steel 304 recovery chamber. Abundant decagonal quasicrystals of average composition Al
Ni
Fe
Cu
Mg
Mo
Mn
with traces of Si and Cr were found along the recovered interface between the Al and permalloy. The experiment also synthesized AlNiFe alloy with the B2 (CsCl-type) structure and the metastable Al
Ni
phase. We present chemical (scanning electron microscopy and electron microprobe) and structural (electron backscatter diffraction and transmission electron microscopy) characterization of the recovered phases and discuss the implications of this shock synthesis for the stability of quasicrystals during high-pressure shocks and for the interpretation of the phase assemblage found in Khatyrka.
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