The Drosophila gene ten-m/odz is the only pair rule gene identified to date which is not a transcription factor. In an attempt to analyze the structure and the function of ten-m/odz in mouse, we isolated four murine ten-m cDNAs which code for proteins of 2,700–2,800 amino acids. All four proteins (Ten-m1–4) lack signal peptides at the NH2 terminus, but contain a short hydrophobic domain characteristic of transmembrane proteins, 300–400 amino acids after the NH2 terminus. About 200 amino acids COOH-terminal to this hydrophobic region are eight consecutive EGF-like domains.Cell transfection, biochemical, and electronmicroscopic studies suggest that Ten-m1 is a dimeric type II transmembrane protein. Expression of fusion proteins composed of the NH2-terminal and hydrophobic domain of ten-m1 attached to the alkaline phosphatase reporter gene resulted in membrane-associated staining of the alkaline phosphatase. Electronmicroscopic and electrophoretic analysis of a secreted form of the extracellular domain of Ten-m1 showed that Ten-m1 is a disulfide-linked dimer and that the dimerization is mediated by EGF-like modules 2 and 5 which contain an odd number of cysteines.Northern blot and immunohistochemical analyses revealed widespread expression of mouse ten-m genes, with most prominent expression in brain. All four ten-m genes can be expressed in variously spliced mRNA isoforms. The extracellular domain of Ten-m1 fused to an alkaline phosphatase reporter bound to specific regions in many tissues which were partially overlapping with the Ten-m1 immunostaining. Far Western assays and electronmicroscopy demonstrated that Ten-m1 can bind to itself.

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Iron-based nanoparticles have attracted much attention because of their ability to induce ferroptosis via a catalyzing Fenton reaction and to further potentiate immunotherapy. However, current iron-based nanoparticles need to be used in cooperation with other treatments or be applied in a high dose for effective therapy because of their low reactive oxygen species production efficacy. Here, we synthesized ultrasmall single-crystal Fe nanoparticles (bcc-USINPs) that stayed stable in a normal physiological environment but were highly active in a tumor microenvironment because of the selective acidic etching of an Fe 3 O 4 shell and the exposure of the Fe(0) core. The bcc-USINPs could efficiently induce tumor cell ferroptosis and immunogenetic cell death at a very low concentration. Intravenous injection of iRGD-bcc-USINPs at three doses of 1 mg/kg could effectively suppress the tumor growth, promote the maturation of dendritic cells, and trigger the adaptive T cell response. Combined with programmed death-ligand 1 (PD-L1) immune checkpoint blockade immunotherapy, the iRGD-bcc-USINP-mediated ferroptosis therapy greatly potentiated the immune response and developed strong immune memory. In addition, these USINPs were quickly renal excreted with no side effects in normal tissues. These iRGD-bcc-USINPs provide a simple, safe, effective, and selectively tumor-responsive Fe(0) delivery system for ferroptosis-based immunotherapy.

Ten-m/Odz/teneurins are a new family of four distinct type II transmembrane molecules. Their extracellular domains are composed of an array of eight consecutive EGF modules followed by a large globular domain. Two of the eight modules contain only 5 instead of the typical 6 cysteine residues and have the capability to dimerize in a covalent, disulfide-linked fashion. The structural properties of the extracellular domains of all four mouse Ten-m proteins have been analyzed using secreted, recombinant molecules produced by mammalian HEK-293 cells. Electron microscopic analysis supported by analytical ultracentrifugation data revealed that the recombinant extracellular domains of all Ten-m proteins formed homodimers. SDS-PAGE analysis under nonreducing conditions as well as negative staining after partial denaturation of the molecules indicated that the globular COOH-terminal domains of Ten-m1 and -m4 contained subdomains with a pronounced stability against denaturing agents, especially when compared with the homologous domains of Ten-m2 and -m3. Cotransfection experiments of mammalian cells with two different extracellular domains revealed that Ten-m molecules have also the ability to form heterodimers, a property that, combined with alternative splicing events, allows the formation of a multitude of molecules with different characteristics from a limited set of genes.The Ten-m/Odz protein was first found in Drosophila where it was proposed to be either a secreted tenascin-like molecule (1) or type I transmembrane receptor (2). We have subsequently identified and characterized the mouse Ten-m and found that it characterizes a new family of genes composed of 4 members (Ten-m1-4). The biochemical analysis of recombinant fragments of mouse Ten-m1 and alkaline phosphatase fusion proteins revealed that Ten-m1 is expressed as a type II transmembrane molecule. Furthermore, we could demonstrate that two of the eight tandemly arranged EGF 1 modules present in the extracellular domain of mouse Ten-m1 containing 5 instead of 6 cysteine residues facilitate the dimerization of two molecules in a covalent, disulfide-linked fashion. Members of the Ten-m family have in the meantime also been described in rat (3), chicken (4 -7), human (8, 9), zebrafish (10), and Caenorhabditis elegans (11).The expression pattern of Ten-m/Odz in flies and mammals suggests important roles during as well as after development. In Drosophila embryogenesis, Ten-m/Odz is expressed in seven stripes during the blastoderm stage (12) and later also in the central nervous system (1), heart (2), and eye (13). Expression studies of Ten-m1-4 in adult mouse tissues showed a widespread expression with the highest levels in the brain (14, 15). In chicken, both teneurin-1 (corresponding to Ten-m1) and teneurin-2 (corresponding to Ten-m2) are expressed in neurons of the developing visual system (4). Furthermore, teneurin-2 mRNA and protein are also found in the developing limbs, somites, and craniofacial mesenchyme (7). During the segmentation period of zebrafish, T...

Neurocan is a chondroitin sulfate proteoglycan of the lectican family and a component of the extracellular matrix of the central nervous system. It is mainly expressed during modeling and remodeling stages of this tissue. Neurocan can bind to various structural extracellular matrix components, such as hyaluronan, heparin, tenascin-C and tenascin-R, and the growth and mobility factors FGF-2, HB-GAM, and amphoterin. Neurocan can also interact with several cell surface molecules, such as N-CAM, L1/Ng-CAM, TAG-1/axonin-1, and an N-cadherin-binding N-acetyl-galactosamine-phosphoryl-transferase, and in vitro studies have shown that neurocan is able to modulate the cell-binding and neurite outgrowth promoting activites of these molecules. Current analysis of the molecular structures and substructures involved in homophilic and heterophilic interactions of these molecules and complementary loss-of-function mutations might shed some light on the roles played by neurocan and interacting molecules in the fine tuning of the nervous system.

S pontaneous intracerebral hemorrhage (ICH) accounts for 10% to 15% of all strokes and is one of the leading causes of stroke-related mortality and morbidity worldwide. Patients with ICH are generally at risk of developing stroke-associated pneumonia (SAP) during acute hospitalization. Evidence has shown that SAP not only increases the length of hospital stay (LOS) and medical cost 1,2 but also is an important risk factor of mortality and morbidity after acute stroke. 3,4 Several risk factors for SAP have been identified, such as older age, 4-12 male sex, 5,6,10,11,13 current smoking, 12 diabetes mellitus, 6 hypertension, 14 atrial fibrillation, 7,10,12 congestive heart failure, 7,12,13,15 chronic obstructive pulmonary disease, 8,[12][13][14] preexisting dependency, 8,12,13,16 stroke severity, 5,6,8,12,17,18 dysphagia, [8][9][10][11][12]14,[18][19][20] and blood glucose. 12 Meanwhile, based on these risk factors, a few risk models have been developed for SAP after acute ischemic stroke. [8][9][10][11][12] Currently, no valid scoring system is available for predicting SAP after ICH in routine clinical practice or clinical trial. We hypothesized that there might be some common grounds for the development of pneumonia after acute ischemic stroke and ICH, and those predictors for SAP after acute ischemic stroke might also be useful for predicting SAP after ICH. For clinical practice, an effective risk-stratification and prognostic model for SAP after ICH would be helpful to identify vulnerable patients, allocate relevant medical resources, and implement tailored preventive strategies. In addition, for clinical trial, it could be used in nonrandomized studies to control for case-mix variation and in controlled studies as a selection criterion.Background and Purpose-We aimed to develop a risk score (intracerebral hemorrhage-associated pneumonia score, ICH-APS) for predicting hospital-acquired stroke-associated pneumonia (SAP) after ICH. Methods-The ICH-APS was developed based on the China National Stroke Registry (CNSR), in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. Variables routinely collected at presentation were used for predicting SAP after ICH. For testing the added value of hematoma volume measure, we separately developed 2 models with (ICH-APS-B) and without (ICH-APS-A) hematoma volume included. Multivariable logistic regression was performed to identify independent predictors. The area under the receiver operating characteristic curve (AUROC), Hosmer-Lemeshow goodness-of-fit test, and integrated discrimination index were used to assess model discrimination, calibration, and reclassification, respectively. Results-The SAP was 16.4% and 17.7% in the overall derivation (n=2998) and validation (n=2000) cohorts, respectively.A 23-point ICH-APS-A was developed based on a set of predictors and showed good discrimination in the overall derivation (AUROC, 0.75; 95% confidence interval, 0. Ji et al Risk Score to Predict SAP After ICH 2621In the study, we aimed to ...

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