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PubMed1999

A nod factor binding lectin with apyrase activity from legume roots.

A lectin isolated from the roots of the legume, Dolichos biflorus, binds to Nod factors produced by rhizobial strains that nodulate this plant and has a deduced amino acid sequence with no significant homology to any lectin reported to date. This lectin also is an enzyme that catalyzes the hydrolysis of phosphoanhydride bonds of nucleoside di- and triphosphates; the enzyme activity is increased in the presence of carbohydrate ligands. This lectin-nucleotide phosphohydrolase (LNP) has a substrate specificity characteristic of the apyrase category of phosphohydrolases, and its sequence contains four motifs characteristic of this category of enzymes. LNP is present on the surface of the root hairs, and treatment of roots with antiserum to LNP inhibits their ability to undergo root hair deformation and to form nodules on exposure to rhizobia. These properties suggest that this protein may play a role in the rhizobium-legume symbiosis and/or in a related carbohydrate recognition event endogenous to the plant.

Amino Acid Sequence↗
PubMed1987

Origin of short latency somatosensory evoked potential in cats: especially potentials derived from thalamus and cortex.

Short latency somatosensory evoked potential (SSEP) was recorded in cats to identify the potentials originating from the cortex and the thalamus, and the following results were obtained. When SSEP was elicited on the bregma by stimulation of the contralateral superficial radial nerve, P2, P4, P4.5, P5.5, P7, P8, N8.5, P11, P9.5, N11.5, N12.5 and N14 were recognized. Of these components N11.5, N12.5 and N14 consisted of large negative potential (LNP). When KCl was applied to the sensorimotor cortex to induce spreading depression, the positive component of the primary evoked potential was markedly decreased and the negative component disappeared. In SSEP, components preceding N8.5 were unchanged. N8.5-P11 and P11-N12.5, however, markedly diminished or disappeared. The latency of the first component of the field potential recorded in the VPL nucleus of the thalamus was about 5 ms. When a small amount of Nembutal was injected into VPL nucleus, components between P2 and P4.5 remained unchanged, but P5.5 disappeared. P7, P8 and N8.5 were preserved. The amplitude of N8.5-P11 was markedly decreased and LNP disappeared. From these results, among various components of SSEP, P5.5 should originate from the thalamus, and P7, P8 and N8.5 from the extralemniscal system. N8.5-P11 should mainly represent post-synaptic potential (PSP) in the deep somatic layer, and P11-N12.5 represent PSP in the apical dentrites of the sensorimotor cortex. N14 probably represents PSP via the diffuse projection system. Thus, LNP should consist of complex potentials of specific and non-specific sensory systems.

Animals↗
PubMed2026

A modular γδ TCR-T platform combining KRAS pMHC targeting with re-dosable mRNA engager redirection.

Solid tumors often evade TCR-engineered αβ T cells when antigen expression varies or when the restricting Human Leukocyte Antigen (HLA) allele is lost. γδ T cells, in contrast, detect cellular dysregulation through non-peptide/Major Histocompatibility Complex (MHC) cues, including phosphoantigens and stress ligands, and can be developed as allogeneic therapies. Although intratumoral γδ T cell signatures are associated with improved outcome across cancers, γδ recognition itself is broad and still selected within the thymus just as αβ T cell receptors (TCRs) are. It does not, however, anchor specificity to a defined driver-mutation pMHC epitope. We therefore asked whether a high-affinity, co-receptor-independent αβ TCR could graft oncogenic-driver specificity onto γδ T cells while leaving the endogenous γδ TCR intact. We knocked the KRASG12V/HLA-A*11:01 TCR A11v into primary human γδ T cells. Engineered cells co-expressed the transgenic αβ TCR and the endogenous γδ TCR and lysed KRASG12V/HLA-A*11:01+ tumor cells in vitro and in vivo. To cover potential resistance through loss of HLA-A*11:01, we delivered an mRNA lipid nanoparticle (LNP) encoding a secreted mesothelin×CD3 (M5) bispecific T cell engager (TCE). LNP-M5 produced circulating TCE that redirected γδ A11v T cells and polyclonal bystander T cells to kill mesothelin+ targets, accompanied by development of higher γδ A11v T cell counts in vivo. In humanized mice bearing mixed HLA-A*11:01+ and HLA-A*11:01 - KRASG12V tumors, γδ A11v T cells produced transient control, whereas adding LNP-M5 yielded complete responses and prolonged survival. Thus, this two-part therapy couples invariant driver targeting to tunable redirection and addresses loss of the restricting HLA allele, a central escape route for TCR-based therapy. It provides an off-the-shelf reagent to enable KRAS-anchored treatment with the ability to redeliver the reagent.

Humans↗
PubMed2005

Intestinal gamma delta T cells develop in mice lacking thymus, all lymph nodes, Peyer's patches, and isolated lymphoid follicles.

Through analysis of athymic (nu/nu) mice carrying a transgenic gene encoding GFP instead of RAG-2 product, it has recently been reported that, in the absence of thymopoiesis, mesenteric lymph nodes and Peyer's patches (PP) but not gut cryptopatches are pivotal birthplace of mature T cells such as the thymus-independent intestinal intraepithelial T cells (IEL). To explore and evaluate this important issue, we generated nu/nu mice lacking all lymph nodes (LN) and PP by administration of lymphotoxin-beta receptor-Ig and TNF receptor 55-Ig fusion proteins into the timed pregnant nu/+ mice that had been mated with male nu/nu mice (nu/nu LNP- mice). We also generated nu/nu aly/aly (aly, alymphoplasia) double-mutant mice that inherently lacked all LN, PP, and isolated lymphoid follicles. Although gammadelta-IEL were slightly smaller in number than those in nu/nu mice, substantial colonization of gammadelta-IEL was found to take place in the intestinal epithelia of nu/nu LNP- and nu/nu aly/aly mice. Notably, the population size of a major CD8alphaalpha+ gammadelta-IEL subset was maintained, the use of TCR-gamma-chain variable gene segments by these gammadelta-IEL was unaltered, and the development of cryptopatches remained intact in these nu/nu LNP- and nu/nu aly/aly mice. These findings indicate that all LN, including mesenteric LN, PP, and isolated lymphoid follicles, are not an absolute requirement for the development of gammadelta-IEL in athymic nu/nu mice.

Animals↗
PubMed2000

[The fate of epithelial cells during fusion of primary palate in vitro].

It has been demonstrated that palatal shelf epithelium transforms into mesenchymal cells during fusion of the secondary palate. However, the fate of epithelial cells in primary palate formation is still unclear. To specify the presumptive fusion area of the primary palate, focal labeling of epithelial cells of medial nasal prominence (MNP), lateral nasal prominence (LNP) and maxillary prominence (Mx) of gestational day 12.0 rat embryos was initially done with fluorescent DiI, and they were cultured for 24 h. As a result, the presumptive fusion area was identified and it was found that there was a difference of the fusion process between MNP-Mx and MNP-LNP. Next, in order to elucidate the fate of epithelial cells in the fusion areas, facial epithelium was labeled with a recombinant adenovirus, Adex-LacZ in the whole embryo culture system and they were observed over time (12 h, 24 h, 36 h and 48 h). LacZ positive cells were observed in the fused region of MNP-Mx and MNP-LNP. Moreover, it was found that there were not only double positive cells of LacZ and TUNEL staining of apoptosis but also some TUNEL nonpositive cells. These findings indicated that a number of epithelial cells in the fusion area become apoptosis, but some cells survive by epithelial-mesenchymal transformation during primary palate formation.

Animals↗
PubMed1980

Enzootic bovine leukosis: prevalence of blood lymphocyte nuclear pockets in dairy bulls in the United States and foreign countries.

Studies of the incidence of enzootic bovine leukosis-related blood lymphlymphocyte nuclear pockets (LNP) were made of 743 dairy breed bulls in the United States and foreign countries. Statistical evaluation disclosed that the prevalence of these anomalous nuclear forms in the studs observed is significantly greater in the United States than in other countries. In particular, the average percentage of LNP-containing cells in each United States stud is estimated to be more than twice the level found in all but two non-United States studs studied and more than three times the level in the majority (10 of 19) of them. Moreover, United States studs exhibited a higher proportion of LNP-suspicious and -positive cases than almost all of the non-United States studs. We believe this is valid evidence that serves to reinforce the expressed need for a federal surveillance program for enzootic bovine leukosis in the United States.

Animals↗
PubMedDate not supplied

Proliferation of nasal epithelial and mesenchymal cells during primary palate formation.

Proliferation of nasal epithelial and mesenchymal cells in mouse embryos was analyzed during primary palate formation using immunohistochemical demonstration of the thymidine analogue, 5-bromodeoxyuridine. Pulse labeling was employed to determine cell proliferation rates, with cell density of the nasal mesenchyme also being measured. To represent the entire nasal groove and prominences, four levels along the superior-inferior direction of three regions were utilized, i.e., the lateral and medial nasal prominences (LNP and MNP) and the bottom of the nasal groove. During the formation period, the labeling indices of the LNP and MNP epithelium decreased with respect to the development stage, whereas those of the bottom epithelium only slightly did. The epithelial cells in the prospective fusion area particularly showed decreased DNA synthesis in comparison with those in the nonfusing areas. In addition, the corresponding activity in the presumptive fusion area of the LNP epithelium was less than that in the MNP epithelium. The time at which a definitive decrease in the labeling index of the presumptive fusion area is believed to occur between tail somite (TS) stages TS5-7. A similar yet smaller decreasing tendency was observed in the labeling indices of the nasal mesenchyme. The cell density of the mesenchyme, however, slightly increased in all examined regions. Our results suggest that epithelial cell proliferation converts to a differentiation-type pattern, especially in the presumptive fusion area.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Pharmacokinetics of 5-fluorouracil in the hamster following inhalation delivery of lipid-coated nanoparticles.

The inhalation delivery of 5-fluorouracil (5-FU) in lipid-coated nanoparticles (LNPs) to hamsters was evaluated to determine the feasibility for use in lung cancer chemotherapy. The inhaled dose, 30 mg LNPs/kg body weight (1.5 mg/kg 5-FU), was delivered over an 8-min interval. Fluorescein isothiocyanate dextran (FITC-dextran) was included within the LNPs to provide an estimate of the particle concentration. The concentration of FITC-dextran and total 5-FU (released and LNP-associated) was determined as a function of time in the lung, trachea, larynx, esophagus, and serum. Concentrations of 5-FU and FITC-dextran were initially high in the trachea, larynx, and esophagus, and lower in the lung. Within 24 h, greater than 99% of the LNPs were cleared from the respiratory tract and total 5-FU concentrations mirrored the LNP concentration. An eight-compartment pharmacokinetic model was used to describe the observed trends in concentrations of LNPs and total 5-FU and to estimate the released 5-FU concentration in the above tissues. From this analysis, effective local targeting as well as sustained efficacious concentrations of 5-FU in the expected tumor sites were demonstrated.

Administration, Inhalation↗
PubMed1991

Inflammatory response induced with an isolated syngeneic activation antigen shared by normal lymphoblasts and YAC lymphoma cells.

An immunogenic protein with an identical Mr (64 kDa) was isolated from syngeneic concanavalin A-induced lymphoblasts (syn-Con A-blasts) and YAC lymphoma cells, both derived from A mice. The 64-kDa protein was purified by a sequence of biochemical steps: Sephadex G-100 gel filtration, ion-exchange chromatography in a fast protein liquid chromatography system, Con A-Sepharose affinity chromatography, and preparative gel electrophoresis. The immunogenic fraction isolated in each step was moved to the next one, and so on. The immunogenicity of the separated fractions was measured by a lymph node proliferation (LNP) assay, which is indicative of a delayed-type hypersensitivity response. For instance, the final 64-kDa isolated protein of the syn-Con A-blasts induced an efficient LNP response in A mice which was detected after challenge with the final 64-kDa isolated protein of YAC cells. In addition to their identical molecular weight, both proteins were eluted at the same ionic strength and both expressed affinity to Con A-Sepharose beads, suggesting that they were glycosilated. Similar 64-kDa proteins were isolated by a different purification procedure, which was performed in the presence of protease inhibitors, excluding the possibility that the final antigen was an autodigested product. As the 64-kDa protein is immunogenic in the syngeneic host, it may be employed as a immunotherapeutic reagent against the original tumor and perhaps against other tumors expressing the same antigen.

Animals↗
PubMed2004

Gas/particle partitioning of seven volatile polycyclic aromatic hydrocarbons in a heavy traffic urban area.

Air samples (vapor- and particle-phase) were taken for 19 sampling events during the period from December 1997 to July 1998 in an urban site in the center of Athens. The urban site is densely populated and characterized by heavy traffic circulation and elevated concentrations of VOCs, NO(x), CO and smoke. Seven volatile polycyclic aromatic hydrocarbons (PAHs) were determined in samples. The temperature dependence of gas-phase atmospheric concentration of PAHs, C(g), was investigated using diagrams of natural logarithm of partial pressures (lnP) vs. reciprocal mid-point temperatures. For the six of seven volatile PAHs, the temperature dependence of lnP was statistically significant (at least at the 90% confidence level) and the temperature accounted for 21-67% of the variability in gas-phase concentrations. The gas-phase concentration C(g) of the very volatile PAHs was affected more significantly by changes in temperature, but the variation of the less-volatile PAHs fluoranthene and pyrene C(g), was better explained by changes in temperature. The temperature dependence of gas/particle partitioning constant K(P) was also examined. Regressions of log(K(P))(-1) vs. T(-1) for fluorene, fluoranthene and pyrene were classified into two different temperature ranges. The gas/particle partitioning of PAHs was studied by correlating the partition constant to the sub-cooled liquid saturation vapor pressure (P(L)(o)). The Junge adsorption model underestimated the particle fraction of volatile PAHs probably due to the presence of non-exchangeable fraction. Slopes (m(r)) of the regressions logK(P) vs. logP(L)(o) were different from the value -1 as Pankow's theory predicts. The short distance between the sampling point and the emission sources is also estimated to be a factor that causes deviations from the theoretical value. Evidence that atmospheric conditions favorable for secondary aerosol formation coincide with higher value of m(r), was provided by limited sampling events. An interrelation was found to exist between the m(r) values, allowing the prediction of the gas/particle partitioning of a series of seven PAHs by the measurement of a single PAH partitioning.

Air Pollutants↗
PubMed2005

Evaluating the immunogenicity and protective efficacy of a DNA vaccine encoding Lassa virus nucleoprotein.

Several viruses in the Arenavirus genus of the family Arenaviridae cause severe, often fatal, hemorrhagic fever. One such virus, Lassa virus (LV), is a frequent cause of disease in Africa, and survivors often are left with substantial neurological impairment. The feasibility of protective immunization against LV infection, and the associated disease, has been demonstrated in animal models, using recombinant vaccinia viruses to deliver Lassa proteins. Circumstantial evidence implicates cellular immunity in this Lassa-induced protection, but this has not been confirmed. Here, we describe DNA vaccines that encode LV proteins. A single inoculation of a plasmid encoding full-length Lassa nucleoprotein (LNP) can induce CD8(+) T cell responses in mice and can protect against challenge with two arenaviruses, lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV). A DNA minigene vaccine encoding a 9 amino acid sequence from LNP also induces CD8(+) T cells and protects against arenavirus challenge, thus confirming prior speculation that protective cellular immunity is induced by LV proteins.

Amino Acid Sequence↗
PubMed2000

Imidazoline receptors: a challenge.

The hypotensive effect of imidazoline-like drugs (IMs) directly injected into the rostroventrolateral part of the brainstem (NRL/RVLM) was shown to involve non-adrenergic imidazoline specific receptors (IRs). Some IMs caused hypotension when injected there, irrespective of their affinity and selectivity for any alpha-adrenoceptor subtype. Compounds, such as LNP 509, S 23515, S 23757 or benazoline with very high selectivities for IRs over alpha 2-adrenoceptors (A2Rs), became available recently. Some of these compounds (LNP 509, S 23515) caused hypotension when injected alone into the NRL/RVLM region. Nevertheless, high selectivity for IRs will not predict by its own the capability of IMs to elicit hypotension as some of these substances behaved as antagonists towards the hypotensive effects of the latter. As far as hybrid drugs, i.e., with mixed binding profiles (I1/alpha 2), were concerned, a significant correlation has been reported between their central hypotensive effect and their affinity for IRs. Imidazoline antagonists, such as idazoxan, were repeatedly shown to competitively prevent and reverse the centrally induced hypotensive effect of IMs. The sole stimulation of A2Rs within the NRL/RVLM region was not sufficient to decrease blood pressure as much as IMs did, as shown by the lack of significant blood pressure lowering effect of alpha-methylnoradrenaline (alpha-MNA). No correlation was observed between affinity of IMs for A2Rs and their central hypotensive effects. It is also noticeable that yohimbine, an A2Rs antagonist, was repeatedly shown to abolish the hypotensive effect of hybrids but usually in a non-competitive manner. Mutation of A2Rs was shown to prevent the hypotensive effects of centrally acting drugs. It is concluded that (i) drugs highly selective for I1Rs over A2Rs can reduce blood pressure by their own; (ii) the central hypotensive effect of IMs needs implication of IRs and appears to be facilitated by additional activation of A2Rs; and (iii) this effect requires intact A2Rs along the sympathetic pathways.

Animals↗
PubMed2003

A global control region defines a chromosomal regulatory landscape containing the HoxD cluster.

During limb development, coordinated expression of several Hoxd genes is required in presumptive digits. We searched for the underlying control sequences upstream from the cluster and found Lunapark (Lnp), a gene which shares limb and CNS expression specificities with both Hoxd genes and Evx2, another gene located nearby. We used a targeted enhancer-trap approach to identify a DNA segment capable of directing reporter gene expression in both digits and CNS, following Lnp, Evx2, and Hoxd-specific patterns. This DNA region showed an unusual interspecies conservation, including with its pufferfish counterpart. It contains a cluster of global enhancers capable of controlling transcription of several genes unrelated in structure or function, thus defining large regulatory domains. These domains were interrupted in the Ulnaless mutation, a balanced inversion that modified the topography of the locus. We discuss the heuristic value of these results in term of locus specific versus gene-specific regulation.

5' Flanking Region↗
PubMed2025

Strain-Promoted mRNA Transdermal Delivery by Lipoic Lipid Nanoparticles for Therapeutic Skin Genome Editing.

Lipid nanoparticle (LNP)-mRNA formulations have revolutionized the field of nucleic acid therapeutics, yet their broader clinical application is constrained by inflammatory side effects and oxidative stress, particularly in the context of inflammatory diseases. Herein, we report the rational design and synthesis of a lipoic acid-based ionizable lipid library to address these limitations. By leveraging the antioxidant properties and thiol-mediated uptake potential of lipoic acid, we identified LA-A2B2CD3 as an optimal candidate through a structure-activity relationship study and design of experiment (DOE) optimization. LA-A2B2CD3 LNPs exhibited superior reactive oxygen species scavenging, enhanced mRNA translation, and reduced inflammatory cytokine production in vitro and in vivo. Mechanistic studies revealed that the efficient cellular uptake and the transdermal delivery capacity of LA-A2B2CD3 heavily rely on the reducible disulfide ring of lipoic acid. Application of LA-A2B2CD3 LNPs for the localized transdermal delivery of Cas9 mRNA and CD93 sgRNA in a murine model of psoriasis resulted in effective CD93 genome editing and the inhibition of the CD93-p38 MAPK-AKT-SMAD2/3 pathway, leading to significant therapeutic improvement. This work presents a robust, biocompatible LNP platform with minimized immunogenicity and strong potential for genome-editing therapies in inflammatory conditions, offering a transformative approach for the mRNA-based treatment of skin and other inflammation-related disorders.

Animals↗
PubMed2026

Influence of protein aggregates, extracellular vesicles, and lipoprotein fusion on ionizable lipid nanoparticles protein corona analysis.

Since 2018, ionizable lipid nanoparticles (LNPs) have revolutionized nucleic acid therapeutics. However, achieving potent extrahepatic delivery remains a formidable challenge, primarily due to rapid hepatic uptake driven by apolipoprotein adsorption. While analyzing the LNP protein corona is essential for engineering organ-specific tropism, these soft materials present unique analytical hurdles. Co-isolation of blood-borne contaminants, such as extracellular vesicles and lipoproteins, often masks the true corona composition. This perspective examines the critical need for refined proteomic strategies to distinguish genuine corona proteins from impurities. We propose tailored investigative approaches, suggesting the LNP protein corona significantly differs from the rigid shells observed on inorganic nanoparticles.

Nanoparticles↗
PubMed2026

Charge-switching ionizable lipids lower the toxicity of lipid nanoparticles.

Lipid nanoparticles (LNPs) have great potential as nucleic acid delivery vehicles; however, they trigger the production of inflammatory cytokines, which limits their medical applications. Developing non-inflammatory LNPs is challenging because the LNP's ionizable lipid and the process of endosomal disruption are the major sources of LNP toxicity but are also essential for delivering nucleic acids. Here we demonstrate that ionizable lipids containing a carboxylic acid and an amine (termed S-lipid) switch their charged state between the pHs of 7.4 and 4.0, allowing them to generate LNPs (termed switchable nanoparticles) that efficiently encapsulate nucleic acid and trigger endosomal release without activation of the TLR4, complement, galectin-8 and platelet activating factor signalling pathways. Finally, we demonstrate that switchable nanoparticles are better at treating lipopolysaccharide-induced acute lung injury than traditional LNPs because they do not exacerbate pre-existing inflammation. Collectively, these results demonstrate that negatively charged ionizable lipids can mitigate the toxicity of LNPs.

Journal Article↗
PubMed2026

mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression.

Proteins encoded by mRNA vaccines can be expressed by a diversity of transfected cell types but how cell-type-specific expression influences immunity is poorly understood. To investigate this, we incorporated synthetic microRNA target sites (miRT) into lipid nanoparticle (LNP)-delivered mRNA vaccines to silence mRNA expression specifically in professional antigen-presenting cells (pAPCs), hepatocytes or myocytes. We found that mRNA expression in pAPCs was dispensable for priming antigen-specific T cells, whereas mRNA expression in myocytes induced similar or stronger immune responses, including for SARS-CoV-2, suggesting that antigen cross-presentation or cross-dressing may be more impactful than direct mRNA expression in pAPCs. In contrast, mRNA expression in hepatocytes suppressed the antigen-specific T cell response, partly through PD1/PDL1. In mice bearing tumor-associated antigen (TAA)-expressing lymphoma cells, miRT-mediated hepatocyte-silenced TAA mRNA vaccine enhanced immune response and reduced tumor burden. Thus, non-pAPC expression shapes immunity to mRNA-encoded protein and inclusion of miRTs can boost or blunt mRNA-LNP immunogenicity.

Journal Article↗
PubMed2003

Disappearance of epidermal growth factor receptor is essential in the fusion of the nasal epithelium.

Abstract Epidermal growth factor (EGF) and receptor (-R) signaling pathway is required for epithelial cell growth and differentiation such as the degeneration of the medial edge epithelial cells during the fusion process of secondary palate formation. As epithelial fusion takes place during primary palate formation, we investigated the involvement of the EGF-R in fusion of the medial (MNP) and lateral (LNP) nasal prominences of the mouse embryo was examined. Immunoreactivity of EGF-R was investigated in embryonic day 10 embryos (32-37 somite stages). The EGF-R immunoreactivity was observed in the nasal epithelia of the presumptive fusion area before fusion. It became undetectable just prior to the fusion and faintly reappeared at the time of the fusion. In contrast, the non-fusing epithelial cells of the nasal groove maintained the immunoreactivity throughout these stages. In order to elucidate whether the EGF/EGF-R signaling pathway was involved in nasal epithelial fusion, EGF solution was injected into the exocoelum of explanted mouse embryos, and the embryos were cultured for 18-24 h by whole embryo culture (WEC). This exogenous EGF inhibited fusion of nasal prominences in 66.7-81.5% of the embryos. Treatment with EGF for 4-14 h showed that exogenous EGF disturbed the EGF-R disappearance and normal alteration of epithelial cell morphology in the fusion area. These results suggest that temporal disappearance of the EGF/EGF-R signaling from presumptive fusion of the nasal prominences is required for morphological change of the epithelial cells leading to the fusion of MNP and LNP.

Animals↗