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Results for “Target plasticity”

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PubMed1978

Selective blocking of T cell-mediated in vitro cytotoxicity to a xenogeneic tumour by anti-immunoglobulin sera.

Rejection of a xenograft by BALB/c mice results in a highly potent immune peritoneal population. When these immune cells are analysed by using two in vitro assays in parallel, at least two active cytotoxic mechanisms can be demonstrated. Target cells can be labelled with [125I]iododeoxyuridine (IUdR) before the effector cells are added and the detachment of the DNA from plastic can be used to detect cell-mediated immunity. This is referred to as the direct cytotoxicity test. This assay is largely dependent on T-cell function and evidence is presented here that it can be inhibited by anti-immunoglobulin (anti-Ig) antisera. The second test, which reflects the inhibition of incorporation of IUdR by previously mixed effector and target cells, is called the cytostatic assay. This test, although presumably affected by cytotoxic T cells, also reflects a T-independent mechanism which is not inhibited by anti-Ig sera.

Animals↗

PubMed1992

A method for experimental dental radiography.

An apparatus was designed for experimental dental radiography, which permitted separate adjustment of the subject, target and film. The precision of the apparatus was tested by radiographing a test subject, consisting of small steel globes embedded in a plastic plate. The subject was placed in the apparatus and exposed 30 times on dental X-ray film with different adjustments of angles and distances. All exposures were repeated after readjustment of the same form. Three linear distances between pairs of the projected steel globes were selected and measured on each radiograph. Depending on the different orientations of film, target and subject, the distances measured ranged from 9.0-11.1 mm, from 7.0-10.7 mm and from 12.7-17.3 mm, respectively. From the measurements on the radiographs the error of method was calculated to be 0.07-0.08 mm and the error of measurement to be 0.05-0.06 mm. The precision of the apparatus was thus found to be adequate for measurement of differences in small, but clinically relevant, distances.

Dental Pulp Cavity↗

PubMed1992

Organization and plasticity of GABA neurons and receptors in monkey visual cortex.

The GABA neurons of monkey area 17 are a morphologically and chemically heterogeneous population of interneurons that are normally distributed most densely within the geniculocortical recipient zones of the visual cortex. In adult monkeys deprived of visual input from one eye, the levels of immunoreactivity for GABA and GAD within neurons of these geniculocortical zones is reduced. Similar changes are seen in the levels of proteins that make up the GABAA receptor sub-type. The effects of monocular deprivation on other substances suggest that specific types of GABA neurons, such as those in which the tachykinin neuropeptide family and parvalbumin coexist with GABA, are greatly influenced by changes in visual input. That some proteins remain normal within deprived-eye neurons and that other proteins are increased indicates the changes in the GABA cells of the cortex are not the result of a general reduction in protein synthesis. Comparisons of what is known about the morphological and synaptic features of GABA cells in area 17 and the characteristics of cells affected by monocular deprivation suggests that certain classes, such as the clutch cell, may be preferential targets of deprivation. Such a selective loss of certain GABA neurons would have broad implications for the possible physiological plasticity of cortical cells, for if ongoing studies determine that specific receptive field properties are affected by monocular deprivation in adults, the correlation of functional properties and classes of GABA cells would be possible.

Animals↗

PubMed1990

Plasticity of GABA- and glutamate-containing terminals in the mouse thalamic ventrobasal complex deprived of vibrissal afferents: an immunogold-electron microscopic study.

GABA and glutamate immunogold staining demonstrated that nerve cells of the thalamic ventrobasal complex (VB) of mice were positive exclusively for glutamate. None of the neuronal perikarya reacted the GABA antibody. By using alternate thin sections of the normal VB, it was also shown that large "specific" somatosensory and small corticothalamic terminals, both of which contained spherical synaptic vesicles, exhibited only glutamate-like immunoreactivity. A third axonal type, containing flat-ovoid synaptic vesicles, stained only for GABA. Seventy-five days after coagulation of the vibrissal follicles in newborn mice, a characteristic multiplication of GABA positive axon terminals was observed. In addition, it was demonstrated that, similarly to modified cortical endings (Hámori et al., J. Comp. Neurol. 254:166-183, '86), many GABA positive terminals appeared as specific afferent endings, replacing the missing "specific" vibrissal afferents. This finding shows a remarkable plasticity of inhibitory GABA axons during developmental synaptogenesis and provides further evidence that the size, location, and the type of attachment of presynaptic terminals are dependent on their postsynaptic target.

Afferent Pathways↗

PubMed2026

Plasmodium knowlesi can adapt to infect Duffy-negative erythrocytes.

Plasmodium knowlesi, a zoonotic malaria species, has become a significant public health concern in Southeast Asia. In regions such as Malaysia and southern Thailand, P knowlesi incidence has risen, even as other human malaria parasites are nearing elimination. Similar to its close relative Plasmodium vivax, P knowlesi relies on the Duffy antigen receptor for chemokine (DARC) as a key receptor for erythrocyte invasion. Only Duffy-positive individuals are thought to be susceptible to clinical infection. Here, we demonstrate that P knowlesi possesses greater invasion plasticity than previously recognized. This parasite can bypass the need for DARC, as shown by its in vitro adaptation to invade and replicate within Duffy-negative (Fy-) erythrocytes. This adaptation is stable and independent of DARC binding, enabling the adapted parasite line to be maintained in Fy- erythrocytes and to resist inhibition by α-DARC antibodies. Genomic analysis identified a genomic recombination event between the parasite's dbpα and dbpγ genes, resulting in a new chimeric gene dbpαγ. Using CRISPR-Cas9 targeted reversion, we could demonstrate that dbpαγ is essential for invasion of Fy- erythrocytes. These findings shed new light on the invasion plasticity of P knowlesi, with implications for the parasite's potential spread beyond Southeast Asia and for understanding the complex host-cell specificity and atypical invasion pathways seen in P vivax.

Plasmodium knowlesi↗

PubMed1992

Computed tomography treatment planning in IR-192 brachytherapy in the head and neck.

Brachytherapy dose prescription and treatment planning lag behind the state-of-the-art for external beam therapy. As altered fractionation of external beam therapy improves patient outcome in head and neck cancer, there will be an increased need to compare the two radiotherapy techniques. Currently, implant techniques and dose prescription documentation are not uniform, dose prescription to a target volume is subjective, and implant quality is poorly understood and not routinely assessed. All contribute to a lack of scientifically rigorous brachytherapy clinical trials. Studies designed to combine tumor imaging and dosimetry data are important in the evolution of brachytherapy treatment planning. Head and neck implants, which often require nonparallel, arching, or looping source carriers for all but small tumors in order to encompass the target volume adequately, were used to evaluate the clinical utility and feasibility of computed tomography as a treatment planning tool in brachytherapy. Following placement of plastic afterloading tubes under general anesthesia, orthogonal radiographs with dummy sources in the afterloading tubes are obtained as customary for source localization. With the patient in the same position, axial CT scans are obtained with the dummy seeds still in place for treatment planning. The implant physician, using data from the pre-treatment diagnostic CT scan, outlines target areas on sequential images creating a 3-dimensional target volume. By superimposing anatomic data with isodose curves one can objectively define implant parameters important in clinical trials analysis. These include minimum target absorbed dose, implant uniformity, and treatment to target volume ratio. The results of the first 10 patients are presented and implications of these data regarding the analysis of implant technique, implant quality, and implant optimization are discussed. The technique as performed is laborious but practicable in the clinical research setting of head and neck implant. Further research efforts should improve, simplify, and objectify brachytherapy and hasten the time when rigorous multi-institutional brachytherapy trials will be reality.

Adult↗

PubMed1991

Cloning of cDNA for the glutamate-binding subunit of an NMDA receptor complex.

The amino acids L-glutamic and L-aspartic acids form the most widespread excitatory transmitter network in mammalian brain. The excitation produced by L-glutamic acid is important in the early development of the nervous system, synaptic plasticity and memory formation, seizures and neuronal degeneration. The receptors activated by L-glutamic acid are a target for therapeutic intervention in neurodegenerative diseases, brain ischaemia and epilepsy. There are two types of receptors for the excitatory amino acids, those that lead to the opening of cation-selective channels and those that activate phospholipase C (ref. 11). The receptors activating ion channels are NMDA (N-methyl-D-aspartate) and kainate/AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitive receptors. The complementary DNAs for the kainate/AMPA receptor and for the metabotropic receptor have been cloned. We report here on the isolation and characterization of a protein complex of four major proteins that represents an intact complex of the NMDA receptor ion channel and on the cloning of the cDNA for one of the subunits of this receptor complex, the glutamate-binding protein.

Amino Acid Sequence↗

PubMed2026

A profile of abandoned fetal and neonatal remains admitted to the Diepkloof forensic pathology service medico-legal mortuary during the COVID-19 and post-COVID-19 periods.

The abandonment of neonates is a global concern, with a higher prevalence of cases present in South Africa. This study aimed to review cases admitted to the Diepkloof Forensic Pathology Service during the COVID-19 (2020-2021) and post-COVID-19 (2023) periods. A total of 158 cases were analysed to determine prevalence, demographic characteristics, circumstances and causes of death, with a comparative analysis between the COVID-19 and post-COVID-19 periods. Most cases were classified as natural. However, many were undetermined due to decomposition. Non-viable fetuses (< 26 wk gestation) comprised 47% of the cases. Among the viable births (n = 72), 23 (32%) were classified as stillbirths, while 11 (15%) were live births. A minority of cases were deemed unnatural, with deaths attributed to trauma (8 cases) or abandonment (2 cases). No statistically significant difference was found between the COVID-19 and post-COVID-19 periods. Decedents were most often found in open spaces, roads or streets, or dumping sites, most commonly wrapped in plastic materials. These findings highlight the severity of fetal and neonatal abandonment. They underscore a pressing need for targeted preventative measures, community outreach, and enhanced support systems in maternal healthcare to address this growing concern.

Humans↗

PubMed1992

The T-lymphocyte is the primary cellular target for potentiation of the in vitro T-dependent IgM antibody response by the B subunit of cholera toxin.

The B (or binding) subunit of cholera toxin (CTB) was reported previously to potentiate the in vitro T-dependent IgM antibody response by a mechanism independent of the cyclic AMP-generating capacity of the intact toxin. In the present report, experiments were designed to determine the immune cell type mediating potentiation by CTB. Firstly, CTB did not potentiate T-independent antibody responses at concentrations that effectively enhanced T-dependent responses. Secondly, separation/reconstitution studies with splenocytes from CTB- and vehicle-treated mice demonstrated potentiation of T-dependent responses by CTB treatment of either the Sephadex G10 non-adherent population or the T-lymphocyte + macrophage population of cells. Potentiation was not observed by CTB treatment of the plastic adherent population or the B-lymphocyte + macrophage population. The evidence indicates that the T-lymphocyte is the primary cellular target for CTB-induced effects on the T-dependent IgM antibody response. Monosialoganglioside GM1, the putative binding site for CTB, is most likely the site of action for CTB on T-lymphocytes. These studies provide new insight on the mechanism of immunomodulation by cholera toxin, and CTB should provide a useful tool for further understanding the role of gangliosides in cellular immune responses.

Adjuvants, Immunologic↗

PubMed1979

Depletion of NK by cellular immunoadsorption.

The binding of human natural killer (NK) cells to their tumor cell targets was investigated by using monolayers of sensitive target cell lines. Monolayers of K562 and HSB, a myeloid and T cell line, respectively, were prepared on poly-L-lysine-coated plastic tissue culture dishes and briefly fixed with 0.2% formaldehyde. Freshly isolated peripheral blood lymphocytes (PBL) were incubated on the monolayers. Nonadherent PBL were then removed, after gentle agitation, by decanting and gently washing the monolayer. They were tested, along with unseparated controls, for NK activity in a short-term 51Cr release assay. PBL that were nonadherent to a tested monolayer had only 20 to 60% of the control cytotoxic activity. Our results suggest that NK recognition sites on the effector lymphocytes were able to interact with reciprocal determinants on the target cell monolayers, resulting in selective loss of NK effector cells from the PBL population. The specificity of the NK effector-target interaction was investigated by testing the ability of each monolayer to remove activity against both targets. These data imply heterogeneity with regard to recognition structure within the NK effector population as well as among the target cells.

Adult↗

PubMed1991

Plasticity of spinal systems after unilateral lumbosacral dorsal rhizotomy in the adult rat.

Plasticity of spinal systems in response to lumbosacral deafferentation has previously been described for the cat, by using immunocytochemistry to demonstrate plasticity of tachykinin systems and degeneration methods to demonstrate plasticity of descending systems. In this study, we describe the response to lumbosacral deafferentation in the adult rat. Application of immunocytochemical methods to visualize tachykinins (predominantly substance P magnitude of SP), serotonin (5-HT), and dopamine B-hydroxylase (DBH), the synthesizing enzyme for norepinephrine, permits us to compare the response of SP systems in rat and cat spinal cord and to examine the response of two descending systems, serotoninergic and noradrenergic, to deafferentation. We used image analysis of light microscopic preparations to quantify the immunoreaction product in the spinal cord in order to estimate the magnitude, time course and localization of changes induced by the lesion. The distribution of SP, serotoninergic (5-HT), and noradrenergic staining in the spinal cord of rat is very similar to that of the cat. Unilateral lumbosacral rhizotomy elicits a partial depletion, followed by a partial replacement of tachykinin immunoreactivity in laminae I and II. This response was similar to that described for the cat, although characterized by a longer time course, and, as in the cat, is likely due to plasticity of tachykinin containing interneurons. The same lesion elicits no depletion but a marked and permanent increase in 5-HT immunoreactivity in laminae I and II, which develops more rapidly than the response by the SP system. These results indicate sprouting or increased production of SP and 5-HT in response to deafferentation. No change was seen in DBH immunoreactivity, indicating that the noradrenergic system does not show plasticity in response to deafferentation. Our results demonstrate that dorsal rhizotomy evokes different effects in different systems in the adult spinal cord of the rat and thus suggests that the response of undamaged pathways to partial denervation of their target is regulated rather than random.

Afferent Pathways↗

PubMed1992

Neurotransmitter transporters. A novel family of integral plasma membrane proteins.

The re-uptake of neurotransmitters into the nerve terminal terminates synaptic transmission at most central synapses and constitutes a key step in the modulation of synaptic efficacy. Recently, the cloning of several Na(+)-driven neurotransmitter transporters has resulted in the description of a novel family of homologous membrane proteins, each with 12 transmembrane segments. These transporters constitute major targets of widely used drugs, and modulation of transporter gene expression and/or activity may represent an important substrate for plasticity in the nervous system.

Amino Acid Sequence↗

PubMed1992

MacMARCKS, a novel member of the MARCKS family of protein kinase C substrates.

MARCKS is a specific protein kinase C (PKC) substrate that binds both calmodulin and actin and is phosphorylated during phagocyte activation, neurosecretion, and growth factor-dependent mitogenesis. We report here on MacMARCKS, a MARCKS homolog, whose synthesis is dramatically increased in macrophages when these cells are exposed to bacterial lipopolysaccharide. We have purified rabbit MacMARCKS and cloned its cDNA from rabbit and mouse. The effector domains of MacMARCKS and MARCKS are nearly identical, and both proteins bind calmodulin in a phosphorylation-regulated manner. MacMARCKS and MARCKS also share a second, highly conserved region also found in the internalization domain of the mannose-6-phosphate receptor. Our data suggest the existence of a family of PKC substrates that are targeted to different subcellular locations and that function to integrate PKC and calcium/calmodulin-dependent signals in the control of the plastic actin cytoskeleton.

Actins↗

PubMed1975

Cytotoxic activity of lymphocytes. V. Role of soluble toxin in macrophage-inhibited cultures of tumor cells.

Macrophage cell-mediated cytolysis (M-CMC) of tumor cells may be measured by culturing target cells on macrophage monolayers and determining target cell survival by either Rb or H-thymidine incorporation. Using these techniques, one can demonstrate cytotoxicity of nonimmune human and rat macrophages to a variety of tumor cell lines. Toxicity becomes maximal 8 to 16 hr after attaching macrophages to plastic surfaces and disappears after 36 to 48 hr. Addition of Escherichia coli endotoxin at 48 hr restores macrophage toxicity. Culture of macrophages on plastic surfaces also results in the release, nonspecifically, of a soluble cytotoxin whose kinetics of release, disappearance, and reappearance after endotoxin all parallel the M-CMC. The amount of toxin released into cultures containing target cells is markedly reduced, suggesting that it is the mediator of the M-CMC and that it is utilized or absorbed during target destruction. Sephadex G-100 chromatography and treatment with heterologous anti-lymphotoxin can distinguish this toxin from lymphotoxin.

Adsorption↗

PubMed2026

Single-cell multiomics reveals exosome-mediated reprogramming and clonotypic remodeling of T cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive and immunogenic subtype lacking targeted therapies. While tumor-derived exosomes are known to modulate immune function, their direct impact on human T cell plasticity and antigen specificity remains poorly defined. Here, we conducted a comprehensive single-cell multiomic analysis of primary human T cells exposed to exosomes derived from 17 genomically diverse TNBC cell lines and 35 patient samples. Integrating single-cell RNA-seq, V(D)J sequencing, non-coding RNA profiling, bulk and single-cell cytokine analyses, we uncovered conserved and subtype-specific immunomodulatory programs induced by TNBC exosomes. Exosome-treated T cells displayed skewing toward regulatory and dysfunctional phenotypes, including Th17-like, Treg, and PD-1⁺/PD-L1⁺ Tfh cells. Functional profiling revealed suppression of early activation markers and cytokine responses, alongside selective preservation of cytotoxic features in γδ T and NKT subsets. Transcriptomic and miRNA network analyses demonstrated widespread downregulation of immune effector genes (e.g., HBEGF and TNFSF9) mediated by exosome-delivered regulatory miRNAs (has-miR-98-5p). Notably, exosome-stimulated T cells displayed distinct clonotypic expansions, characterized by the emergence of five tumor-specific γδ TCR clonotypes and 30 unique αβ TCR CDR3 sequences that were absent in mock-treated controls, underscoring the role of exosomes in shaping TCR repertoire dynamics.

Humans↗

PubMed2026

Balancing under constraint: Structural insights into norovirus evolution and antigenic innovation.

Norovirus is the leading cause of acute viral gastroenteritis worldwide. While genomic studies have revealed its diversity and evolutionary patterns, the structural mechanisms driving viral adaptation remain poorly understood. Here, we establish a comprehensive structural database of norovirus VP1 P-domains across nine genogroups (GI-GIX) through large-scale AlphaFold2 predictions. By integrating phylogenetic analysis of VP1 sequences and structures, we demonstrate that sequence and structural evolution show overall concordance under purifying selection, yet significant local discrepancies reveal distinct patterns of convergent evolution shaped by structural constraints and functional divergence. Focusing on the predominant GII.4 genotype, we found that compared to near-full-genome and nucleotide trees, only the VP1 amino acid tree reliably clustered GII.4 variants in chronological order as monophyletic groups. We further identify a hierarchical evolutionary strategy: positive selection may drive structural hypervariability in major antigenic epitopes D and C for immune escape, with epitope D exhibiting pronounced structural flexibility that complicates its structural characterization, whereas coevolutionary analysis uncovers a broad network of compensatory interactions spanning multiple epitopes, with striking enrichment in epitope A. These epitopes exhibited a pattern of "sequence plasticity with structural conservation", maintained by coevolutionary constraints that preserve conformational integrity. Together, these findings suggest that norovirus vaccine strategies targeting the structurally conserved conformations of epitopes A and G could overcome the limitations of traditional strain-specific approaches, offering a pathway toward broad protection against evolving viral diversity.

Norovirus↗

PubMed1976

Cytotoxicity in graft-versus-host reaction. II. Lysis of target cells of parental genotyppe by F1 hybrid macrophages.

Graft-versus-host (GVH) reactions were induced in adult F1 hybrid mice with the i.p. injection of parental strain spleen cells. Peritoneal exudate and spleen cells of the F1 hybrids taken 8 days after the induction of GVH reaction had a nonspecific in vitro cytotoxic effect which was measured by using 51Cr-labeled target cells of parental genotype. The cytotoxic cells in the peritoneal exudates were shown to be macrophages which adhered to plastic surfaces and were sensitive to the toxic action of crystalline silica particles. Moreover, the injection of partially purified syngeneic macrophages into the F1 hybrids undergoing GVH reactions increased the cytotoxic activity of the peritoneal exudate cells obtained from these animals. These results suggest that during GVH reaction host macrophages are activated into a state of nonspecific cytotoxicity.

Animals↗

PubMed1992

Neuronal specificity and plasticity in the autonomic nervous system.

The autonomic nervous system is divided into the sympathetic, parasympathetic and enteric subdivisions. The present review is focussed upon the highly specialized reflex organization and neurochemistry of sympathetic parasympathetic neurons. The currently available informations allow to conclude that autonomic control of each peripheral target tissue is specifically regulated under normal conditions but nevertheless able to respond to altered conditions by changes in neural activity and mediator expression.

Animals↗