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Abstract: The Negative Selection Algorithm developed by Forrest et al. was inspired by the way in which T-cell lymphocytes mature within the thymus before being released into the blood system. The mature T-cell lymphocytes exhibit an interesting characteristic, in that they are only activated by non-self cells that invade the human body. The Negative Selection Algorithm utilises an affinity matching function to ascertain whether the affinity between a newly generated (NSA) T-cell lymphocyte and a self-cell is less than a particular threshold; that is, whether the T-cell lymphocyte is activated by the self-cell. T-cell lymphocytes not activated by self-sells become mature T-cell lymphocytes. A new affinity matching function termed the feature-detection rule is introduced in this paper. The feature-detection rule utilises the interrelationship between both adjacent and non-adjacent features of a particular problem domain to determine whether an antigen is activated by an artificial lymphocyte. The performance of the feature-detection rule is contrasted with traditional affinity matching functions, currently employed within Negative Selection Algorithms, most notably the r-chunks rule (which subsumes the r-contiguous bits rule) and the hamming distance rule. This paper shows that the feature-detection rule greatly improves the detection rates and false alarm rates exhibited by the NSA (utilising the r-chunks and hamming distance rule) in addition to refuting the way in which permutation masks are currently being applied in artificial immune systems. [Copyright &y& Elsevier]

Biologically and environmentally resorbable electronic devices support application possibilities that cannot be addressed with conventional technologies. This paper presents highly conductive, water-soluble composites that can be printed to form contacts, interconnects, antennas, and other important features that are essential to nearly all systems of this type. An optimized material formulation involves in situ polymerization to yield a polyanhydride containing a dispersion of molybdenum microparticles at appropriate concentrations. Comparisons of essential physical and electrical properties of these materials to those of composites formed with other polymers and other metal microparticles reveal the relevant considerations. Various functional demonstrations of screen-printed test structures and devices illustrate the suitability of these conductive inks for use in water-soluble electronic devices. A key advantage of the material introduced here compared to alternatives is its ability to maintain conductance over significant periods of time while immersed in relevant aqueous solutions. Studies involving live animal models establish the biocompatibility. [ABSTRACT FROM AUTHOR]

Enhancer of zeste homolog 2 (EZH2), the core component of the polycomb group complex, plays a major role in normal hematopoiesis. The molecular function of EZH2 is to establish H3K27me3 mark on specific genes by which promotes transcriptional repression of target genes. The activity of EZH2 affects the balance between self-renewal and differentiation of hematopoietic stem cells. In addition, EZH2 contributes to the cell cycle regulation in mature lymphocytes. A large number of studies have been performed to identify the implication of EZH2 in tumor development of leukemia. Aberrant expression of EZH2 is increasingly recognized in leukemic malignancies. To clarify its therapeutic potential in hematopoietic malignancies it should be determined whether EZH2 is involved in the pathology of these neoplasms. This paper reviews the current knowledge of the role of EZH2 in the pathogenesis of myeloid and lymphoid leukemia. We will discuss the mechanisms in which microRNAs regulate the expression of EZH2 in different types of leukemias that may provide a means to alter cancer epigenetics associated to tumorogenesis to achieve therapeutic benefits. [ABSTRACT FROM AUTHOR]

Platelet-rich plasma (PRP) is an autologous product prepared from whole blood (WB) that is widely used in regenerative medicine. In clinical practice, discontinuous centrifugation is used for both hand- and machine-prepared PRP. However, separation of WB fractions via centrifugation is a complex process, and the lack of clear mechanisms limits the understanding and evaluation of PRP preparation methods This paper focuses on the distribution, recovery and concentration factor of platelets and leukocytes in L-PRP (leukocyte and platelet-rich plasma) to define a concentration pattern for these blood components due to centrifugation conditions. WB collected from three healthy donors was centrifuged for 10 min at 50–800 xg in a first step and then at 400 xg in a second step. The results from the first centrifugation step showed most platelets to be distributed in the upper layer (UL) and the buffy coat (BC), with approximately 14.5 ± 5.2% retained in the bottom layer (BL). Most leukocytes were present in the BL. The greatest platelet recoveries from L-PRP were obtained at up to 150 xg (88.5 ± 16.9%). The cumulative concentration factors with respect to the WB from the second centrifugation step were 6 and 1.2 for platelets and leukocytes, respectively. Thus, the concentration patterns delineated three centrifugation ranges with platelet/leukocyte ratios of 205 ± 18, 325 ± 15 and 107 ± 4 and lymphocyte/granulocyte ratios of 1.54 ± 0.74, 0.90 ± 0.08 and 0.42 ± 0.07. These findings contribute to a scientifically based standardization of L-PRP preparations. [ABSTRACT FROM AUTHOR]

This article presents the research papers presented in the Thirteenth Annual ADF Meeting, which was held in November 1985 at Vienna, Austria. The paper on "Tac Antigen Expression by Malignant Lymphocytes Infiltrating the Skin-Pathogenetic Considerations," by V. Groh, U. Kö ller and G. Stingi focuses on T cell proliferation. Some other topics covered are cutaneous lesions in histiocytosis X, HTLV-1 positive primary cutaneous B-cell Lymphoma, and human epidermal, Langerhans cells in culture.

This article presents abstracts for various research papers to be presented in the European Society for Dermatological Research's symposium on September 26-28, 1997. These research papers pertain to subjects like the eortic classification for primary cutaneous lymphomas, different prognosis between cutaneous and systemic lymphoproliferative disorders, parapsoriasis and early cutaneous T cell lymphoma, immunoglobulin gene rearrangement of pseudo B-cell lymphomas and prognostic significance of polymerase chain reaction detectable dominant T lymphocyte clones.

Gestagens are the most frequently used steroid hormones in hormone-replacement therapy in the treatment of threatened miscarriage during the first trimester of pregnancy. This therapy has been applied in a large number of women with threatened abortion, despite various degrees of success of its efficacy. Genetic factors play a key role in miscarriages, especially in the initial stages. Cytogenetic biomarkers such as micronucleus (MN) test, chromosomal aberrations (CAs), and sister chromatid exchanges (SCEs) provide information on DNA damage. Cytogenetic markers detecting DNA damage have become very popular and useful in analysing genetic risk associated with hormone-replacement therapy. Cytogenetic studies presented heterogenous information. In many in vitro studies synthetic gestagens have been shown to induce genotoxic effects, and it was evaluated using three cytogenetic biomarkers. Genotoxic effects of gestagens have also been confirmed in in vivo studies that were conducted involving patients who received gestagen therapy during pregnancy and their newborns. However, some studies have shown that hormone-replacement therapy does not have genotoxic effects. In this paper, we summarize the results from previous studies. We also describe the usefulness of these biomarkers in the detection of genotoxic effects of hormone-replacement therapy. [ABSTRACT FROM AUTHOR]

The koala ( Phascolarctos cinereus ) is an arboreal herbivorous marsupial that is an Australian icon. Koalas in many parts of Australia are under multiple threats including habitat destruction, dog attacks, vehicular accidents, and infectious diseases such as Chlamydia spp. and the koala retrovirus (KoRV), which may contribute to the incidence of lymphoma and leukaemia in this species. Due to a lack of koala-specific immune reagents and assays there is currently no way to adequately analyse the immune response in healthy, diseased or vaccinated animals. This paper reports the production and characterisation of the first anti-koala CD4 monoclonal antibody (mAb). The koala CD4 gene was identified and used to develop recombinant proteins for mAb production. Fluorochrome-conjugated anti-CD4 mAb was used to measure the levels of CD4 + lymphocytes collected from koala spleens (41.1%, range 20–45.1%) lymph nodes (36.3%, range 19–55.9%) and peripheral blood (23.8%, range 17.3–35%) by flow cytometry. Biotin-conjugated anti-CD4 mAb was used for western blot to determine an approximate size of 52 kDa for the koala CD4 molecule and used in immunohistochemistry to identify CD4 + cells in the paracortical region and germinal centres of spleen and lymph nodes. Using the anti-CD4 mab we showed that CD4 cells from vaccinated, but not control, koalas proliferated following in vitro stimulation with UV-inactivated Chlamydia pecorum and recombinant chlamydial antigens. Since CD4 + T cells have been shown to play a pivotal role in clearing chlamydial infection in both human and mouse infections, using this novel antibody will help determine the role CD4 + T cells play in protection against chlamydial infection in koalas and also enhance our knowledge of how KoRV affects the koala immune system. [ABSTRACT FROM AUTHOR]

Marsupials are a group of mammals that give birth to immature young lacking mature immune tissues at birth, and are unable to mount their own specific immune defence. Their immune tissues develop in a non-sterile ex-utero environment unlike that of eutherian mammals such as ourselves. Marsupials are therefore ideal models for studying the development of immune tissues, in particular haematopoiesis, yet relatively little has been investigated. Most studies have been restricted to histological or immunohistological studies, however some factors likely to be involved, based on eutherian studies in haematopoiesis, have been isolated and characterised, including a few key markers, and some cell signaling and regulation molecules, mostly involved in lymphocytopoiesis. However the role of many molecules in haematopoiesis is largely presumed. We currently lack much of the rudimentary information regarding time of appearance and expression levels of these molecules, and no functional studies have been conducted. This paper reviews our knowledge of marsupial haematopoiesis to date, and highlights the need for future research in marsupials to gain further insights into the evolution of haematopoiesis. [ABSTRACT FROM AUTHOR]

Given the fact that NF-κB stays as a dormant molecule in the cytoplasm in steady state, one common step in all the metabolic activities comprising NF-κB is its activation. Consequently there are two pathways of interest related to NF-κB activation: Canonical and alternate. Both the pathways involve ubiquitination of its repressors, that is to say ubiquitination of I-κB by NEMO/IKK-α/IKK-β complex in case of NF-κB1 and that of p100 by IKK-α homodimer in case of NF-κB2. This paper attempts to figure out the ubiquitination sites in alternate pathway of NF-κB activation using a purely computational approach. We initiated the work by acquiring the genes involved in NF kappa B alternate pathway through Agilent literature search. For this we employed the Cytoscape and STRING database. Secondly, the MSA was built using the sequences obtained through BLAST search, and the results were used to update the original sequence list, which was further refined using HMMER. Structural alignment was achieved via Modeller libraries. The final model has been refined using loop_model and asses_dope functions of Modeller. Ubiquitination site is predicted to be comprised of residues ‘SPECLDLLVDS’ between sites 178 and 188, both positions inclusive. Unlike the classical pathway, due to absence of parallel studies for p100/RelB, a quality match could not be performed, but future studies are in pipeline to replicate the methodology for NF-κB1 activation and compare the results with existing observations. The study can be used to understand the cofactors involved and ubiquitination sites employed during the activation process during drug designing activities. The methodology can be easily scaled and adapted for classical pathway as well. [ABSTRACT FROM AUTHOR]

Abstract: Cytogenetic analysis of peripheral blood lymphocytes is the most sensitive and reliable method currently available for in vivo assessment of the biological effects of exposure to radiation and provides the most informative measurement of radiation induced health risks. Data indicates that space missions of a few months or more can induce measureable increases in the yield of chromosome damage in the blood lymphocytes of astronauts that can be used to estimate an organ dose equivalent, and biodosimetry estimates lie within the range expected from physical dosimetry. Space biodosimetry poses some unique challenges compared to terrestrial biological assessments of radiation exposures, but data provides a direct measurement of space radiation damage, which takes into account individual radiosensitivity in the presence of confounding factors such as microgravity and other stress conditions. Moreover if chromosome damage persists in the blood for many years, results can be used for retrospective dose reconstruction. In contrast to physical measurements, which are external to body and require multiple devices to detect all radiation types all of which have poor sensitivity to neutrons, biodosimetry is internal and includes the effects of shielding provided by the body itself plus chromosome damage shows excellent sensitivity to protons, heavy ions, and neutrons. In addition, chromosome damage is reflective of cancer risk and biodosimetry values can therefore be used to validate and develop risk assessment models that can be used to characterize health risk incurred by crewmembers. The current paper presents a review of astronaut biodosimetry data, along with recently derived data on the relative cancer risk estimated using the quantitative approach derived from the European Study Group on Cytogenetic Biomarkers and Health database. [Copyright &y& Elsevier]

Human SLC25A13 gene encodes citrin, the liver-type aspartate–glutamate carrier isoform 2, and SLC25A13 mutations lead to citrin deficiency (CD). The definitive diagnosis of CD relies on SLC25A13 analysis, but conventional DNA analysis could not identify all SLC25A13 mutations. We investigated transcriptional features of SLC25A13 gene in peripheral blood lymphocytes (PBLs) from CD patients and healthy volunteers. SLC25A13 mutations were explored by PCR/LA-PCR, PCR-RFLP and direct sequencing. SLC25A13 cDNA was amplified by RT-PCR, cloned and then sequenced. All diagnoses of the CD patients were confirmed, including a heterozygote of g.2T>C and an unknown mutation yielding an aberrant transcript r.16_212dup. Twenty-eight alternative splice variants (ASVs) were identified from normal SLC25A13 alleles. Among them, r.213_328del took account for 53.7%, the normal transcript r.=, 16.6%, and the remaining 26 novel ASVs, collectively 29.3%, of all cDNA clones. Moreover, similar ASVs, all reflecting corresponsive mutations, were detected from the mutated alleles. These results indicated that the normal SLC25A13 transcript could be cloned, and the abundance of the ASV r.213_328del predicted the existence of a constructively novel protein isoform for this gene in human PBLs. And, the 26 novel ASVs, along with the novel aberrant transcript r.16_212dup and the SNP g.2T>C, enriched the transcript/variation spectrum of SLC25A13 gene in human beings. The findings in this paper, for the first time, uncovered the marked transcript diversity of SLC25A13 gene in human PBLs, and suggested that cDNA cloning analysis of this gene in human PBLs might be a feasible tool for CD molecular diagnosis. [ABSTRACT FROM AUTHOR]

Abstract: It has been reported that treatment with tricin (4′,5,7-trihydroxy-3′,5′-dimethoxyflavone), a derivative of Sasa albo-marginata, after human cytomegalovirus (HCMV) infection significantly suppressed both infectious virus production and HCMV replication in the human embryonic fibroblast cell line MRC-5. In this paper, we examined the mechanisms for the anti-HCMV effects of tricin in MRC-5 cells. Exposure of fibroblasts to tricin inhibited infectious HCMV production, with concomitant decreases in levels of transcripts of the CXC chemokine IFN-inducible T cell alpha chemoattractant (I-TAC or CXCL11) gene. We also found that the transcripts of the HCMV immediate early (IE) gene and replication of HCMV were lower in CXCL11 gene-knockdown cells. These results suggest that tricin is a novel compound with potential anti-HCMV activity and that CXCL11 is one of the chemokines involved in HCMV replication. In addition, it is possible that CXCL11 is the one of the targets of tricin. [Copyright &y& Elsevier]

Abstract: There are a lot of questions about genetic effects of ionizing radiation, the main one is does ionizing radiation induce mutations in humans? There is no direct evidence that exposure of parents to radiation leads to excess heritable disease in offspring. What is the difference between human and other species in which radiation induced mutations are easily registered? During evolution germ cell selection ex vivo has been changed to a selection in vivo and we cannot observe such selection of radiation damaged cells in human. Low radiation doses – are they harmful or beneficial? The “hormesis” phenomenon as well as radioadaptive response proves positive effects of low radiation dose. Can analysis of chromosomal aberration rate in lymphocytes be used for dosimetry? Many uncontrolled factors may be responsible for significant mistakes of this method. Why did evolution preserve the bystander effect? This paper is discussion one and its goal is to pay attention on some effects of ionizing radiation. [Copyright &y& Elsevier]

Abstract: In this paper we evaluate the role of human γδ T cells in control of Francisella tularensis infection. Using an in vitro model of infection, a reduction in bacterial numbers was detected in the presence of human γδ T cells for both attenuated LVS and virulent SCHU S4 strains of F. tularensis. Antibody neutralisation of IFN-γ caused an increase in survival of F. tularensis LVS suggesting that γδ T cell-mediated control of F. tularensis infection is partially mediated by IFN-γ. [Copyright &y& Elsevier]

Abstract: Fetal cattle B-cell development proceeds via a pre-B cell stage that is characterized by the expression of surrogate light chain and recombination activation genes. In this paper, we identify a new member of bovine pre-B lymphocyte genes, VPREB2. Using RT-qPCR, we assess the expression of VPREB2 and three other surrogate light chain genes as well as RAG1 and RAG2 in fetal and adult cattle tissues. The absence of VPREB1, IGLL1, RAG1 and RAG2 expression in adult tissues and the lack of B-lymphoid differentiation in adult bone marrow – OP9 stromal cell co-culture, suggest a decline of B lymphopoiesis in adult cattle. The marked differences in the expression profiles of VPREB2 and VPREB3 in comparison to those of VPREB1, IGLL1 and RAGs suggest that the biological roles of VPREB2 and VPREB3 are unrelated to the pre-B cells. [Copyright &y& Elsevier]

Abstract: This paper discusses the design and engineering of a biologically-inspired intrusion detection system, based on interval type-2 fuzzy set paradigm, for protecting computer networks. To this end, we have proposed a performance-based Artificial Immune System (AIS) that mimics the workings of an adaptive immune system and consists of a number of running artificial white blood cells, which search, recognize, store and deny anomalous behaviors on individual hosts. The proposed AIS monitors the system through analyzing the set of parameters to provide general information on its state. For the analysis, we have suggested a dynamic technique based on interval type-2 fuzzy set paradigm that enable identifying the system status – i.e. Non-Attack, Suspicious-Non-Attack, Non-Decidable, Suspicious-Attack, Attack. In conclusion, for proving the effectiveness of the suggested model, an exhaustive testing is conducted and results are reported. [Copyright &y& Elsevier]

Although essential for T cell function, the identity of the T cell receptor (TCR) "inside-out" pathway for the activation of lymphocyte function-associated antigen 1 (LFA-1) is unclear. SKAP1 (SKAP-55) is the upstream regulator needed for TCR-induced RapL-Rap1 complex formation and LFA-1 activation. In this paper, we show that SKAP1 is needed for RapL binding to membranes in a manner dependent on the PH domain of SKAP1 and the PI3K pathway. A SKAP1 PH domain-inactivating mutation (i.e. R131M) markedly impaired RapL translocation to membranes for Rap1 and LFA-1 binding and the up-regulation of LFA-1-intercellular adhesion molecule 1 (ICAM-1) binding. Further, N-terminal myr-tagged SKAP1 for membrane binding facilitated constitutive RapL membrane and Rap1 binding and effectively substituted for PI3K and TCR ligation in the activation of LFA-1 in T cells. [ABSTRACT FROM AUTHOR]

Abstract: Many of the existing network theory based artificial immune systems have been applied to data clustering. The formation of artificial lymphocyte (ALC) networks represents potential clusters in the data. Although these models do not require any user specified parameter of the number of required clusters to cluster the data, these models do have a drawback in the techniques used to determine the number of ALC networks. This paper discusses the drawbacks of these techniques and proposes two alternative techniques which can be used with the local network neighbourhood artificial immune system. The end result is an enhanced model that can dynamically determine the number of clusters in a data set. [ABSTRACT FROM AUTHOR]

Although allogeneic hematopoietic progenitor cell transplant (HPCT) is curative therapy for many disorders, it is associated with significant morbidity and mortality, which can be related to graft-versus-host disease (GVHD) and the immunosuppressive measures required for its prevention and/or treatment. Whether the immunosuppression is pharmacologic or secondary to graft manipulation, the graft recipient is left at increased risk of the threatening opportunistic infection. Refractory viral diseases in the immunocompromised host have been treated by infusion of virus-specific lymphotyces and by unmanipulated donor lymphocyte infusion (DLI) therapy. L-leucyl-L-leucine methyl ester (LLME) is a compound that induces programmed cell death of natural killer (NK) cells, monocytes, granulocytes, most CD8+ T cells, and a small fraction of CD4+ T cells. We have undertaken a study of the use of LLME-treated DLI following T cell-depleted allogeneic HPCT, specifically to aid with immune reconstitution. In this ongoing clinical trial, we have demonstrated the rapid emergence of virus-specific responses following LLME DLI with minimal associated GVHD. This paper examines the pace of immune recovery and the rapid development of antiviral responses in 6 patients who developed viral infections during the time period immediately preceding or coincident with the administration of the LLME DLI. [Copyright &y& Elsevier]

Abstract: Literature data on carbofuran genotoxicity in vitro and in vivo are very scarce. There are few papers indicating that occupational exposure to this AChE inhibiting insecticide might be connected to increased risk of developing non-Hodgkin’s lymphoma and lung cancer. Other authors showed its genotoxicity in vitro. We used comet and CBMN micronucleus assay combined with centromere probes to evaluate genome damage in lymphocytes of workers employed in carbofuran production. Also, the level of AChE activity in blood and plasma was measured. Only few workers exhibited AChE activity below 85%. Comet assay parameters were slightly but significantly elevated compared to control subjects, especially the long-tailed nuclei ratio. We found poor correlation between AChE activity and comet assay parameters, but significant effect of smoking and alcohol intake on the latest. In binucleated lymphocytes of workers significantly increased number of micronuclei, nuclear buds, and nucleoplasmic bridges was detected. Proportion of micronuclei with centromere, DAPI signal positive micronuclei was also elevated. Micronucleus assay parameters also appeared to be significantly influenced by duration of exposure to carbofuran. Together with published data on carbofuran’s effect on health our results might indicate the need for further evaluations of its genotoxicity using a range of different cytogenetic techniques. [Copyright &y& Elsevier]

Pesticides are widely used throughout the world in agriculture to protect crops and in public health to control diseases. Nevertheless, exposure to pesticides represents a potential risk to humans. This paper describes a study of possible genetic damage in the people living in regions contaminated with complex mixture of pesticides in Göksu Delta. In this study, used methods were chromosomal aberration (CA), sister chromatid exchange analysis (SCE) in the peripheral blood lymphocytes, and micronucleus (MN) assay in the buccal epithelial cells. In the present investigation, 32 affected subjects consist of 16 smoking and 16 non-smokings and an equal number of control subjects were assessed for genome damage. Micronucleus (MN), Broken egg (BE), Karyorrhexis (KR), Karyolysis (KL) and Binucleus (BN) frequencies were higher in affected subjects than in controls. Smoking had a statistically significant effect on the Micronucleus, Karyorrhexis and Binucleus frequencies for both the control and the exposed group. Also smoking and exposure affected the frequency of sister chromatid exchange and chromosomal aberrations compared with control groups. [Copyright &y& Elsevier]

Abstract: Aim of the study was to investigate the impact of coffee on DNA-stability in humans. DNA-damage was monitored in lymphocytes of eight individuals with single cell gel electrophoresis assays before and after consumption of 600 ml coffee (400ml paper filtered and 200ml metal filtered/d) for five days. Under standard conditions, no alteration of DNA-migration was seen, but a strong reduction of DNA-migration attributable to endogenous formation of oxidised purines and pyrimidines was detected with restriction enzymes; furthermore DNA-damage caused by reactive oxygen radicals (H2O2 treatment) and by the heterocyclic aromatic amine 3-amino-1-methyl-5H-pyrido[4,3-b]indole-acetate was significantly reduced after coffee consumption by 17% and 35%, respectively. Also in in vitro experiments, inhibition of H2O2 induced DNA-damage was observed with coffee at low concentrations (⩽25μl/ml) whereas the diterpenoids cafestol and kahweol caused only marginal effects indicating that the effects of coffee are due to scavenging effects of other constituents. Enzyme measurements showed that additionally induction of antioxidant enzymes may play a role: while the activity of glutathione peroxidase was only marginally increased after coffee consumption, a significant (38%) increase of superoxide dismutase activity was detected. Comparisons with results of earlier studies suggest that coffee consumption may prevent oxidative DNA-damage to a higher extent as diets enriched in fruits and vegetables. [Copyright &y& Elsevier]

Abstract: The paper presents a new algorithm for feature selection and classification. The algorithm is based on an immune metaphor, and combines both negative and clonal selection mechanisms characteristic for B- and T-lymphocytes. The main goal of the algorithm is to select the best subset of features for classification. Two level evolution is used in the proposed system for detectors creation and feature selection. Subpopulations of evolving detectors (T-lymphocytes) are able to discover subsets of features well suited for classification. The subpopulations cooperate during evolution by means of a novel suppression mechanism which is compared to the traditional suppression mechanism. The proposed suppression method proved to be superior to the traditional suppression in both recognition performance and its ability to select the proper number of subpopulations dynamically. Some results in the task of ECG signals classification are presented. The results for binary and real coded T-lymphocytes are compared and discussed. [Copyright &y& Elsevier]

Abstract: The vertebrate adaptive immune system, with its learning and memory capabilities, is a particularly rich example of the complexity of biological systems. The most difficult challenge in immunological research is the understanding of lymphocyte repertoires—the generation of their diversity and the forces that shape the ever-changing dynamics of lymphocyte clones. The explosively growing quantities of immunological information, which are rapidly becoming available from experimental and clinical studies, necessitate the use of theoretical tools, namely, mathematical and computational modeling and bioinformatical methods of analysis. In this paper, I review several examples of problems in lymphocyte repertoire modeling and analysis, demonstrate the types of solutions employed, and highlight the contribution of these theoretical studies to immunological research. [Copyright &y& Elsevier]

Abstract: In the present paper the relationship between cell cycle delays induced by Fe-ions of differing LET and the aberration yield observable in human lymphocytes at mitosis was examined. Cells of the same donor were irradiated with 990 MeV/n Fe-ions (LET=155 keV/μm), 200 MeV/n Fe-ions (LET=440 keV/μm) and X-rays and aberrations were measured in first cycle mitoses harvested at different times after 48–84 h in culture and in prematurely condensed G2-cells (PCCs) collected at 48 h using calyculin A. Analysis of the time-course of chromosomal damage in first cycle metaphases revealed that the aberration frequency was similar after X-ray irradiation, but increased two and seven fold after exposure to 990 and 200 MeV/n Fe-ions, respectively. Consequently, RBEs derived from late sampling times were significantly higher than those obtained at early times. The PCC-data suggest that the delayed entry of heavily damaged cells into mitosis results especially from a prolonged arrest in G2. Preliminary data obtained for 4.1 MeV/n Cr-ions (LET=3160 keV/μm) revealed, that these delays are even more pronounced for low energy Fe-like particles. Additionally, for the different radiation qualities, BrdU-labeling indices and apoptotic indices were determined at several time-points. Only the exposure to low energy Fe-like particles affected the entry of lymphocytes into S-phase and generated a significant apoptotic response indicating that under this particular exposure condition a large proportion of heavily damaged cells is rapidly eliminated from the cell population. The significance of this observation for the estimation of the health risk associated with space radiation remains to be elucidated. [Copyright &y& Elsevier]

Interaction of B7 with CD28 and CTLA4 plays an important function in T-cell activation and homeostasis. Disruption of CD28, CTLA4, or both has shown impact on T-cell biology. This paper examined the consequences of overexpressing a tailless mutant form of CTLA4 on T-cell activation and in vivo expansion.Retroviral gene transfer was used to infect bone marrow progenitor cells with either a control vector or a cytoplasmic domain-deleted mutant of CTLA-4 (ΔCTLA4). The cells were subsequently adoptively transferred to RAG-/- mice and allowed to repopulate. The T cells derived from the reconstituted RAG-/- mice were analyzed functionally in vitro and in vivo.The T cells were defective in their ability for IL-2 secretion, survival, and proliferation in response to Ag/APC stimulation in vitro. Addition of exogenous IL-2 or normal T cells was able to rescue the survival defect and allow cell-cycle progression. In adoptive transfer studies, the naïve T cells expressing ΔCTLA4 exhibited compromised capability to expand in RAG-/- mice. Memory ΔCTLA4T cells, however, were capable of proliferating in lymphopenic hosts to a similar extent as control memory T cells, but showed reduced survival.Surface ΔCTLA4 has similar tolerogenic/regulatory activity as CTLA4-Ig. In contrast to CTLA4-Ig, the effect of ΔCTLA-4 is autonomous. The inhibition of in vivo expansion by ΔCTLA4 indicates developmental and/or activation stage dependency of costimulation in T cells. [Copyright &y& Elsevier]

Abstract: We develop and analyze a model for the interactions of T-cells, antigen presenting cells (APCs), and HIV-1. Our model consists of five components: APCs, resting helper T-cells, activated uninfected helper T-cells, activated and infected helper T-cells, and the free virus. We emphasize the impact of APCs during HIV infection and the cell-to-cell contact manner in the transference of HIV-1 in vivo. The existence and stability of the uninfected steady state and those of the infected steady states are discussed. The uniform persistence of the system is also obtained. As a novel approach, multiple exposures of HIV-1 are illustrated and discussed in the paper. Through numerical stimulations, we check the sensitivity of APCs and helper T-cells in impacting the infection outcome and obtain some relevant results. We also give the lowest infectioe dose for certain individuals. [Copyright &y& Elsevier]

The sIgG+ lymphoblastoid B cell line CESS spontaneously produces a high amount of nerve growth factor (NGF) and expresses both high affinity (p140Trk-A) and low affinity (p75NTR) NGF receptors. Autocrine production of NGF maintains the survival of CESS cells through the continuous deactivation of p38 MAPK, an enzyme able to induce Bcl-2 phosphorylation and subsequent cytochrome c release and caspase activation. In this paper, we show that NGF induces transcriptional activation and synthesis of MAPK phosphatase 1 (MKP1), a dual specificity phosphatase that dephosphorylates p38 MAPK, thus preventing Bcl-2 phosphorylation. Furthermore, NGF increases MKP-1 protein stability by preventing its degradation through the proteasome pathway. Following NGF stimulation, MKP- protein mainly localizes on mitochondria, suggesting an interaction with p38 MAPK in this compartment. Incubation of CESS cells with MKP-1-specific antisense oligonucleotides induces cell death, which was not prevented by exogenous NGF. By contrast, overexpression of native MKP-1, but not of its catalytically impaired form, inhibits apoptosis induced by NGF neutralization in CESS cells. Thus, the molecular mechanisms underlying the survival function of NGF in CESS B cell line predominantly consist in maintaining elevated levels of MKP-1 protein, which controls p38 MAPK activation. [ABSTRACT FROM AUTHOR]

Autologous tumor infiltrating lymphocyte (TIL) therapy refers to a kind of immunotherapy in which the tumor-resident lymphocytes are harvested, cultured, and then transferred into the patient. In spite of some well-known TILs expansion recommendations, there is a lack of well-established TILs injection protocol. This paper addresses the challenge using a feedback-based control strategy. Utilizing Lyapunov technique, a novel dose calculation method is proposed which considers TILs pharmacokinetics. Then, to determine the timing of TILs administration, the concept of therapeutic window in pharmacy is exploited. The resultant therapy protocol is both practical and implementable while it ensures tumor remission. Comparing with previous studies, the proposed method takes the discontinuity of TILs delivery process into consideration. Computational results suggest the following therapy protocol which is in accordance with experimental observations: A few high dose TILs injections are required. Then, there is a longtime drug free interval. [ABSTRACT FROM AUTHOR]

The article presents information on various research papers related to investigative dermatology. The paper "Atopic Dermatitis and Cancer Risk" reports that blood and skin-homing lymphocytes in adults with atopic dermatitis (AD) have telomerase erosion and increased telomerase activity of T lymphocytes. In addition, immunosuppressive AD therapies may increase cancer risk. Another paper "Immortal Portal" discusses the mechanisms by which epithelial cells bypass growth arrest and become immortal. It was suggested that tumor suppressor p16 is selectively induced by a mechanism involving tyrosine kinase activity and the urokinase plasminogen activation system.

This article presents abstracts of papers published in the July 1, 1990 issue of the "Journal of Investigative Dermatology." Cutaneous T-cell Lymphoma is an indolent lymphoma that begins in the skin and may spread to involve other extracutaneous lymphoid sites. The course may be long and protracted, or explosive and rapid. Differences in skin color among different racial groups are determined by multiple factors involved in the production, packaging, and distribution of melanin in the skin. Melanin is a complex heteropolymer that provides protection for the epidermis by absorbing ultraviolet and visible light across a broad spectrum.

The article presents an abstract of the research paper "Macrophage-conditioned media enhances lymphocyte proliferation," by L.A. Flatow and K.C. Klasing.