Characterising negative regulation of CD8+ T cell function in tolerance and exhaustion

CD8+ T cells play a vital role in the immune system by clearing pathogen-infected tissues, however self-reactive CD8+ T cells that escape thymic selection pose the danger of causing autoimmune disease. These self-reactive CD8+ T cells are controlled in the periphery by tolerance mechanisms, which inhibit their function (anergy) or induce apoptosis (deletion). However, the specific molecular pathways crucial for negatively regulating self-reactive CD8+ T cells are not well elucidated. A distinct form of negative regulation called "exhaustion" occurs within chronically stimulated effector CD8+ T cells during cancer and chronic infection. Due to the phenotypical similarities between CD8+ T cell tolerance and exhaustion, we aimed to understand if common underlying molecular pathways regulate these states. The pro-apoptotic protein BIM is important in deletion of self-reactive CD8+ T cells, however the transcriptional control of Bim induction has been unclear. In Chapter 2, we assessed the contribution of the transcription factor FOXO3 in deletion of self-reactive CD8+ T cells given its role in Bim induction and cell death in effector and exhausted CD8+ T cells. While FOXO3 protein underwent activatory dephosphorylation during tolerance, FOXO3-deficient CD8+ T cells maintained the ability to induce BIM expression and undergo deletion. This result indicated that FOXO3 plays distinct roles in cell death of tolerant versus effector CD8+ T cells. To further characterise CD8+ T cell tolerance pathways, in Chapter 3, we investigated whether the ubiquitin ligase adaptor NDFIP1, which is crucially required for CD4+ T cell anergy, influences CD8+ T cell tolerance. In a model of peptide-induced anergy, Ndfip1-deficient CD8+ T cells aberrantly expanded and differentiated into effector cells against high dose exogenous antigen, likely driven by increases in TCR signaling. In contrast, NDFIP1 was dispensable for peripheral deletion to low-dose exogenous antigen, and had little impact upon effector responses to acute infection. These results showed the importance of NDFIP1 in regulating CD8+ T cell tolerance and indicated that CD8+ T cell deletion and anergy are molecularly separable checkpoints. While CD8+ T cell exhaustion appears distinct from tolerance, the transcriptional regulator EGR2 is commonly expressed between these states. In Chapter 4, we showed that exhausted CD8+ T cells in chronic LCMV infection expressed elevated levels of EGR2 compared to functional effectors. Loss of Egr2 severely disrupted terminal CD8+ T cell exhaustion in a cell intrinsic manner, with RNA-Seq results indicating a global enrichment of the exhaustion "stem cell" gene set in Egr2-deficient cells. Strikingly, the genes regulated by Egr2 during exhaustion appeared distinct from those controlled by Egr2 during T cell tolerance, suggesting that EGR2 is repurposed during T cell exhaustion. These findings indicate that while there is molecular overlap between CD8+ T cell tolerance and exhaustion, shared proteins may differ in their mechanism of action. Such insight into the differences between tolerance and exhaustion checkpoints is important for refining future immunotherapies against cancer and autoimmune diseases

Data Mining in Clinical Practices Guidelines

This paper proposes text mining of clinical practices to extract decision-making steps. These steps should be formed in- logical functions capable of branching on different plan set on some deciding variables. The probable action sequence will be notified on the data of patient given to the conditions of clinical guideline and this will also give critical conditions that need immediate attention. In this project medical grammar rules are applied to extract key decision making steps from the clinical guidelines. In the first step lexical analysis is performed to key- words like 2018;if this then perform this, all the medical terms will be identified and this extracted rule set will be used to create a XSLT file. The patient data in form of an XML file will be then applied to the XSLT transformations or rule sets to derive final result of action plan specific to that patient

PEMILIHAN BAHASA DALAM KELUARGA CAMPURANRNDI KECAMATAN KEJURUAN MUDA KABUPATEN ACEH TAMIANG

ABSTRAKKata kunci : pemilihan bahasa, keluarga campuran, bahasa IndonesiaPenelitian yang berjudul Pemilihan Bahasa dalam Keluarga Campuran diKecamatan Kejuruan Muda Kabupaten Aceh Tamiang ini mengangkat masalah (1)bahasa apa yang dipilih oleh keluarga campuran di Kecamatan Kejuruan MudaKabupaten Aceh Tamiang dan (2) faktor apakah yang melatarbelakangi pemilihanbahasa oleh keluarga campuran di Kecamatan Kejuruan Muda Kabupaten AcehTamiang tersebut. Sumber data penelitian ini adalah keluarga campuran yang terdiriatas ayah, ibu, dan anak yang ayah dan ibunya berasal dari suku yang berbeda.Keluarga campuran yang dijadikan sumber data berjumlah 28 KK dan terdiri atasberbagai suku, yaitu: Mandailing-Jawa, Mandailing-Aceh, Aceh-Mandailing, Aceh-Tamiang, Aceh-Sunda, Aceh-Minangkabau, Aceh-Jawa, Jawa-Aceh, Jawa-Minangkabau, Minangkabau-Aceh, Minangkabau-Tamiang, Minangkabau-Batak,Batak-Jawa, Tamiang-Jawa, Tamiang-Aceh, Tamiang-Karo, dan Gayo-Aceh.Metode penilitian menggunakan metode deskriptif kualitatif. Instrumen yangdigunakan dalam penelitian terdiri atas (1) peneliti, dan (2) alat rekam dan catat.Pengumpulan data dilakukan dengan pengamatan dan cakap (wawancara)berdasarkan masing-masing keluarga campuran yang ada di Kecamatan KejuruanMuda. Penganalisisan data dilakukan dengan langkah sebagai berikut: (1) datadikelompokkan berdasarkan rumusan masalah, (2) mengklasifikasikan data sesuaidengan aspek yang diteliti, (3) membenahi hasil catatan pengamatan dan wawancara,(4) mendata semua data dan melakukan analisis ulang serta menyampaikan hasilnyasesuai dengan masalah dalam bentuk deskriptif, dan (5) membuat simpulan akhir.Hasil penelitian menunjukkan bahwa pemilihan bahasa yang dilakukan oleh keluargacampuran di Kecamatan Kejuruan Muda sebanyak 16 keluarga memilih bahasaIndonesia dalam proses komunikasi, 2 keluarga terdapat penggunaan bahasa Jawadalam proses komunikasi, 1 keluarga terdapat penggunaan bahasa Minangkabaudalam proses komunikasi, 5 keluarga terdapat penggunaan bahasa Aceh dalam proseskomunikasi, 2 keluarga terdapat penggunaan bahasa Tamiang dalam proseskomunikasi, 1 keluarga terdapat penggunaan bahasa Aceh dan Jawa di dalamkeluarganya, dan 1 keluarga terdapat penggunaan bahasa Tamiang dan Karo didalam keluarganya. Faktor yang melatarbelakangi pemilihan bahasa dalam keluargacampuran di Kecamatan Kejuruan Muda adalah (1) lingkungan tempat tinggal dansekolah, (2) orang tua tidak menurunkan bahasa daerah kepada anak, (3) hendakmerahasiakan pembicaraan, (4) penguasaan bahasa yang sama, (5) penguasaanbahasa yang berbeda, (6) kebiasaan berbahasa, (7) untuk mempermudah komunikasi,(8) motivasi, dan (9) ingin mewariskan bahasa daerah kepada anak

In silico Gene Characterization and biological annotation of Aspergillus niger CBS 513.88

Genome annotation is the process of estimation of biological features from genomic data. The target of a genome annotation is to identify the key features of the genome sequence particularly, the genes and gene products. The characteristics of a gene, its products, and gene prediction programs of Aspergillus niger are discussed. Although the number of genomes in genomic databases are increasing day by day, genome-wide analyses are affected by the quality of the genome annotations. This study illustrates the importance of integrative approaches for automatic annotations of genomes of Aspergillus niger by computational methods. However, the annotation process is more complicated in Eukaryotes; we used a comparative study for gene prediction using the FgenesH algorithm by various software providers. The final annotation of Aspergillus niger CBS 513.88. has been created as a GB file in Artemis, A sequence viewer and annotation tool was developed in the anger Institute

Studies on Electrochemical Hydrogen Isotope Separation

Graphene-integrated Proton Exchange Membrane (PEM) electrochemical cells have emerged as a novel area of scientific investigation in the realm of hydrogen isotope separation. Chemical Vapor Deposited (CVD) graphene has been especially useful due to its large-scale production capability for scaling-up purposes. The research described in this dissertation explores the role that inadvertent introduction of cations, notably ammonium and copper, during the CVD graphene transfer onto PEM substrates, such as Nafion, might play in affecting hydrogen ion transport and isotope separation in PEM electrochemical cells. An extensive review of existing literature exposed a gap concerning unintentional cation introductions during graphene transfer, and this research posits that observations of apparent isotope separation could be attributable to effects from ammonium or copper cations in the membranes. Central to these studies is the elucidation of the challenges in reproducing optimal H/D selectivities, attributed to methodological inconsistencies. Seeking deeper insights, this study tapped into the capabilities of the Online Electrochemistry Mass Spectrometry (OEMS) system. Rather than relying on comparative studies in separate H and D electrochemical pump cells, the OEMS facilitated time-dependent studies of evolved gases in electrochemical pump cells, allowing for the direct analysis of true isotope separation from gas mixtures. Employing techniques to directly probe H/D separation, this dissertation identifies a minimal impact of graphene on this process. This investigation aligns with other recent works that question established beliefs regarding CVD graphene\u27s pronounced impact on hydrogen isotope separation

DRUG DISCOVERY OF NEWER ANALOGS OF ANTI-MICROBIALS THROUGH ENZYME-INHIBITION: A REVIEW

There is a growing interest towards the development of new antibiotics from last decades due to emergence of newer pathogenic bacterial strains with high resistance to powerful antibiotics of last resort. This has caused decline in research for developing newer antibacterial agents. Hence, there is continuous need to develop newer antibiotics that interact with essential mechanisms in bacteria. Recently, enzymes responsible for bio synthesis of the essential amino acid lysine in bacteria have been targeted and it has augmented interest to develop novel antibiotics and to enhance lysine yields in over-producing organisms. Peptidoglycan layer consists of a beta-1,4-linked polysaccharide of alternating N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) sugar units, cross linked by short pentapeptide (muramyl residues) side chain of general structure L-Ala-g-D-Glu-X- D-Ala-D-Ala, where X is either L–Lysine or meso-DAP. Formation of the cross-links makes bacterial cell wall resistant to lysis by intracellular osmotic pressure. Compounds which inhibit lysine or DAP biosynthesis could therefore be very effective antibiotics and novel targets. Lysine is a constituent in gram-positive bacteria while meso-DAP occurs in gram negative ones. In this review, substrate-based inhibitors of enzymes in the DAP pathway and inhibitors that allow better understanding of enzymology of the targets and provide insight for design of new inhibitors have been discussed. Resistant bacterial strains can be inhibited by using synthetic enzyme inhibitors of DAP pathway that are less toxic to mammals. Newer antimicrobial drugs can be thus developed by targeting the enzymes involved in this pathway

Customizable Tele-Operated Unmanned Ground Vehicle

Unmanned Ground Vehicles will play a very important role in the nation’s next generation ground forces. Control of the UGV is accomplished remotely, through a command system that allows an operator to receive sensor data and send motion commands to the vehicle. Being able to modify the UGV as per need will help us enlarge its scope of use

Self Names in The Mula Tau Text

Mula Tau episode as a part of the text of La Galigo, is a masterpiece of Bugis literature that has begun to be marginalized by millennials in Buloé, South Sulawesi. The uniqueness of the episode lies in the similarity of some of its parts to the dynamics of other ethnic texts in Indonesia. For example, on the role of the agent structure as the driving force of a literary work. It is these agents who with their respective roles have built a system of literary works. As the energy of a literary work, they are marked with their names according to their respective characters and roles. In simple terms, understanding the self-name can also be used as the key to understanding the storyline, it can even show the outlines of the cosmological view and the cosmogony of the Bugis autochthon. This study focuses on library research considering that the object of the study is in the form of documents. However, field research is still needed to translate and obtain a recording of the reading of the manuscript for transliteration purposes. The Mula Tau text is written in lontarak script. It's read as a literal Bugis language, so the self-name data collection begins with a translation; structuring sentence patterns, and identifying linguistic units that precede a name. Furthermore, the semantic theory used is based on referential theory. Research findings include various self-names and their meanings collected in two types of language styles, namely metaphor and metonymy. Likewise, the findings of self-names with article markers, morphemes, and unsigned ones

Decomposition analysis of the decline in binary and triad undernutrition among preschool children in India

Background: To examine the socio-demographic factors associated with the decline in undernutrition among preschool children in India from National Family Health Survey (NFHS)-3, 2005–06 to NFHS– 5, 2019–21. Methods: For this study data were obtained from India’s nationally representative datasets such as NFHS-3 and NFHS-5. The outcome variables for this study were Binary undernutrition which were defined as the coexistence of anemia and either stunting or wasting and Undernutrition triad which were defined as the presence of Iron deficiency anemia, stunting and wasting, respectively. Decomposition analysis was used to study the factors responsible for a decline in undernutrition. This method was employed to understand how these factors contributed to the decline in undernutrition whether due to change in the composition (change in the composition of the population) or propensity (change in the health-related behaviour of the population) of the population over a period of 16 years. Results: Results showed that rate, which contributes 85.26% and 65.64%, respectively, to total change, was primarily responsible for a decline in both binary undernutrition and undernutrition triad. Reduction in Binary undernutrition was mainly explained by the change in the rate of education level of the mothers and media exposer during the inter-survey period. On the other hand, the decline in the Undernutrition triad can be explained by household wealth index, mother’s education, birth order and a change in people’s knowledge or practice about the preceding birth interval. Conclusion: Identifying important factors and understanding their relationship with the decline of undernutrition can be beneficial for reorienting nutrition-specific policies to achieve the targets of the Sustainable Development Goals by 2030