Transcriptional Profiles of Leukocyte Populations Provide a Tool for Interpreting Gene Expression Patterns Associated with High Fat Diet in Mice

Microarray experiments in mice have shown that high fat diet can lead to elevated expression of genes that are disproportionately associated with immune functions. These effects of high fat (atherogenic) diet may be due to infiltration of tissues by leukocytes in coordination with inflammatory processes.The Novartis strain-diet-sex microarray database (GSE10493) was used to evaluate the hepatic effects of high fat diet (4 weeks) in 12 mouse strains and both genders. We develop and apply an algorithm that identifies "signature transcripts" for many different leukocyte populations (e.g., T cells, B cells, macrophages) and uses this information to derive an in silico "inflammation profile". Inflammation profiles highlighted monocytes, macrophages and dendritic cells as key drivers of gene expression patterns associated with high fat diet in liver. In some strains (e.g., NZB/BINJ, B6), we estimate that 50-60% of transcripts elevated by high fat diet might be due to hepatic infiltration by these cell types. Interestingly, DBA mice appeared to exhibit resistance to localized hepatic inflammation associated with atherogenic diet. A common characteristic of infiltrating cell populations was elevated expression of genes encoding components of the toll-like receptor signaling pathway (e.g., Irf5 and Myd88).High fat diet promotes infiltration of hepatic tissue by leukocytes, leading to elevated expression of immune-associated transcripts. The intensity of this effect is genetically controlled and sensitive to both strain and gender. The algorithm developed in this paper provides a framework for computational analysis of tissue remodeling processes and can be usefully applied to any in vivo setting in which inflammatory processes play a prominent role

Dissecting the psoriasis transcriptome: inflammatory- and cytokine-driven gene expression in lesions from 163 patients

Abstract Background Psoriasis lesions are characterized by large-scale shifts in gene expression. Mechanisms that underlie differentially expressed genes (DEGs), however, are not completely understood. We analyzed existing datasets to evaluate genome-wide expression in lesions from 163 psoriasis patients. Our aims were to identify mechanisms that drive differential expression and to characterize heterogeneity among lesions in this large sample. Results We identified 1233 psoriasis-increased DEGs and 977 psoriasis-decreased DEGs. Increased DEGs were attributed to keratinocyte activity (56%) and infiltration of lesions by T-cells (14%) and macrophages (11%). Decreased DEGs, in contrast, were associated with adipose tissue (63%), epidermis (14%) and dermis (4%). KC/epidermis DEGs were enriched for genes induced by IL-1, IL-17A and IL-20 family cytokines, and were also disproportionately associated with AP-1 binding sites. Among all patients, 50% exhibited a heightened inflammatory signature, with increased expression of genes expressed by T-cells, monocytes and dendritic cells. 66% of patients displayed an IFN-γ-strong signature, with increased expression of genes induced by IFN-γ in addition to several other cytokines (e.g., IL-1, IL-17A and TNF). We show that such differences in gene expression can be used to differentiate between etanercept responders and non-responders. Conclusions Psoriasis DEGs are partly explained by shifts in the cellular composition of psoriasis lesions. Epidermal DEGs, however, may be driven by the activity of AP-1 and cellular responses to IL-1, IL-17A and IL-20 family cytokines. Among patients, we uncovered a range of inflammatory- and cytokine-associated gene expression patterns. Such patterns may provide biomarkers for predicting individual responses to biologic therapy.http://deepblue.lib.umich.edu/bitstream/2027.42/112670/1/12864_2012_Article_5257.pd

Against Artificial Education: Towards an Ethical Framework for Generative Artificial Intelligence (AI) Use in Education

The arrival of Generative Artificial Intelligence (AI) is fundamentally different from prior technologies used in educational settings. Educators and researchers of online, blended, and in-person learning are still coming to grips with possible applications of AI in the learning experience with existing technologies; let alone understanding the potential consequences that future developments in AI will produce. Despite potential risks, AI may revolutionize previous models of teaching and learning and perhaps create opportunities to realize progressive educational goals. Given the longstanding tradition of philosophy to examine questions surrounding ethics, ontology, technology, and education, the purpose of this critical reflection paper is to draw from prominent philosophers across these disciplines to address the question: how can AI be employed in future educational contexts in a humanizing and ethical manner? Drawing from the work of Gunther Anders, Michel Foucault, Paolo Freire, Benjamin Bloom, and Hannah Arendt, we propose a framework for assessing the use and ethics of AI in modern education contexts regarding human versus AI generated textual and multimodal content, and the broader political, social, and cultural implications. We conclude with applied examples of the framework and implications for future research and practice

Psoriasis drug development and GWAS interpretation through in silico analysis of transcription factor binding sites

BackgroundPsoriasis is a cytokine‐mediated skin disease that can be treated effectively with immunosuppressive biologic agents. These medications, however, are not equally effective in all patients and are poorly suited for treating mild psoriasis. To develop more targeted therapies, interfering with transcription factor (TF) activity is a promising strategy.MethodsMeta‐analysis was used to identify differentially expressed genes (DEGs) in the lesional skin from psoriasis patients (n = 237). We compiled a dictionary of 2935 binding sites representing empirically‐determined binding affinities of TFs and unconventional DNA‐binding proteins (uDBPs). This dictionary was screened to identify “psoriasis response elements” (PREs) overrepresented in sequences upstream of psoriasis DEGs.ResultsPREs are recognized by IRF1, ISGF3, NF‐kappaB and multiple TFs with helix‐turn‐helix (homeo) or other all‐alpha‐helical (high‐mobility group) DNA‐binding domains. We identified a limited set of DEGs that encode proteins interacting with PRE motifs, including TFs (GATA3, EHF, FOXM1, SOX5) and uDBPs (AVEN, RBM8A, GPAM, WISP2). PREs were prominent within enhancer regions near cytokine‐encoding DEGs (IL17A, IL19 and IL1B), suggesting that PREs might be incorporated into complex decoy oligonucleotides (cdODNs). To illustrate this idea, we designed a cdODN to concomitantly target psoriasis‐activated TFs (i.e., FOXM1, ISGF3, IRF1 and NF‐kappaB). Finally, we screened psoriasis‐associated SNPs to identify risk alleles that disrupt or engender PRE motifs. This identified possible sites of allele‐specific TF/uDBP binding and showed that PREs are disproportionately disrupted by psoriasis risk alleles.ConclusionsWe identified new TF/uDBP candidates and developed an approach that (i) connects transcriptome informatics to cdODN drug development and (ii) enhances our ability to interpret GWAS findings. Disruption of PRE motifs by psoriasis risk alleles may contribute to disease susceptibility.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155494/1/ctm2s4016901500545-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155494/2/ctm2s4016901500545-sup-0018.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155494/3/ctm2s4016901500545-sup-0002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155494/4/ctm2s4016901500545.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155494/5/ctm2s4016901500545-sup-0009.pd

ALTERATION OF THE EPHA2/EPHRIN-A SIGNALING AXIS IN PSORIATIC EPIDERMIS

EphA2 is a receptor tyrosine kinase (RTK) that triggers keratinocyte differentiation upon activation and subsequently down-regulation by ephrin-A1 ligand. The objective for this study was to determine if the EphA2/ephrin-A1 signaling axis was altered in psoriasis, an inflammatory skin condition where keratinocyte differentiation is abnormal. Microarray analysis of skin biopsies from psoriasis patients revealed increased mRNA transcripts for several members of this RTK family in plaques, including the EphA1, EphA2 and EphA4 subtypes prominently expressed by keratinocytes. Of these, EphA2 showed the greatest up-regulation, a finding that was confirmed by quantitative RT-PCR, IHC analysis and ELISA. In contrast, psoriatic lesions exhibited reduced ephrin-A ligand immunoreactivity. Exposure of primary keratinocytes induced to differentiated in high calcium or a 3-dimensiosnal raft culture of human epidermis to a combination of growth factors and cytokines elevated in psoriasis increased EphA2 mRNA and protein expression while inducing S100A7 and disrupting differentiation. Pharmacological delivery of a soluble ephrin-A1 peptidomimetic ligand led to a reduction in EphA2 expression and ameliorated proliferation and differentiation in raft cultures exposed to EGF and IL-1α. These findings suggest that ephrin-A1-mediated down-regulation of EphA2 supports keratinocyte differentiation in the context of cytokine perturbation

Proteogenomic analysis of psoriasis reveals discordant and concordant changes in mRNA and protein abundance

Abstract Background Psoriasis is a chronic disease characterized by the development of scaly red skin lesions and possible co-morbid conditions. The psoriasis lesional skin transcriptome has been extensively investigated, but mRNA levels do not necessarily reflect protein abundance. The purpose of this study was therefore to compare differential expression patterns of mRNA and protein in psoriasis lesions. Methods Lesional (PP) and uninvolved (PN) skin samples from 14 patients were analyzed using high-throughput complementary DNA sequencing (RNA-seq) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results We identified 4122 differentially expressed genes (DEGs) along with 748 differentially expressed proteins (DEPs). Global shifts in mRNA were modestly correlated with changes in protein abundance (r = 0.40). We identified similar numbers of increased and decreased DEGs, but 4-fold more increased than decreased DEPs. Ribosomal subunit and translation proteins were elevated within lesions, without a corresponding shift in mRNA expression (RPL3, RPS8, RPL11). We identified 209 differentially expressed genes/proteins (DEGPs) with corresponding trends at the transcriptome and proteome levels. Most DEGPs were similarly altered in at least one other skin disease. Psoriasis-specific and non-specific DEGPs had distinct cytokine-response patterns, with only the former showing disproportionate induction by IL-17A in cultured keratinocytes. Conclusions Our findings reveal global imbalance between the number of increased and decreased proteins in psoriasis lesions, consistent with heightened translation. This effect could not have been discerned from mRNA profiling data alone. High-confidence DEGPs were identified through transcriptome-proteome integration. By distinguishing between psoriasis-specific and non-specific DEGPs, our analysis uncovered new functional insights that would otherwise have been overlooked.http://deepblue.lib.umich.edu/bitstream/2027.42/112309/1/13073_2015_Article_208.pd

Gerakan Kemandirian Pangan Melalui Program Desa Mandiri Pangan: Analisis Kinerja Dan Kendala

Program Desa Mandiri Pangan (Demapan) dilaksanakan tahun 2006 dan sampaisekarang masih berlanjut. Program dirancang dalam kurun waktu 4 tahun (tahap) dengan tujuan akhir mengurangi rawan pangan di perdesaan (mandiri). Sudah 158 desa masuk tahap kemandirian dan diharapkan desa yang sudah mandiri bisa membina 3 desa lainnya dalam program Gerakan Kemandirian Pangan. Tetapi dalam pelaksanaannya program ini tidak berhasil menjadikan seluruh desa mandiri menjadi desa inti, hal ini disebabkan kelembagaan Demapannya tidak aktif. Sementara kelembagaan tersebut akan menjadi narasumber dan tempat magang desa yang akan dibina (replikasi). Kelembagaan tersebut adalah Kelompok Afinitas (KA), Lembaga Keuangan Desa (LKD) dan Tim Pangan Desa (TPD). Bagi desa yang sudah tidak aktif kelembagaannya, maka program tidak perlu dilanjutkan. Sebaliknya bagi desa yang kelembagaannya kurang aktif, maka diperlukan kegiatan pemberdayaan kelembagaan. Selain itu diperlukan dana dari pemerintah untuk pengurus dalam menggerakkan lembaga TPD dan LKD. Dana itu diinisiasi dahulu dari Badan Ketahanan Pangan Kementerian Pertanian yang dimasukkan dalam dana kegiatan Gerakan Kemandirian Pangan. Tahun berikutnya dana tersebut diharapkan dari dana APBD Tk I dan APBD Tk II. Selanjutnya untuk mensukseskan kegiatan Demapan maka peranan BKP Provinsi perlu ditingkatkan lagi agar masalah kabupaten tidak melakukan monev kegiatan dengan baik dan seringnya pergantian SDM di tingkat kabupaten bisa diatasi

Cellular dissection of psoriasis for transcriptome analyses and the post-GWAS era

Abstract Background Genome-scale studies of psoriasis have been used to identify genes of potential relevance to disease mechanisms. For many identified genes, however, the cell type mediating disease activity is uncertain, which has limited our ability to design gene functional studies based on genomic findings. Methods We identified differentially expressed genes (DEGs) with altered expression in psoriasis lesions (n = 216 patients), as well as candidate genes near susceptibility loci from psoriasis GWAS studies. These gene sets were characterized based upon their expression across 10 cell types present in psoriasis lesions. Susceptibility-associated variation at intergenic (non-coding) loci was evaluated to identify sites of allele-specific transcription factor binding. Results Half of DEGs showed highest expression in skin cells, although the dominant cell type differed between psoriasis-increased DEGs (keratinocytes, 35%) and psoriasis-decreased DEGs (fibroblasts, 33%). In contrast, psoriasis GWAS candidates tended to have highest expression in immune cells (71%), with a significant fraction showing maximal expression in neutrophils (24%, P < 0.001). By identifying candidate cell types for genes near susceptibility loci, we could identify and prioritize SNPs at which susceptibility variants are predicted to influence transcription factor binding. This led to the identification of potentially causal (non-coding) SNPs for which susceptibility variants influence binding of AP-1, NF-κB, IRF1, STAT3 and STAT4. Conclusions These findings underscore the role of innate immunity in psoriasis and highlight neutrophils as a cell type linked with pathogenetic mechanisms. Assignment of candidate cell types to genes emerging from GWAS studies provides a first step towards functional analysis, and we have proposed an approach for generating hypotheses to explain GWAS hits at intergenic loci.http://deepblue.lib.umich.edu/bitstream/2027.42/109537/1/12920_2013_Article_485.pd

Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis

Abstract Background Imiquimod (IMQ) produces a cutaneous phenotype in mice frequently studied as an acute model of human psoriasis. Whether this phenotype depends on strain or sex has never been systematically investigated on a large scale. Such effects, however, could lead to conflicts among studies, while further impacting study outcomes and efforts to translate research findings. Methods RNA-seq was used to evaluate the psoriasiform phenotype elicited by 6 days of Aldara (5% IMQ) treatment in both sexes of seven mouse strains (C57BL/6 J (B6), BALB/cJ, CD1, DBA/1 J, FVB/NJ, 129X1/SvJ, and MOLF/EiJ). Results In most strains, IMQ altered gene expression in a manner consistent with human psoriasis, partly due to innate immune activation and decreased homeostatic gene expression. The response of MOLF males was aberrant, however, with decreased expression of differentiation-associated genes (elevated in other strains). Key aspects of the IMQ response differed between the two most commonly studied strains (BALB/c and B6). Compared with BALB/c, the B6 phenotype showed increased expression of genes associated with DNA replication, IL-17A stimulation, and activated CD8+ T cells, but decreased expression of genes associated with interferon signaling and CD4+ T cells. Although IMQ-induced expression shifts mirrored psoriasis, responses in BALB/c, 129/SvJ, DBA, and MOLF mice were more consistent with other human skin conditions (e.g., wounds or infections). IMQ responses in B6 mice were most consistent with human psoriasis and best replicated expression patterns specific to psoriasis lesions. Conclusions These findings demonstrate strain-dependent aspects of IMQ dermatitis in mice. We have shown that IMQ does not uniquely model psoriasis but in fact triggers a core set of pathways active in diverse skin diseases. Nonetheless, our findings suggest that B6 mice provide a better background than other strains for modeling psoriasis disease mechanisms.http://deepblue.lib.umich.edu/bitstream/2027.42/136167/1/13073_2017_Article_415.pd

Genome-Wide Expression Profiling of Five Mouse Models Identifies Similarities and Differences with Human Psoriasis

Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments