Статті в журналах з теми "Center manifold projection"

We show that the global aspects of Abelian and center projection of a SU (2) gauge theory on an arbitrary manifold are naturally described in terms of smooth Deligne cohomology. This is achieved through the introduction of a novel type of differential topological structure, called Cho structure. Half integral monopole charges appear naturally in this framework.

Conditions for vegetation spreading and pattern formation are mathematically framed through an analysis encompassing three fundamental processes: flow stochasticity, vegetation dynamics, and sediment transport. Flow unsteadiness is included through Poisson stochastic processes whereby vegetation dynamics appears as a secondary instability, which is addressed by Floquet theory. Results show that the model captures the physical conditions heralding the transition between bare and vegetated fluvial states where the nonlinear formation and growth of finite alternate bars are accounted for by Center Manifold Projection. This paves the way to understand changes in biogeomorphological styles induced by man in the Anthropocene and of natural origin since the Paleozoic (Devonian plant hypothesis).

Malignant chromophobe renal cancer (chRCC) and benign oncocytoma (RO) are two renal tumor types difficult to differentiate using histology and immunohistochemistry-based methods because of their similarity in appearance. We previously developed a transcriptomics-based classification pipeline with “Chromophobe-Oncocytoma Gene Signature” (COGS) on a single-molecule counting platform. Renal cancer patients (n = 32, chRCC = 17, RO = 15) were recruited from Augusta University Medical Center (AUMC). Formalin-fixed paraffin-embedded (FFPE) blocks from their excised tumors were collected. We created a custom single-molecule counting code set for COGS to assay RNA from FFPE blocks. Utilizing hematoxylin-eosin stain, pathologists were able to correctly classify these tumor types (91.8%). Our unsupervised learning with UMAP (Uniform manifold approximation and projection, accuracy = 0.97) and hierarchical clustering (accuracy = 1.0) identified two clusters congruent with their histology. We next developed and compared four supervised models (random forest, support vector machine, generalized linear model with L2 regularization, and supervised UMAP). Supervised UMAP has shown to classify all the cases correctly (sensitivity = 1, specificity = 1, accuracy = 1) followed by random forest models (sensitivity = 0.84, specificity = 1, accuracy = 1). This pipeline can be used as a clinical tool by pathologists to differentiate chRCC from RO.

We continue to study of the Grassmann-like manifold of -centered planes. A special case is considered when the center de­scribes an -dimensional surface . We will denote this mani­fold by . An analogue of the strong Norden normalization of the manifold is realized. It is proved that this normalization induces a connection in the bundle associated with the manifold . A geometric characteristic of this connection is given with the help of parallel displacements. In our research we use the Cartan method of external forms and the group-theoretical method of Laptev. These methods are used by many geometers and physicists. The Grassmann-like manifold is closely related to such a well-known and popular manifold as the Grassmann manifold. The Grassmann mani­fold is an example of a homogeneous space and forms an important fun­damental class of projective manifolds, and the projective space itself can be represented as a Grassmann manifold.

Abstract Introduction: Multiple myeloma (MM) is a complex hematological malignancy with the heterogenous immune bone marrow (BM) environment contributing to tumor growth, drug resistance, and immune escape. T-Cells play a critical role in the clearance of malignant plasma cells from the tumor environment. However, T-Cells in multiple myeloma demonstrate impaired cytotoxicity, proliferation, and cytokine production due to the activation of immune inhibitory receptors from ligands produced by the myeloma cells. In this study, we investigate the behavior of T-Cells in MM patients by using single-cell RNA-Seq (scRNA-Seq) to compare the transcriptomic profiles of BM T-Cells of patients with rapid progressing (FP; PFS < 18mo) and non-progressing (NP; PFS > 4yrs) disease. Methods: Newly diagnosed MM patients (n=18) from the Multiple Myeloma Research Foundation (MMRF) CoMMpass study (NCT01454297) were identified as either rapid progressors or non-progressors based on their progression free survival since diagnosis. To capture transcriptomic data, scRNA-Seq was performed on 48 aliquots of frozen CD138-negative BM cells at three medical centers/universities (Beth Israel Deaconess Medical Center, Boston, Washington University in St. Louis, and Mount Sinai School of Medicine, NYC). Samples were collected at diagnosis prior to treatment. Surface marker expression for 29 proteins was captured for at least one sample per patient using CITE-Seq. After integration and batch correction, clustering was performed to identify cells of T or NK lineage. Uniform Manifold Approximation and Projection (UMAP) and differential expression were used to identify T-Lymphoid subtypes, and differences in NP and FP samples. Results: In this study, single cell transcriptomic profiles were identified for ~102,207 cells from 48 samples of 18 MM patients. 40,328 T (CD3+) and NK (CD3-, NKG7+) cells were isolated, and subclustered for further analysis (Fig 1A). Using differentially expressed markers for each cluster, the T-Lymphoid subset was refined into seven subtypes, consisting of various CD4+ T-Cells, CD8+ T-Cells, and NK cells (Fig 1B). The CD8+ cells were divided into three distinct phenotypes, namely a GZMK-, GZMB- CD8+ T-Cell cluster, a GZMK+ CD8+ Exhausted T-Cell cluster enriched in TIGIT and multiple chemokines (CCL3, CCL4, XCL2), and a GZMB+ NkT cluster enriched in cytolytic markers (PRF1, GNLY, NKG7) (Fig 1C). Differential expression between NP and FP samples in this CD8+ subset showed enrichment of the NkT cytotoxic markers in NP samples, while FP samples were enriched in the CD8+ Exhausted chemokine markers (Fig 1D). Furthermore, the proportion of CD8+ Exhausted T-Cells was enriched in FP samples (p.val < 0.05) (Fig 1E). Exhaustion markers were measured through both RNA and surface marker levels. In RNA, TIGIT was uniquely associated with the FP-enriched CD8+ Exhausted T-Cell cluster, and CD160 was uniquely expressed in FP samples (Fig 1F). CITE-Seq surface marker expression confirms enrichment of both TIGIT and PD1 in the CD8+ Exhausted T-Cell cluster, and along with more exhaustion in FP samples (p.val < 0.01). Conclusion: In this study, we have identified significant differences in T-Cell activity in patients with non-progressing and rapid-progressing multiple myeloma. T-Cells in rapid progressing patients appear to be in a suppressed state, with low cytolytic activity and enriched exhaustion markers. This GZMK+ T-Cell population shows strong similarities with an aging-associated subtype of effector memory T-Cells found to be enriched in older populations (Mogilenko et al, Immunity 54, 2021). These findings will be further validated in an expanded study, consisting both of a larger number of samples, and multiple samples at different timepoints from the same patient. Figure 1 Figure 1. Disclosures Jayasinghe: MMRF: Consultancy; WUGEN: Consultancy. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria. Kumar: Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Bluebird Bio: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Roche-Genentech: Consultancy, Research Funding; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy.

The current paper continues consideration of geometry of projective frame orbits started in the author’s article in the previous issue. The ndimensional projective space with a distinguished point (the center) is considered. The action of matrix affine group of order n on the adapted projective frame manifold is given. It is shown that the linear frames, i. e., bases of the tangent space, can be identified with the orbits of adapted projective frames under the action of some normal subgroup of this group. Two adapted frames are said to be equivalent if they belong to the same orbit. The strict perspectivity relation between two adapted frames is introduced. The proofs of the theorem on the Desargues hyperplane and of the criterion of equivalence are simplified. According to this criterion, two adapted frames in strict perspective are equivalent if and only if the Desargues hyperplane generated by these frames is passing through the center.

We prove the existence and uniqueness of equilibrium states for a family of partially hyperbolic systems, with respect to Hölder continuous potentials with small variation. The family comes from the projection, on the center-unstable direction, of a family of partially hyperbolic horseshoes introduced by Díaz et al [Destroying horseshoes via heterodimensional cycles: generating bifurcations inside homoclinic classes. Ergod. Th. & Dynam. Sys.29 (2009), 433–474]. For the original three-dimensional system we consider potentials with small variation, constant on local stable manifolds, obtaining existence and uniqueness of equilibrium states.

Introduction: Multiple myeloma (MM) is a genetically complex and clinically heterogeneous disease. Disease biology and phenotype is heavily influenced by the tumor microenvironment and the interaction between the immune milieu and malignant plasma cell population. Understanding the molecular profile of tumor along with the immune ecosystem can provide insights into key pathways that are important in disease pathobiology. Therefore, in this study, we have used single-cell RNA-Seq (scRNA-Seq) to compare the detailed maps of the bone marrow microenvironment of patients with rapid progressing disease (PFS < 18 months) with those whose disease had not progressed at the time of analysis (PFS < 4 years) Methods: MM patients (n=18) with rapid and no progression were identified from the Multiple Myeloma Research Foundation (MMRF) CoMMpass study, a longitudinal genomic study of patients with newly diagnosed, active multiple myeloma (NCT01454297). To generate a robust scRNA-Seq profile with minimal false positive, we profiled multiple technical replicates/aliquots of viably frozen CD138-negative bone marrow cells from each patient at three medical centers/universities (Beth Israel Deaconess Medical Center, Boston, Washington University in St. Louis and Mount Sinai School of Medicine, NYC using droplet-based single-cell barcoding technique. After batch correction and normalization, the cellular clusters were identified using principal component analysis and Uniform Manifold Approximation and Projection (UMAP) approach (Becht et al, 2018). Differential expression, pathways and systems biology analysis between rapid and non-progressors revealed differences for specific cell clusters (Panigrahy, Gartung et al. 2019). To determine association of plasma cell overexpressed genes with survival in CoMMpass study, survival analysis was performed using Kaplan-Meier (K-M) approach. Results: In this study, comparative analysis was performed of the bone marrow microenvironment of patients with aggressive and indolent disease by generating single-cell profiles of ~102,207 cells from 48 samples of 18 patients with MM. The UMAP approach identified multiple transcriptionally diverse clusters of plasma (CD138+), immune (PTPRC+) and erythroid (GYPA1/2+) cells (Fig 1a). Interestingly, the analysis identified CD138+ plasma/tumors cells clusters in a subset of samples from patients with rapid -progression and these clusters depicted a high degree of inter-patient heterogeneity (Fig 1a). Further characterization of plasma tumor cells depicted significant activation (Z score >2 and P-value <.001) of pathway related to "Unfolded protein response", epithelial-mesenchymal transition (EMT), and "p38 MAPK Signaling". These rapid progressions associated with plasma cells overexpressing multiple genes (e.g., Hazard ratio (HR) CCL3=1.9 95% CI= (1.5-3.9) log-rank P=0.0004, HSPA5 HR=1.4 (1-2.6), P=0.03) that are associated with poor outcome in multiple myeloma based CoMMpass data. The bone marrow microenvironment cells formed 22 clusters, comprising of cells from myeloid, macrophages, T cells, B cells, dendritic cells, Natural Killer T (NKT) cells, and erythroid lineages. The Non-progressive patients depicted enrichment of GZMB+ T and NKT cells with overexpression of genes associated with "Natural Killer Cell Signaling", "CD28 Signaling in T Helper Cells", "NF-kB Signaling" and "Th17 Activation Pathway" (Fig1b, c). Systems biology analysis depicted significant activation of TNF, STAT4, and NFATC2 regulatory signatures in NKT cells. The analysis also observed enrichment of macrophages, several types of monocytes, and myeloid cells in the samples from patients with non-progressive disease (Fig 1d). The myeloid/monocytes cluster depicted significant activation of multiple metabolic (i.e., Glycolysis, Gluconeogenesis) and immune response (i.e. IL8) pathways (Fig 1e). In summary, this multi-site study provides insights into potentially significant differences in the transcriptomic landscape of multiple myeloma patients with rapid and non-progression of disease. The non-progressive patients depict significant enrichment of activated T cells and myeloid lineage populations, suggesting their role toward better outcomes. These findings will be further expanded by ongoing single cell analyses of the CoMMpass tissue bank under the MMRF Immune Atlas initiative. Figure 1 Disclosures Bhasin: Canomiiks Inc: Current equity holder in private company, Other: Co-Founder. Dhodapkar:Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other; Amgen: Membership on an entity's Board of Directors or advisory committees, Other; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Other; Janssen: Membership on an entity's Board of Directors or advisory committees, Other; Kite: Membership on an entity's Board of Directors or advisory committees, Other; Lava Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other. Kumar:Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Genecentrix: Consultancy; Tenebio: Other, Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Sanofi: Research Funding; MedImmune: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Cellectar: Other; Carsgen: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding.

A compiled hyperplane distribution is considered in an n-dimensional projective space . We will briefly call it a -distribution. Note that the plane L(A) is the distribution characteristic obtained by displacement in the center belonging to the L-subbundle. The following results were obtained: a) The existence theorem is proved: -distribution exists with arbitrary (3n – 5) functions of n arguments. b) A focal manifold is constructed in the normal plane of the 1st kind of L-subbundle. It was obtained by shifting the cen­ter A along the curves belonging to the L-distribution. A focal manifold is also given, which is an analog of the Koenigs plane for the distribution pair (L, L). c) It is shown that a framed -distribution in the 1st kind normal field of H-distribution induces tangent and normal bundles. d) Six connection theorems induced by a framed -distri­bu­tion in these bundles are proved. In each of the bundles , the framed -distribution induces an intrin­sic torsion-free affine connection in the tangent bundle and a centro-affine connection in the corresponding normal bundle. e) In each of the bundles (d) in the differential neighborhood of the 2nd order, the covers of 2-forms of curvature and curvature tensors of the corresponding connections are constructed.

Abstract Follicular lymphoma (FL) is an indolent, but incurable malignancy as most patients eventually experience progressive disease. We hypothesized that clonal heterogeneity and patient-specific immune responses would contribute to variable clinical outcomes and that understanding the complexity of the entire tumor "ecosystem" would allow us to better match patients with specific types of tumor- and immune-targeted therapies. In this study, we performed 38-dimensional single-cell phenotyping by mass cytometry (CyTOF) to simultaneously characterize both the substructure of malignant B cell populations as well as the T cell microenvironment in a cohort of 77 diagnostic patient FL biopsies and 35 benign reactive LN (rLN) biopsies. We first applied the t-distributed Stochastic Neighbour Embedding (t-SNE) algorithm to explore intra- and inter- tumoral heterogeneity among malignant B cell populations. t-SNE mapping of individual samples showed that more than a third of FL samples contain at least two phenotypically distinct tumor subpopulations, supporting the notion of multi-clonal tumor architectures presumably due to ongoing clonal evolution. Batched analysis combining all 77 FL cases together with 35 rLN samples revealed two distinct tumor subtypes comprising about 25% (type "A") and 10% (type "B") of total FL samples, respectively, with individual tumors within each subtype showing highly similar and partially overlapping phenotypes. Mapping the same data using Uniform Manifold Approximation and Projection (UMAP), a dimensional reduction algorithm similar to t-SNE but preserves global structure more accurately, revealed that type A tumors localized in close proximity to normal germinal center (GC) B cells, thus fulfilling conventional expectations as to the histogenesis of FL. In contrast, type B tumors localized more closely to pre-GC B cells, implying the existence of an alternate histogenic path in FL. Importantly, we also performed single-cell RNA-Seq on a subset of FL cases which independently confirmed the type A vs type B distinction in whole transcriptomic space. We next analyzed matching T cell data using a modified Statistical Scaffold algorithm in order to place distinct subsets in context with conventionally defined normal T cell populations. Clustering analysis using multi-layer phenograph performed on T cells from all FL and rLN samples combined yielded hundreds of small, but phenotypically distinct populations that were then annotated according to the nearest conventionally defined T cell subset. These imputed designations were used as features to perform hierarchical clustering of samples which revealed 3 major clusters. Cluster1 was characterized by mostly naive T cell populations and contained the majority of rLN samples. Cluster2 was characterized by more differentiated effector T cell populations and was dominated by FL samples. Samples within Cluster2 could be further divided into Tfh, Treg and Th1-rich subgroups. Cluster3 was characterized by a diverse T cell environment including naive, memory and differentiated effector subsets and contained a mixture of rLN and FL samples. Integrative analysis correlating B- and T- cell features revealed type B FL tumors were associated with a Tfh-rich immune landscape. Taken together, these data reveal pervasive phenotypic heterogeneity in both malignant and immune cell compartments of patient FL samples and suggest that defining tumoral subtypes as well as the status of the local immune response within individual samples will support more refined diagnostic classification and highlight functional interactions most amenable to therapeutic targeting. Disclosures Gascoyne: NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Celgene: Consultancy, Honoraria; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Janssen: Research Funding. Steidl:Juno Therapeutics: Consultancy; Seattle Genetics: Consultancy; Nanostring: Patents & Royalties: patent holding; Bristol-Myers Squibb: Research Funding; Tioma: Research Funding; Roche: Consultancy.

In n-dimensional projective space Pn a manifold , i. e., a family of pairs of planes one of which is a hyperplane in the other, is considered. A principal bundle arises over it, . A typi­cal fiber is the stationarity subgroup of the generator of pair of planes: external plane and its multidimensional center — hyperplane. The princi­pal bundle contains four factor-bundles. A fundamental-group connection is set by the Laptev — Lumiste method in the associated fibering. It is shown that the connection object contains four subobjects that define connections in the corresponding fac­tor-bundles. It is proved that the curvature object of fundamental-group connection forms pseudotensor. It contains four subpseudotensors, which are curvature objects of the corresponding subconnections. The composite equipment of the family of hypercentered planes set by means of a point lying in the plane and not belonging to its hypercent­er and an (n – m – 1)-dimensional plane, which does not have common points with the hypercentered plane. It is proved, that composite equip­ment induces the fundamental-group connections of two types in the as­sociated fibering.

This paper considers a rumor transmission model with incubation that incorporates constant recruitment and has infectious force in the latent period and infected period. By carrying out a global analysis of the model and studying the stability of the rumor-free equilibrium and the rumor-endemic equilibrium, we use the geometric approach for ordinary differential equations which is based on the use of higher-order generalization of Bendixson’s criterion. It shows that either the number of rumor infective individuals tends to zero as time evolves or the rumor persists. We prove that the transcritical bifurcation occurs atR0crosses the bifurcation thresholdR0=1by projecting the flow onto the extended center manifold. Since the rumor endemic level at the equilibrium is a continuous function ofR0, as a consequence for successful eradication of the rumor, one should simply reduceR0continuously below the threshold value 1. Finally, the obtained results are numerically validated and then discussed from both the mathematical and the sociological perspectives.

In this paper, we explore the mega riverbed-patterns, whose longitudinal and vertical length dimensions scale with a few channel widths and the flow depth, respectively. We perform the stability analyses from both linear and weakly nonlinear perspectives by considering a steady-uniform flow in an erodible straight channel comprising a uniform sediment size. The mathematical framework stands on the dynamic coupling between the depth-averaged flow model and the particle transport model including both bedload and suspended load via the Exner equation, which drives the pattern formation. From the linear perspective, we employ the standard linearization technique by superimposing the periodic perturbations on the undisturbed system to find the dispersion relationship. From the weakly nonlinear perspective, we apply the centre–manifold-projection technique, where the fast dynamics of stable modes is projected on the slow dynamics of weakly unstable modes to obtain the Stuart–Landau equation for the amplitude dynamics. We examine the marginal stability, growth rate and amplitude of patterns for a given quintet formed by the channel aspect ratio, wavenumber of patterns, shear Reynolds number, Shields number and relative roughness number. This study highlights the sensitivity of pattern formation to the key parameters and shows how the classical results can be reconstructed on the parameter space.

Introduction: Maintenance therapy with the immunomodulatory drug (IMiD) lenalidomide improves progression-free survival (PFS) and overall survival among patients with multiple myeloma (MM). It has been suggested that IMiDs enhance immune-mediated anti-tumor responses through increased activation and proliferation of T cells and natural killer (NK) cells as well as inhibition of regulatory T cells. Despite the effectiveness of this therapy, nearly all patients relapse for reasons that remain uncharacterized. We sought to elucidate mechanisms of resistance to lenalidomide maintenance through investigation of mutations in cell-free DNA (cfDNA) and identification of changes in the innate and adaptive immune system by single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs). While MM is a cancer of plasma cells that primarily reside in the bone marrow, we focused on the peripheral blood which offers a comprehensive view of multiple sites of disease including extramedullary locations commonly found at the time of relapse. Methods: Twenty-four patients with MM and no minimal residual disease by 10-color flow cytometry and IGHVnext-generation sequencing (Invivoscribe) after induction therapy with or without an autologous stem cell transplant were selected for analysis. All patients were enrolled in NCT02538198 at Memorial Sloan Kettering Cancer Center. Peripheral blood was collected serially including timepoints prior to lenalidomide maintenance and after disease progression. Plasma and PBMCs were isolated by Ficoll-Paque density gradient centrifugation. cfDNA was extracted from plasma and targeted next-generation sequencing using a 70-gene panel of recurrently mutated genes in myeloma was performed using the QIAseq Targeted DNA kit (QIAGEN). DNA sequencing was also performed using the same gene panel on granulocytes to exclude germline variants. On PBMC samples, 5' gene expression and T and B cell receptor single-cell sequencing were performed using the Chromium Single Cell V(D)J kit (10X Genomics). Analysis of single-cell sequencing was performed on the top 100 principal components and visualized by Uniform Manifold Approximation and Projection (UMAP). A regression-based classifier was trained to automatically assign clustered cells into 26 immune cell phenotypes using lists of genes reported to be uniquely expressed by each cell type. Results: cfDNA sequencing was performed on 12 patients characterized as durable responders (PFS > 57 months) and 12 early progressors (median PFS 25 months). Prior to maintenance therapy, no significant difference was observed in the number of cfDNA mutations between these groups. The number of non-synonymous somatic mutations in cfDNA tended to increase over time and was significantly higher among patients taking lenalidomide for more than 2 years compared to patients at the time of relapsed disease (mean number of mutations was 7 in responders versus 3 in progressors).ZNF292was among the genes most significantly mutated in responders compared to progressors. ZNF292encodes a zinc finger protein involved in RNA binding and has previously been identified as a potential source of tumor-associated antigens in patients with monoclonal gammopathy of undetermined significance. To identify changes in immune cell phenotype and function that associate with disease progression, we performed single-cell RNA sequencing on PBMCs from the 12 progressors before maintenance and at the time of relapse. The median number of cells sequenced per PBMC sample was 3,132. Over 90% of cells could automatically be classified into a specific immune cell type by their gene expression. We observed the frequency of NK cells and plasmablasts were significantly increased at the time progression on lenalidomide while monocytes, dendritic cells, and basophils were decreased. Conclusion: Mechanisms of resistance among patients receiving treatment with IMiDs is not well known. Using targeted sequencing of cfDNA, we identify patients responding to maintenance tended to have a higher mutational load in cfDNA including genes previously reported to encode tumor-associated antigens. Additionally, we show that a decline in antigen-presenting dendritic cells is more common at the time of disease progression. Taken together, these results suggest reduced neoantigen production and a decline in antigen presentation may contribute to IMiD resistance. Disclosures Landgren: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Green:Celgene: Consultancy; Cellectar Biosciences: Research Funding; Seattle Genetics: Research Funding; Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; GSK: Consultancy.

BackgroundPredictive biomarkers for response to IO therapies remain insufficient. Although multiplex immunofluorescence has the potential to provide superior biomarkers, the information garnered from these studies is frequently underleveraged. Due to the large number of markers that must be analyzed (6 - 40 +), and the complexity of the spatial information, the number of hypotheses is large and must be tested systematically and automatically. GraphITE (Graphs-based Investigation of Tissues with Embeddings) is a novel method of converting multiplex IF image analysis results into embeddings, numerical vectors which represent the phenotype of each cell as well as the immediate neighborhood. This allows for the clustering of embeddings based on similarity as well as the discovery of novel predictive biomarkers based on both the spatial and multimarker data in multiplex IF images. Here we demonstrate initial observations from deployment of GraphITE on 564 commercially-sourced NSCLC and HNSCC resections stained with a multiplex IF panel containing CD8, PDL1, PD1, CD68, Ki67, and CK.Methods4 μm FFPE tumor sections were stained with CD8, PDL1, PD1, CD68, Ki67, and CK at Akoya Biosciences using OPAL TSA-linked fluorophores and imaged on a Vectra Polaris. Images were analyzed by Computational Biology (AstraZeneca). Graphs were built by mapping each cell in the mIF image as a node, using the X, Y coordinates and connecting nodes with edges according to distance. 64-dimensional embeddings were generated using Deep Graph InfoMax (DGI).1 Embeddings are downprojected to 2 dimensions using UMAP.2. Details are available in the preprint of the GraphITE methods manuscript.3ResultsA single downprojection was developed using embeddings from 158 HNSCC and 406 NSCLC cases. 60–80 distinct clusters were observed, some of which contained embeddings from both indications and others which were exclusive to one indication. Exclusive clusters describe tissue neighborhoods observed only in one indication. Drivers of cluster exclusivity included increased cell density in HNSCC as compared to NSCLC both in PD-L1- tumor centers with few infiltrating lymphocytes as well as in PD-L1- macrophagedominated neighborhoods. HNSCC and NSCLC embeddings were more colocalized in PD-L1+ tumor centers and in tumor stroma with high CD8+ or CD68+ immune cell content and high PD-L1+ expression.ConclusionsThis study demonstrates the utility and potential of the GraphITE platform to discriminate between and describe both unique and common neighborhood-level features of the tumor microenvironment. Deploying GraphITE across multiple indications effectively leverages spatial heterogeneity and multimarker information from multiplex IF panels.References1. Veličković P, Fedus W, Hamilton WL, Liò P, Bengio Y, DevonHjelm R. Deep Graph Infomax. 2018. arxiv:1809.10341 [stat.ML].2. McInnes L, Healy J, Melville J. UMAP: Uniform manifold approximationand projection for dimension reduction. 2020; arxiv:1802.03426 [stat.ML].3. Innocenti C, Zhang Z, Selvaraj B, Gaffney I, Frangos M, Cohen-Setton J, Dillon LAL, Surace MJ, Pedrinaci C, Hipp J, Baykaner K. An unsupervised graph embeddings approach to multiplex immunofluorescence image explorationbioRxiv 2021.06.09.447654; doi: https://doi.org/10.1101/2021.06.09.447654Ethics ApprovalThe study was approved by AstraZeneca.

Abstract. Water vapour and ozone are important for the thermal and radiative balance of the upper troposphere (UT) and lowermost stratosphere (LMS). Both species are modulated by transport processes. Chemical and microphysical processes affect them differently. Thus, representing the different processes and their interactions is a challenging task for dynamical cores, chemical modules and microphysical parameterisations of state-of-the-art atmospheric model components. To test and improve the models, high-resolution measurements of the UT–LMS are required. Here, we use measurements taken in a flight of the GLORIA (Gimballed Limb Observer for Radiance Imaging of the Atmosphere) instrument on HALO (High Altitude and LOng Range Research Aircraft). The German research aircraft HALO performed a research flight on 26 February 2016 that covered deeply subsided air masses of the aged 2015/16 Arctic vortex, high-latitude LMS air masses, a highly textured region affected by troposphere-to-stratosphere exchange and high-altitude cirrus clouds. Therefore, it provides a challenging multifaceted case study for comparing GLORIA observations with state-of-the-art atmospheric model simulations in a complex UT–LMS region at a late stage of the Arctic winter 2015/16. Using GLORIA observations in this manifold scenario, we test the ability of the numerical weather prediction (NWP) model ICON (ICOsahedral Nonhydrostatic) with the extension ART (Aerosols and Reactive Trace gases) and the chemistry–climate model (CCM) EMAC (ECHAM5/MESSy Atmospheric Chemistry – fifth-generation European Centre Hamburg general circulation model/Modular Earth Submodel System) to model the UT–LMS composition of water vapour (H2O), ozone (O3), nitric acid (HNO3) and clouds. Within the scales resolved by the respective model, we find good overall agreement of both models with GLORIA. The applied high-resolution ICON-ART set-up involving an R2B7 nest (local grid refinement with a horizontal resolution of about 20 km), covering the HALO flight region, reproduces mesoscale dynamical structures well. Narrow moist filaments in the LMS observed by GLORIA at tropopause gradients in the context of a Rossby wave breaking event and in the vicinity of an occluded Icelandic low are clearly reproduced by the model. Using ICON-ART, we show that a larger filament in the west was transported horizontally into the Arctic LMS in connection with a jet stream split associated with poleward breaking of a cyclonically sheared Rossby wave. Further weaker filaments are associated with an older tropopause fold in the east. Given the lower resolution (T106) of the nudged simulation of the EMAC model, we find that this model also reproduces these features well. Overall, trace gas mixing ratios simulated by both models are in a realistic range, and major cloud systems observed by GLORIA are mostly reproduced. However, we find both models to be affected by a well-known systematic moist bias in the LMS. Further biases are diagnosed in the ICON-ART O3, EMAC H2O and EMAC HNO3 distributions. Finally, we use sensitivity simulations to investigate (i) short-term cirrus cloud impacts on the H2O distribution (ICON-ART), (ii) the overall impact of polar winter chemistry and microphysical processing on O3 and HNO3 (ICON-ART and EMAC), (iii) the impact of the model resolution on simulated parameters (EMAC), and (iv) consequences of scavenging processes by cloud particles (EMAC). We find that changing the horizontal model resolution results in notable systematic changes for all species in the LMS, while scavenging processes play a role only in the case of HNO3. We discuss the model biases and deficits found in this case study that potentially affect forecasts and projections (adversely) and provide suggestions for further model improvements.

In this paper, we analyze the dynamical behavior of the delayed fractional-order tumor model with Caputo sense and discretized conformable fractional-order tumor model. The model is constituted with the group of nonlinear differential equations having effector and tumor cells. First of all, stability and bifurcation analysis of the delayed fractional-order tumor model in the sense of Caputo fractional derivative is studied, and the existence of Hopf bifurcation depending on the time delay parameter is proved by using center manifold and bifurcation theory. Applying the discretization process based on using the piecewise constant arguments to the conformable version of the model gives a two-dimensional discrete system. Stability and Neimark-Sacker bifurcation analysis of the discrete system are demonstrated using the Schur-Cohn criterion and projection method. This study reveals that the delay parameter $ \tau $ in the model with Caputo fractional derivative and the discretization parameter $ h $ in the discrete-time conformable fractional-order model have similar effects on the dynamical behavior of corresponding systems. Moreover, the effect of the order of fractional derivative on the dynamical behavior of the systems is discussed. Finally, all results obtained are interpreted biologically, and numerical simulations are presented to illustrate and support theoretical results.

The motion of the human body can be described by the motion of its center of mass (CoM). Since the trajectory of the CoM is a crucial variable during running, one can assume that trained runners would try to keep their CoM trajectory constant from stride to stride. However, when exposed to fatigue, runners might have to adapt certain biomechanical parameters. The Uncontrolled Manifold approach (UCM) and the Tolerance, Noise, and Covariation (TNC) approach are used to analyze changes in movement variability while considering the overall task of keeping a certain task relevant variable constant. The purpose of this study was to investigate if and how runners adjust their CoM trajectory during a run to fatigue at a constant speed on a treadmill and how fatigue affects the variability of the CoM trajectory. Additionally, the results obtained with the TNC approach were compared to the results obtained with the UCM analysis in an earlier study on the same dataset. Therefore, two TNC analyses were conducted to assess effects of fatigue on the CoM trajectory from two viewpoints: one analyzing the CoM with respect to a lab coordinate system (PVlab) and another one analyzing the CoM with respect to the right foot (PVfoot). Full body kinematics of 13 healthy young athletes were captured in a rested and in a fatigued state and an anthropometric model was used to calculate the CoM based on the joint angles. Variability was quantified by the coefficient of variation of the length of the position vector of the CoM and by the components Tolerance, Noise, and Covariation which were analyzed both in 3D and the projections in the vertical, anterior-posterior and medio-lateral coordinate axes. Concerning PVlab we found that runners increased their stride-to-stride variability in medio-lateral direction (1%). Concerning PVfoot we found that runners lowered their CoM (4 mm) and increased their stride-to-stride variability in the absorption phase in both 3D and in the vertical direction. Although we identified statistically relevant differences between the two running states, we have to point out that the effects were small (CV ≤ 1%) and must be interpreted cautiously.

This paper is concerned with time. Specifically, this paper is concerned with the way in which a human-centered model of time can be shifted, as a result of the digital encounter, toward a conception of a highly differentiated and thickening model of duration. I propose that this thickening of duration, or multitemporality, comes about through the intersection of the differentiated structures of narrative and database. My central concern is therefore to provide a description and explanation of the way in which an anthropocentric model of duration, in other words, a model of time that privileges the human experience, can be challenged by theorising the intersection of the non-linear temporality of the database and the linear temporality of narrative. My paper will work this proposed theory of multitemporality through a case study of the 2007 interactive work T_Visionarium II (see http://www.icinema.unsw.edu.au/projects/prj_tvis_II.html for images). This work was produced by the iCinema Centre for Interactive Cinema Research at the University of New South Wales. The project was co-directed by Dennis Del Favero, Jeffrey Shaw, Peter Weibel and Neil Brown. Through the investigation of the concept of multitemporality, I propose a concept of thickening duration within T_Visionarium II as actual duration comes into contact with virtual duration and as the linear structure of narrative comes into contact with the nonlinear structure of the database. Being concerned with time, I am also concerned with the processes of the aesthetic event of new media. Events, as they occur in time, link together in order to form a process. This process, following A. N. Whitehead, leads to various levels of adaptation that are primarily brought about through interconnections and concrescence. Through my extrapolation of Whitehead’s process philosophy, which I present in the later sections of this paper, I am able to grapple with questions of process. Specifically, I use Whitehead to present the ecology of occasions throughout the duration of the digital encounter and also to indicate the way in which we may begin to conceptualise the interconnection of the differentiated structures of narrative and database. T_Visionarium II has recordings taken from over thirty hours of Australian television, encoded by a content recognition algorithm, and stored in its database (Del Favero, 1). These media images are made visible on the machine’s substrate and are subject to the viewer-user’s navigation. Once the viewer-user selects a particular moving image from those displayed, the surrounding clips cluster around this image, due to the tag ascribed to them by the content recognition algorithm, in a hierarchy of relationality; those with the strongest relationship to the thematic and visual characteristics of the selected media clip cluster around the clip while those with weaker relationships shift away from this clip, behind the viewer. After the reassembly of the audio and visual information is completed, the clips either loop in a short repetitious duration, based on the temporal length of the specific shot, or can be played in a linear fashion. Also, windows may be dragged on top of one another, which causes the television clips from each window to be combined into one window and played back to back. This function allows the viewer-user to select and create a linear narrative. The viewer-user thus navigates through the moving images—in doing so, navigating through the time of the images, and forming lines of relations between images and times where perhaps none existed before. In this way, a type of ecology of the various media images and an ecology of temporality is produced in which the interrelationship between media images, temporalities and also that of the viewer-user to the environment is brought to the fore. T_Visionarium II presents a time that is out of joint. Its presentation of multiple durations of televisual information fractures the medium’s imaging of the world into multiple, largely incoherent, durations. The televisual images within each “window” are quite obviously from different historical periods in time. For instance, images from re-runs of soap operas may be actualised, as well as historical documentary footage, along with a near current news story or a relatively recent Hollywood blockbuster. These media images, from different time periods, when presented and recombined within the immersive environment—a purpose built structure that the iCinema artists and technicians call the Advanced Visualisation and Interaction Environment—allow the viewer to re-experience the actual time of these events as a simultaneity of out-of-joint durations. Here, I propose that the digital encounter within the immersive environment has prompted an adaptation to the way the viewer-user experiences time vis-à-vis the machine. This adaptation is brought about as the viewer-user experiences multitemporal actual durations through the multiple durations displayed in the windows of T_Visionarium II. The model of multitemporality presented here is a result of the viewer-user’s ability to access video streams from different time periods simultaneously. The time of T_Visionarium II also seems out of joint as the particular duration of a particular window tends toward rendering the episode incoherent. This is due to the way the television segments are edited. On average each television clip is four and a half seconds long. Each image is edited in terms of individual shots; any particular image has its start and end point when the original television image changes shot. This may occur in mid narrative stream, or may only capture a small movement, which is deprived of its link with the movement of the next shot. In this way the time of the duration of each shot seems to be flowing toward its extension in the next intended shot. However, the arrangement of the television images into discrete shots disallows this flow. The resulting temporal loop makes time seem trapped in the short four and a half second duration of each shot. In this way, linear television time has been adapted into an experience that is quite different. In order to think the connection between the narrative images of T_Visionarium II we must avoid thinking of these images as compartmentalised sets. If we think of each media image as an event within duration, rather than a compartmentalised image, we are able to see that each actual occasion of interaction contains a trace of the past and future media images. Moments are contemporaneous with those “just-past” and those which are “just-future”. Here, the traces of “just-past” and “just-future” are imbued within the conscious present so as to become meaningful. Also, these interrelationships are made visible on the substrate of T_Visionarium II. The past video clips linger upon the projection screen and affect the narrativity of every other clip. The television images become like a montage, with every clip transferring signification to the others. In this way, the television images of T_Visionarium II are to be read as pregnant with the trace of images past and future; the duration of a particular television image forms a nexus with the duration of the images “just-past” and “just-future”. Also, the television images contain a trace of the temporality of the database. Each television image is potentially linked to every other image archived within the database. Through this link to the potentiality of the database, each media image links to the virtual. The virtual realm that I am discussing here is not the perceived “virtuality” of “cyberspace” or “virtual reality”. I use the term “virtual” as Henri Bergson does and as Gilles Deleuze furthers this usage; that is, to signify the incorporeal structures of the potential of the future and the traces of the past that direct the actualisation of the present moment (Bergson, 196; Deleuze, 45). For the purposes of my argument, we may say that the virtual exists as an ontological but incorporeal structure that contains potential events. In this way, the virtual contains events that await actualisation. Deleuze’s virtual also contains past events that may be made actual as memory-images. As Dorothea Olkowski points out, the past and future can no longer be thought of as successive points on a time line; they rather exist as virtual structures that are contemporary with the actual present (Olkowski, 163). The virtual structures may be called upon by the actual present based on their usefulness, and, because of this, may direct the route of actualisation (Olkowski, 110). Each image of T_Visionarium II links to the virtual in that any selection may trigger various other narrative directions. If we think of each virtual narrative instance, that is each potential narrative instance and every past narrative instance, as existing on separate planes of potential, then we may say that each of T_Visionarium II’s television images contains traces of various planes of the virtual, of which one will be actualised. The duration of any one television image is thus made thick with the traces of the potential images that it may trigger. The duration of the narrative event of any television image is contemporaneous with the duration of the database. As a result, any particular narrative instance may be understood to contain sections of the duration of past and future television images. The moving image of the narrative links to the potential of the database and also links to the potential of the virtual. As a consequence, the experience of time that emerges from the narrative of the moving image is one which is imbued with the multiple levels of duration that may be triggered from the database and displayed on the substrate of T_Visionarium II. The duration of any moving image is thus imbued with those narrative instances that came before it, those that could potentially come after it, and those that are simultaneous with it. In addition to the model of multitemporality that is presented by the simultaneously distributed video streams of T_Visionarium II, a further model of duration may be cited when we consider the mesh of database and narrative. The highly differentiated durative passages of the digital encounter are constituted on one side by the temporality of T_Visionarium II’s database and on the other by the narrative image of the machine’s substrate. The latter opens itself to experience as anthropocentric lived time, while the former does not open itself to actual human experience, other than our imaginings. The database, as an actual entity, occupies a different section of duration, but it is also present in those narrative durations that it relates to; thus forming a concrescence between the narrative sections of duration and the database sections of duration. This constitutes a multitemporal duration between anthropocentric time and machine time; the duration of the actual occasion thickens so as to include both the lived time of the subject and the machine time of the database. The outcome of this is a differentiated duration that is experienced as the convergence of machine time and lived time. It is as if, following Manuel DeLanda’s work on manifolds and degrees of freedom, each level of duration exists on a different manifold of duration (DeLanda, 27). The particular direction that the passage of the narrative of interaction takes is directed by the degrees of freedom of each manifold. If we think of duration as thick, and, as argued above, each moment pregnant with instances “just-past” and potentialities of “just-future”, we can gain a picture of these different manifolds of duration. We can picture past actual occasions and future potential occasions, following on from Deleuze’s and Brian Massumi’s concepts of the virtual, existing as a cloud of the virtual that surrounds the present actual occasion (Deleuze and Parnet; Massumi). In other words, the manifold of any particular present actual occasion is surrounded on all sides by manifolds of virtual occasions. These structures can be understood to intermingle and adapt to one another in such a way that they provide the potential for new experiences within the digital encounter. Duration has thus thickened from a concept that only includes the manifold of actual occasions to one that includes the manifolds of the virtual. As well as the structures of the virtual, the duration of the non-linear database can be conceptualised as existing on separate manifolds of duration that surround the actual narrative event. Both narrative duration and database duration must be theorised as separate and, at the same time, in constant collision with one another. These two conceptions of duration are contemporaneous; they exist side by side without either one being wholly contained by the other. Turning from Bergson’s, Deleuze’s and Massumi’s concepts of the virtual and the actual to Whitehead’s notion of process, we can begin to think about the processes of adaptation that are brought about by this process of concrescence. Deleuze, Bergson and Massumi have provided a means to think about the virtual and the actual in duration, and here Whitehead provides a means to think about the process of adaptation as an interconnection of the enduring objects of the virtual and actual. We may think of database and narrative structures as similar to Whitehead’s concept of actual occasions. As Whitehead states, each actual occasion has its own distinct duration, but also each actual occasion lies in many durations (125). Following Whitehead, any one actual occasion may be present in several other actual occasions. For Whitehead, the essence of any actual entity is that each entity is a prehending thing; it has a definite connection with each item in the universe and that connection makes a positive contribution to the constitution of the event (109). In the case of narrative and database, both substances prehend the other, they form a definite bond, and this makes a positive contribution to the constitution of the narrative-database event. If we think of the material and machinic of the digital encounter as two distinct enduring objects, different in character but not contrary, it may then be said that both are able to qualify the same actual occasion. I use the term “enduring object” in the Whiteheadian sense as a characteristic or stable pattern that is inherited in the historic route of actual occasions (199). In other words, an enduring object can be said to be an object, which may be either an atomic material body or an incorporeal structure that, through its intersection with other enduring objects, gives satisfaction to the presiding situation. Thus, the enduring object of the database and the enduring object of the pattern of actual experience intersect to satisfy the presiding occasion of the digital encounter. The intermingling of the machinic duration and the actual narrative duration within T_Visionarium II is a fluid process that constitutes the particular nexus of actual occasions. The information from both enduring objects flows through their intersection. Whitehead, using a cup and saucer as metaphors for eternal objects, describes the way in which two enduring objects come together. He states, “it is as though the cup and saucer were at one instant identical and then, later on, resumed their distinct existence” (199). If we think of database and narrative in such a fashion, we can begin to conceptualise the multitemporality of T_Visionarium II. In T_Visionarium II, data flows mutually from the actualised narrative of interaction to the database structure and from the database to the narrative. The nexus of actual occasions is thus constituted by the intermingling of the two eternal objects; they, in essence, become, or adapt into, one enduring object. On the other hand, both structures remain separate. The narrativity of the work is able to exist solely in the particular narrative regime, as the database is able to exist solely in its coded regime. The nexus of actual occasions, that is the temporal passage of interaction within T_Visionarium II, is brought to satisfaction by this assemblage and de-assemblage of narrative and database. The narrativity of the work exists in its own realm of duration, as its own eternal object, which is able to form a nexus of narrative actual occasions. Also, the database structure inhabits its own machinic duration, which is able to form a nexus of information flows. In this way, the database can be thought of as in time, as affected by the changing nature of process through time. The time that has been described in this paper is a time of fibrous duration. In a culture of new media, time can no longer be thought of as a linear structure that houses human experience and memory. The structure of time has become thick and fibrous with the introduction of a machinic non-linear temporal logic. Deleuze has been used to show that each actual occasion of duration can be thought of as surrounded by virtual, potential occasions. In order to further this, Whitehead has been used to show that each of these occasions connects with every other event in duration. In this Whiteheadian and Deleuzian model, adaptation occurs as the events of duration, whether actual or virtual, interconnect, respond to one another and coalesce. The differentiated experiences of narrative duration and database duration mesh, in order that these two Whiteheadian enduring objects may adapt into another separate enduring object. This is the multitemporal experience of the digital encounter. If we view the digital encounter with new media, such as T_Visionarium II, through a multitemporal paradigm, we are then provided with a particular method with which to conceptualise other processes of adaptation. If we view differentiated sections of duration as existing upon separate manifolds, but also, at the same time, as containing traces of their surrounding durations, we can see that each section of duration imposes something of itself upon those that surround it. Each section of duration, whether virtual or actual, is morphogenic; in other words, it may adapt in various ways. The parameters of this morphogenesis are set by the degrees of freedom found within any particular duration. As each section of duration imposes itself on others, it transfers its degrees of freedom. Following on from this, the passage of evolution, or adaptation, is directed by the degrees of freedom of every level of duration, whether actual or virtual. The database duration that surrounds the narrative duration of T_Visionarium II directs the passage of narrative evolution as it imposes degrees of freedom in respect of the possible narrative images that it may trigger. Adaptation occurs as the dynamic mesh between the differentiated structures of narrative duration and database duration. References Bergson, Henri. Matter and Memory. London: George, Allen and Unwin, 1950. Del Favero, Dennis, Neil Brown, Jeffrey Shaw, and Peter Weibel. T_Visionarium II. Sydney: iCinema Centre for Interactive Cinema Research, UNSW, 2006. DeLanda, Manuel. Intensive Science and Virtual Philosophy. Transversals: New Directions in Philosophy. Ed. Keith Ansell Pearson. London: Continuum, 2002. Deleuze, Gilles. Cinema 2: The Time Image. Trans. Hugh Tomlinson and Robert Galeta. London: Continuum, 1985. ———, and Claire Parnet. “The Actual and the Virtual.” Dialogues 2. Ed. Eliot Ross Albert. London and New York: Continuum, 1987. Massumi, Brian. “Parables for the Virtual.” Post-Contemporary Interventions. Eds. Stanley Fish and Fredric Jameson. Durham and London: Duke University Press, 2002. Olkowski, Dorothea. Gilles Deleuze and the Ruin of Representation. Berkley: University of California Press, 1998. Whitehead, Alfred North. Process and Reality: An Essay in Cosmology. New York: The Free Press, 1978. Citation reference for this article MLA Style Barker, Tim. "Adapting a Model of Duration: The Multitemporality of T_Visionarium II." M/C Journal 10.2 (2007). echo date('d M. Y'); ?> <http://journal.media-culture.org.au/0705/14-barker.php>. APA Style Barker, T. (May 2007) "Adapting a Model of Duration: The Multitemporality of T_Visionarium II," M/C Journal, 10(2). Retrieved echo date('d M. Y'); ?> from <http://journal.media-culture.org.au/0705/14-barker.php>.