Intrinsic Fashion Research Articles

Abstract 3185: Treatment with an engineered decoy receptor targeting the CLCF1-CNTFR signaling axis prevents oncogenesis in Kras mutant lung adenocarcinoma via both cell autonomous and non-cell autonomous mechanisms

Abstract Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remain underexploited. Previously, we validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. From our genetically engineered mouse and our syngeneic modelling of LUAD we have observed that eCNTFR seems to work via two mechanisms, firstly in a tumor intrinsic fashion where it may modulate altered guanosine triphosphate loading, as we see differential effectiveness of eCNTFR-Fc, depending on the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate. Alternatively, eCNTFR also effects the tumor microenvironment and alters the composition of the tumor immune infiltrate, where using single cell genomics we see vast changes to the myeloid compartment, and alteration of the CAF populations, which we have previously shown to be the primary location of CLCF1 expression in mouse LUAD. To further enhance the efficacy of eCNTFR-Fc we have identified potential targets for combination therapy from both the autonomous and non-cell autonomous mechanisms of eCNTFR-Fc. We conclude that eCNTFR-Fc acts through two distinct mechanisms to be a highly effective treatment for Kras mutant LUAD, and combining eCNTER with targets, identified by a rational combination approach, could further enhance its therapeutic potential. Citation Format: Kieren D. Marini, Emma C. Champion, Jennifer R. Cochrane, E. Alejandro Sweet-Cordero. Treatment with an engineered decoy receptor targeting the CLCF1-CNTFR signaling axis prevents oncogenesis in Kras mutant lung adenocarcinoma via both cell autonomous and non-cell autonomous mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3185.

Epigenetic Modulation of Class-switch DNA Recombination to IgA by miR- 146a through Downregulation of Smad2, Smad3 and Smad4

Abstract IgA is the predominant isotype at intestinal mucosae, where it plays a critical role in homeostasis and first line of immune protection. Class-switch DNA recombination (CSR) to IgA is directed by TGF-b which induces activation of Smad2 and Smad3 transcription factors. Activated Smad2/Smad3 dimers are recruited with Smad4 to IgH α locus Iα promoter to activate germline Iα-Cα transcription, the first step in CSR to IgA. Epigenetic factors, such as microRNAs, regulate immune cells and, as we have shown, modulate the antibody response in a B cell- intrinsic fashion. We found that miR-146a targets Smad2, Smad3 and Smad4 mRNA 3’UTRs, and keeps CSR to IgA in check in resting B cells. Enforced miR-146a expression in B cells aborted CSR to IgA by decreasing Smad levels. Induction of CSR to IgA, as directed by TGF-b, downregulated B cell miR-146a, thereby reversing the silencing of Smad2, Smad3 and Smad4, which, once expressed, led to recruitment of Smad2, Smad3 and Smad4 to Iα promoter for activation of germline Iα-Cα transcription. miR- 146a−/− mice significantly increased circulating levels of total IgA, but not IgM, IgG or IgE, and heightened the specific IgA antibody response to OVA. In miR-146a−/− mice, this was associated with increased IgA+ B cells in intestinal mucosae, increased amounts of fecal free and bacteria-bound IgA, kidney IgA deposition and IgA nephropathy. The B cell-intrinsic role of miR-146a in repression of Smad2, Smad3 and Smad4 and CSR to IgA was confirmed in miR-146a −/− B cells in vitro and in vivo in mixed bone marrow μMT/miR-146a−/− chimeric mice. Thus, by specific inhibition of Smad2, Smad3 and Smad4 expression, miR-146a plays an important and B cell intrinsic role in modulation of CSR to IgA and the IgA antibody response. Supported by NIH grants AI 079705, AI 105813, AAI 167416 and LRA grant 641363 to PC.

Finite Element Modeling of Pavement and State Awareness Using Fiber Optic Sensing

A variety of efforts have been put into sensing and modeling of pavements. Such capability is commonly validated with experimental data and used as reference for damage detection and other structural changes. Finite element models (FEM) often provides a high fidelity physics-base benchmark to evaluate the pavement integrity. On the monitoring of roads and pavements in general, FEM combining with in-situ data largely extends the awareness of the pavement condition, and enhances the durability and sustainability for the transportation infrastructures. Although many studies were performed in order to simulate static stress and strain in the pavement, FEM also show potential for dynamic analysis, allowing to extract both frequency response and wave propagation at any location, including the behavior of the soil on the surroundings. Fiber optical sensing is adopted in this research, which outperforms the traditional sensing techniques, such as accelerometers or strain gauges, given its nature of providing continuous measurement in a relatively less intrinsic fashion. Moreover, the data is adopted to validate and calibrate the FEM with complex material properties, such as damping and viscoelasticity of the pavement as well as other nonlinear behavior of the surrounded soil. The results demonstrate a successful FEM with good accuracy of the waveform prediction.

GM-CSF instigates a dendritic cell–T-cell inflammatory circuit that drives chronic asthma development

Steroid-resistant asthma is often characterized by high levels of neutrophils and mixed TH2/TH17 immune profiles. Indeed, neutrophils are key drivers of chronic lung inflammation in multiple respiratory diseases. Their numbers correlate strongly with disease severity, and their presence is often associated with exacerbation of chronic lung inflammation. What factors drive development of neutrophil-mediated chronic lung disease remains largely unknown, and we sought to study the role of GM-CSF as a potential regulator in chronic asthma. Different experimental animal models of chronic asthma were used in combination with alveolar macrophage-reconstitution of global GM-CSF receptor knockout mice as well as cell-type-specific knockout animals to elucidate the role of GM-CSF signaling in chronic airway inflammation. We identify GM-CSF signaling as a critical factor regulating pulmonary accumulation of neutrophils. We show that although being not required for intrinsically regulating neutrophil migration, GM-CSF controls lung dendritic cell function, which in turn promotes T-cell-dependent recruitment of neutrophils to the airways. We demonstrate that GM-CSF regulates lung dendritic cell antigen uptake, transport, and TH2/TH17 cell priming in an intrinsic fashion, which in turn drives pulmonary granulocyte recruitment and contributes to development of airway hyperresponsiveness in chronic disease. We identify GM-CSF as a potentially novel therapeutic target in chronic lung inflammation, describing a GM-CSF-dependent lung conventional dendritic cell-T-cell-neutrophil axis that drives chronic lung disease.

Intrinsicality, Independence and Grounding

AbstractThis paper investigates the plausibility of Witmer, Butchard and Trogdon’s proposal to distinguish intrinsic properties from extrinsic ones in terms of independence from accompaniment and grounding. I argue that the proposed criterion is not adequate to determine intrinsicality, since according to it some intuitively extrinsic properties turn out to be intrinsic. I suggest and evaluate two responses: first, one could characterize a conception of independence which is specific to the individual instantiating the property; and second, one could justify two assumptions about properties which entail that counterexample properties of the kinds I present do not exist, most importantly that there are no fundamental properties which are instantiated in an intrinsic fashion by some individuals and an extrinsic fashion by others. Although the latter seems prima facie plausible, I present some potential counterexamples to it from current physical theory. I conclude that the grounding- and independence-based criterion of intrinsicality can be defended from my objections, although the cost of doing so might make it more attractive to characterize intrinsicality in terms of independence, or in terms of grounding, alone.

RNA and Toll-Like Receptor 7 License the Generation of Superior Secondary Plasma Cells at Multiple Levels in a B Cell Intrinsic Fashion.

Secondary plasma cells (PCs) originate from memory B cells and produce increased levels of antibodies with higher affinity compared to PCs generated during primary responses. Here we demonstrate that virus-like particles (VLPs) only induce secondary PCs in the presence of toll-like receptor (TLR) 7 and if they are loaded with RNA. Furthermore, adoptive transfer experiments demonstrate that RNA and TLR7 signaling are required for secondary PC generation, both at the level of memory B cell as well as PC differentiation. TLR7-signaling occurred in a B cell intrinsic manner as TLR7-deficient B cells in an otherwise TLR7-competent environment failed to differentiate into secondary PCs. Therefore, RNA inside VLPs is essential for the generation of memory B cells, which are competent to differentiate to secondary PCs and for the differentiation of secondary PCs themselves. While we have not tested all other TLR or non-TLR adjuvants with our VLPs, these data have obvious implications for vaccine design, as RNA packaged into VLPs is a simple way to enhance induction of memory B cells capable of generating secondary PCs.

Density dependent re-tuning of autoreactive T cells alleviates their pathogenicity in a lymphopenic environment

Peripheral T cell tolerance is challenging to induce in partially lymphopenic hosts and this is relevant for clinical situations involving transplant tolerance. While the shortage of regulatory cells is thought to be one reason for this, T cell-intrinsic tolerance processes such as anergy are also poorly triggered in such hosts. In order to understand the latter, we used a T cell deficient mouse model system where adoptively transferred autoreactive T cells are significantly tolerized in a cell intrinsic fashion, without differentiation to regulatory T cells. Intriguingly these T cells often retain sufficient effector functions to trigger autoimmune pathology. Here we find that the high population density of the autoreactive T cells that accumulated in such a host limits the progression of the cell-intrinsic tolerance process in T cells. Accordingly, reducing the cell density during a second transfer allowed T cells to further tune down their responsiveness to antigenic stimulation. The retuning of T cells was reflected by a loss of the T cell’s abilities to proliferate, produces cytokines or help B cells. We further suggest, based on altering the levels of chronic antigen using miniosmotic pumps, that the effects of cell-density on T cell re-tuning may reflect the effective changes in the antigen dose perceived by individual T cells. This could proportionally elicit more negative feedback downstream of the TCR. Consistent with this, the retuned T cells showed signaling defects both proximal and distal to the TCR. Therefore, similar to the immunogenic activation of T cells, cell-intrinsic T cell tolerance may also involve a quantitative and progressive process of tuning down its antigen-responsiveness. The progress of such tuning seems to be stabilized at multiple intermediate stages by factors such as cell density, rather than just absolute antigen levels.

Unified description of structure and reactions: implementing the nuclear field theory program

The modern theory of the atomic nucleus results from the merging of the liquid drop model of Niels Bohr and Fritz Kalckar, and of the shell model of Marie Goeppert Meyer and Hans Jensen. The first model contributed the concepts of collective excitations. The second, those of independent-particle motion. The unification of these apparently contradictory views in terms of the particle-vibration and particle-rotation couplings carried out by Aage Bohr and Ben Mottelson has allowed for an ever more complete, accurate and detailed description of nuclear structure. Nuclear field theory (NFT), developed by the Copenhagen–Buenos Aires collaboration, provided a powerful quantal embodiment of this unification. Reactions are not only at the basis of quantum mechanics (statistical interpretation, Max Born), but also the specific tools to probe the atomic nucleus. It is then natural that NFT is being extended to deal with processes which involve the continuum in an intrinsic fashion, so as to be able to treat them on an equal footing with those associated with bound states (structure). As a result, spectroscopic studies of transfer to continuum states could eventually make use of the NFT rules, properly extended to take care of recoil effects. In the present contribution we review the implementation of the NFT program of structure and reactions, setting special emphasis on open problems and outstanding predictions.

G-CSF-Induced Alterations in the Bone Marrow Microenvironment Suppress B Lymphopoiesis

Abstract 1246Infectious stress is associated with a shift in the bone marrow from lymphopoiesis to granulopoiesis. Expression of granulocyte colony-stimulating factor (G-CSF), the principal cytokine regulating granulopoiesis, is often induced during infection. We previously reported that G-CSF treatment is associated with marked suppression of B lymphopoiesis in murine bone marrow. After 5 days of G-CSF treatment (250 μg/kg), total B cells in the bone marrow were reduced 8.1 ± 0.9-fold. Pre-pro-B cells were reduced 1.6 ± 0.3-fold, pro-B cells 12.4 ± 1.9-fold, pre-B cells 5.6 ± 0.8-fold, immature B cells 7.5 ± 1.2-fold, and mature naïve B cells 83 ± 7.6-fold. B-committed lymphoid progenitors (BLP) were modestly but significantly decreased (1.4 ± 0.2-fold), while common lymphoid progenitors (CLP) were not affected by G-CSF treatment. Increased apoptosis of mature naïve B cells in the bone marrow was observed. Studies of G-CSF receptor deficient (Csf3r−/−) bone marrow chimeras show that G-CSF acts in a non-cell intrinsic fashion to suppress B lymphopoiesis. Consistent with this observation, we show that G-CSF treatment results in decreased expression in the bone marrow microenvironment of multiple B-supportive factors including CXCL12, interleukin-6, interleukin-7, and B cell activating factor (BAFF). Prior studies have established that CXCL12-abundant reticular (CAR) cells in the bone marrow play a key role in B cell development. CAR cells are perivascular stromal cells that express very high levels of CXCL12 and are in direct contact with pre-pro-B cells. G-CSF treatment did not affect CAR cell number. However, RNA expression profiling of sorted CAR cells showed that expression of several genes associated with B cell development are significantly decreased by G-CSF, including CXCL12 (4.2 ± 1.5-fold). In addition to CAR cells, other stromal cells in the bone marrow express CXCL12, including osteoblasts and endothelial cells. To assess the role of CXCL12 production by each of these cell types to B lymphopoiesis, we generated Cxcl12flox mice and crossed them with mice expressing the following tissue-specific Cre-recombinase transgenes: Osteocalcin-Cre (Oc-Cre) targeting mature mineralizing osteoblasts; Osterix-Cre (Osx-Cre) targeting CAR cells and all osteolineage cells; or Prx1-Cre targeting mesenchymal progenitors and their progeny. Deletion of Cxcl12 using Oc-Cre or Osx-Cre had a similar effect on B cell development, with an isolated loss of mature naïve B cells in the bone marrow (2.7 ± 0.5 and 4.1 ± 1.7-fold, respectively). In contrast, deletion of Cxcl12 using Prx1-Cre resulted in severe suppression of B lymphopoiesis that included a loss of CLP (3.3 ± 2.0-fold), BLP (5.6 ± 4.3-fold), and pre-pro-B cells (12.4 ± 5.1-fold). Interestingly, treatment of Prx1-Cre Cxcl12flox/- mice with G-CSF resulted in additional B cell loss, indicating that deletion of Cxcl12 in mesenchymal stromal cells is not sufficient to fully recapitulate G-CSF-induced B cell suppression. In summary, G-CSF treatment results in marked changes in the bone marrow microenvironment that lead to a suppression of B lymphopoiesis. While G-CSF-induced inhibition of CXCL12 expression from stromal cells contributes to B cell suppression, additional alterations in the microenvironment also contribute to this phenotype. Disclosures:No relevant conflicts of interest to declare.

On an intrinsic formulation of time-variant Port Hamiltonian systems

In this contribution we present an intrinsic description of time-variant Port Hamiltonian systems as they appear in modeling and control theory. This formulation is based on the splitting of the state bundle and the use of appropriate covariant derivatives, which guarantees that the structure of the equations is invariant with respect to time-variant coordinate transformations. In particular, we will interpret our covariant system representation in the context of control theoretic problems. Typical examples are time-variant error systems related to trajectory tracking problems which allow for a Hamiltonian formulation. Furthermore we will analyze the concept of collocation and the balancing/interaction of power flows in an intrinsic fashion.

IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses

During T cell–dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell–intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell–autonomous effect of IL-21 receptor (R) signaling throughout all stages of the GC response. IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1+ GC B cells but did not affect formation of early memory B cells. IL-21R was required on GC B cells for maximal expression of Bcl-6. In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.

The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity

The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity

The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunity

T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-β/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor–related orphan receptor γt (RORγt). We identify the nuclear receptor peroxisome proliferator–activated receptor γ (PPARγ) as a key negative regulator of human and mouse Th17 differentiation. PPARγ activation in CD4+ T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, or regulatory T cells. Control of Th17 differentiation by PPARγ involved inhibition of TGF-β/IL-6–induced expression of RORγt in T cells. Pharmacologic activation of PPARγ prevented removal of the silencing mediator for retinoid and thyroid hormone receptors corepressor from the RORγt promoter in T cells, thus interfering with RORγt transcription. Both T cell–specific PPARγ knockout and endogenous ligand activation revealed the physiological role of PPARγ for continuous T cell–intrinsic control of Th17 differentiation and development of autoimmunity. Importantly, human CD4+ T cells from healthy controls and MS patients were strongly susceptible to PPARγ-mediated suppression of Th17 differentiation. In summary, we report a PPARγ-mediated T cell–intrinsic molecular mechanism that selectively controls Th17 differentiation in mice and in humans and that is amenable to pharmacologic modulation. We therefore propose that PPARγ represents a promising molecular target for specific immunointervention in Th17-mediated autoimmune diseases such as MS.

Fashion in the globalized world and the role of virtual networks in intrinsic fashion design

The emergence of global fashion has transformed the way fashion is perceived in the contemporary world. While it has brought the consumer the in‐vogue style at the right price, a strong focus on standardization and low‐cost advantage has disbanded the traditional ethos of fashion design which is inspired by a variety of physical and psychological needs in a given precinct. Migration of fashion production offshore and resultant dependence on economies of scale not only threatens the existence of domestic small fashion manufacturers, but also prohibits up‐coming designers from creating intrinsic fashion on a small but sustainable scale. This paper, through a case study of a Japanese non‐profit organization, explores the way in which such an intrinsic fashion creation restores its salience as a counter style of global fashion capitalism. Emphases are placed on corroborating the necessity of intrinsic fashion in today’s society vis‐à‐visthe drawbacks of global fashion in cultural, ethical, ergonomic, and environmental terms.

Abnormal immune function of hemopoietic cells from alymphoplasia (aly) mice, a natural strain with mutant NF-kappa B-inducing kinase.

Alymphoplasia (aly) mice, a natural strain with a mutant NF-kappa B-inducing kinase (NIK) gene, manifest a unique phenotype; they lack lymph nodes and Peyer's patches, have a disturbed spleen architecture, and exhibit defects in both Ab and cellular immune responses. Although a stromal defect caused by impaired lymphotoxin-beta receptor signaling accounts for their abnormal lymphoid organogenesis, the exact mechanisms underlying the development of immunodeficiency in aly mice are poorly understood. We therefore investigated the contribution of hemopoietic cells with the aly NIK mutation to the development of immunodeficiency. Transfer of aly/aly bone marrow cells into aly/+ mice resulted in poorly developed B cell follicles and lack of support for the development of germinal centers and isotype switching, indicating that the hemopoietic cells of aly mice contain an autonomous defect. However, follicular dendritic cell clusters were maintained in the spleens of these bone marrow chimeras, suggesting that the lack of follicular dendritic cell clusters in aly mice is probably due to the stromal defect. The aly mice lacked marginal zone B cells in their spleens, and aly/aly B cells showed an impaired proliferative response after in vitro stimulation. IL-2 production by activated T cells was also impaired. By contrast, the dendritic cells of aly mice exhibited grossly normal development and function. Supporting the concept of an autonomous cell defect, Rel protein expression was altered in aly/aly spleens. Thus, the aly NIK mutation affects hemopoietic cell function in an intrinsic fashion and, together with the stromal defect, may contribute to the development of immunodeficiency in aly mice.

British Mass Perceptions of the Anglo-American Special Relationship

Immediately after World War II one of the most popular songs was entitled, Seems Like Old Times. Nearly a half century later that title well characterized Anglo-American relations, which appeared to have returned to that earlier era. Despite the breadth of the coalition that the United States built to oppose Iraq, the chief U.S. acolyte was Britain. The French sent a tough, highly trained force, but their contribution was much smaller than Britain's and had initially seemed more hesitant. The Italian contribution was even smaller than the French. The Germans, preoccupied with reunification, hid behind constitutional niceties and just sent money, as did Japan. Once again the Anglo-Saxons, as Charles de Gaulle liked to call them, found that in a crisis they could count only on each other for whole-hearted, ungrudging support. Clearly, relations between Britain and the United States long have appeared to be special (in de Gaulle's view sinister); they differ in some intrinsic fashion from those that have existed between other pairs of friendly countries.

Fractals, their transfer matrices and their eigen-dimensional sequences

This paper defines and studies a general algorithm for constructing new families of fractals in Euclidean space. This algorithm involves a sequence of linear interscale transformations that proceed from large to small scales. The authors find that the fractals obtained in this fashion decompose in intrinsic fashion into linear combinations of a variable number of 'addend' fractals. The addends' relative weights and fractal dimensionalities are obtained explicitly through an interscale matrix, which they call the transfer matrix of the fractal (TMF). The authors first demonstrate by a series of examples, then prove rigorously, that the eigenvalues of our TMFs are real and positive, and that the fractal dimensions of the addend fractals are the logarithms of the eigenvalues of their TMF. They say that these dimensions form the overall fractal's eigendimensional sequence. The eigenvalues of their TMF are integers in the non-random variants of the construction, but are non-integer in the random variants. A geometrical interpretation of the eigenvalues and the eigenvectors is given. Their TMF have other striking and very special properties that deserve additional attention.

An Extension of Plancherel's Formula to Separable Unimodular Groups

We show that for any f square-integrable on a separable unimodular locally compact group G (relative to Haar measure), the integral over G of the square of the absolute value of f equals the integral over a certain measure space of the square of the (at each point of the space) of the Fourier transform of f. By relative norm we mean that defined by von Neumann [5] for factors, and for the present we define the Fourier transform thru the use of the von Neumann reduction theory [6]. The formula which is obtained here has as instances, though not as direct corollaries, the formula of Plancherel, its generalization to separable locally compact abelian groups, the Peter-Weyl theorem, and a formula recently obtained by Gelfand and Neumark [2] for the case of the Lorentz group. The measure space in question has its measure ring isomorphic to the Boolean ring B of closed linear manifolds in L2(G) invariant under both left and right translations, and the corresponding measure is uniquely determined, modulo normalization of the at each point of the space. This measure ring acts as a kind of measure-theoretic to the group. For example, making the so-called standard normalization of the norm, if G is abelian, then B as a measure ring is abstractly identical with the measure ring of the character group of G, under Haar measure; if G is compact, then B is abstractly the measure ring of a discrete set of points, the set being in one-to-one correspondence with the collection of equivalence classes of continuous irreducible representations of G, the measure of a point being proportional to the degree of the corresponding representation. Basic in our work is a certain countably-additive non-negative function, which we call the dual of G, defined on the lattice of all projections in the weak closure V of the algebra generated by left translations in L2(G),-or alternatively, on the lattice of closed linear manifolds in L2(G) invariant under right translations. The gage, which is defined in an intrinsic fashion, is invariant under transformation by unitary operators in V, and is in fact a weight function in the terminology of von Neumann [6]. His reduction theory consequently yields a representation of the gage as an integral over the measure space described above of constituents (relative dimension functions) arising from factors. This representation together with the facts that the convolution operator on L2(G) defined by a self-adjoint element of L2(G) is hypermaximal symmetric (Ambrose [1]) and that every bounded linear operator on L2(G) which commutes with all right translations is in V (Segal [4]), are the principal known results used in our derivation of the generalized Plancherel formula.