The Phantom Burster Model for Pancreatic β-Cells

Abstract Pancreatic β-cells exhibit bursting oscillations with a wide range of periods. Whereas periods in isolated cells are generally either a few seconds or a few minutes, in intact islets of Langerhans they are intermediate (10–60 s). We develop a mathematical model for β-cell electrical activity capable of generating this wide range of bursting oscillations. Unlike previous models, bursting is driven by the interaction of two slow processes, one with a relatively small time constant (1–5 s) and the other with a much larger time constant (1–2 min). Bursting on the intermediate time scale is generated without need for a slow process having an intermediate time constant, hence phantom bursting. The model suggests that isolated cells exhibiting a fast pattern may nonetheless possess slower processes that can be brought out by injecting suitable exogenous currents. Guided by this, we devise an experimental protocol using the dynamic clamp technique that reliably elicits islet-like, medium period oscillations from isolated cells. Finally, we show that strong electrical coupling between a fast burster and a slow burster can produce synchronized medium bursting, suggesting that islets may be composed of cells that are intrinsically either fast or slow, with few or none that are intrinsically medium

Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine-gingipain inhibitor COR388.

COR388, a small-molecule lysine-gingipain inhibitor, is currently being investigated in a Phase 2/3 clinical trial for Alzheimer's disease (AD) with exploratory endpoints in periodontal disease. Gingipains are produced by two species of bacteria, Porphyromonas gingivalis and Porphyromonas gulae, typically associated with periodontal disease and systemic infections in humans and dogs, respectively. P. gulae infection in dogs is associated with periodontal disease, which provides a physiologically relevant model to investigate the pharmacology of COR388. In the current study, aged dogs with a natural oral infection of P. gulae and periodontal disease were treated with COR388 by oral administration for up to 90 days to assess lysine-gingipain target engagement and reduction of bacterial load and downstream pathology. In a 28-day dose-response study, COR388 inhibited the lysine-gingipain target and reduced P. gulae load in saliva, buccal cells, and gingival crevicular fluid. The lowest effective dose was continued for 90 days and was efficacious in continuous reduction of bacterial load and downstream periodontal disease pathology. In a separate histology study, dog brain tissue showed evidence of P. gulae DNA and neuronal lysine-gingipain, demonstrating that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of P. gingivalis in humans. Together, the pharmacokinetics and pharmacodynamics of COR388 lysine-gingipain inhibition, along with reduction of bacterial load and periodontal disease in naturally occurring P. gulae infection in the dog, support the use of COR388 in targeting lysine-gingipain and eliminating P. gingivalis infection in humans

Mouse cytomegalovirus-experienced ILC1s acquire a memory response dependent on the viral glycoprotein m12.

Innate lymphoid cells (ILCs) are tissue-resident sentinels that are essential for early host protection from pathogens at initial sites of infection. However, whether pathogen-derived antigens directly modulate the responses of tissue-resident ILCs has remained unclear. In the present study, it was found that liver-resident type 1 ILCs (ILC1s) expanded locally and persisted after the resolution of infection with mouse cytomegalovirus (MCMV). ILC1s acquired stable transcriptional, epigenetic and phenotypic changes a month after the resolution of MCMV infection, and showed an enhanced protective effector response to secondary challenge with MCMV consistent with a memory lymphocyte response. Memory ILC1 responses were dependent on the MCMV-encoded glycoprotein m12, and were independent of bystander activation by proinflammatory cytokines after heterologous infection. Thus, liver ILC1s acquire adaptive features in an MCMV-specific manner

Gender as a Moderator of the Relationship Between Preparty Motives and Event-Level Consequences

Prepartying is often associated with increased alcohol consumption and negative alcohol-related consequences among college students. General drinking motives are often only weakly related to preparty alcohol use, and few studies have examined the associations between preparty-specific drinking motives and alcohol-related consequences that occur during or after a preparty event. The current study utilizes event-level data to address this gap in the literature by examining the relationship between four types of preparty motives (prepartying to relax or loosen up, to increase control over alcohol use, to meet a dating partner, and to address concerns that alcohol may not be available later) and alcohol consequences as a function of gender. Participants (N = 952) reported on their most recent preparty event in the past month. After controlling for general drinking motives, all four preparty motives predicted greater event-level consequences for both males and females. Further, prepartying to increase control over alcohol consumed was associated with greater consequences for males as compared to females. The findings are consistent with research suggesting that preparty specific motives may further our understanding of prepartying outcomes over and above the use of general drinking motive measures

Smaller & Sooner: Exploiting High Magnetic Fields from New Superconductors for a More Attractive Fusion Energy Development Path

The current fusion energy development path, based on large volume moderate magnetic B field devices is proving to be slow and expensive. A modest development effort in exploiting new superconductor magnet technology development, and accompanying plasma physics research at high-B, could open up a viable and attractive path for fusion energy development. This path would feature smaller volume, fusion capable devices that could be built more quickly than low-to-moderate field designs based on conventional superconductors. Fusion’s worldwide development could be accelerated by using several small, flexible devices rather than relying solely on a single, very large device. These would be used to obtain the acknowledged science and technology knowledge necessary for fusion energy beyond achievement of high gain. Such a scenario would also permit the testing of multiple confinement configurations while distributing technical and scientific risk among smaller devices. Higher field and small size also allows operation away from well-known operational limits for plasma pressure, density and current. The advantages of this path have been long recognized—earlier US plans for burning plasma experiments (compact ignition tokamak, burning plasma experiment, fusion ignition research experiment) featured compact high-field designs, but these were necessarily pulsed due to the use of copper coils. Underpinning this new approach is the recent industrial maturity of high-temperature, high-field superconductor tapes that would offer a truly “game changing” opportunity for magnetic fusion when developed into large-scale coils. The superconductor tape form and higher operating temperatures also open up the possibility of demountable superconducting magnets in a fusion system, providing a modularity that vastly improves simplicity in the construction, maintenance, and upgrade of the coils and the internal nuclear engineering components required for fusion’s development. Our conclusion is that while tradeoffs exist in design choices, for example coil, cost and stress limits versus size, the potential physics and technology advantages of high-field superconductors are attractive and they should be vigorously pursued for magnetic fusion’s development

Regulation of the Transcriptional Activity of the IRF7 Promoter by a Pathway Independent of Interferon Signaling

Genes containing an interferon (IFN)-stimulated response element (ISRE) can be divided into two groups according to their inducibility by IFN and virus infection: one induced only by IFN and the other induced by both IFN and virus infection. Although it is now clear that IFN regulatory factor 7 (IRF7) is a multifunctional gene essential for induction of type I IFNs, regulation of the IRF7 promoter (IRF7p) is poorly understood. The IRF7 gene includes two IFN responsive elements, an IRF-binding element (IRFE) in the promoter region and an ISRE in the first intron, and is induced by the IFN-triggered Jak-STAT pathway by binding of the IFN-stimulated gene factor 3 (ISGF3) complex to the ISRE. In this study, we demonstrate that IRF3 and IRF7, which with the coactivators CREB-binding protein and P300 form the virus-activated factor (VAF) complex upon Sendai virus infection, bind to the IRF7 ISRE and IRFE and can directly activate IRF7 transcription. Promoter reporter assays show that both the ISRE and IRFE are responsive to activation by IRF7 and IRF3. In cells transiently expressing IRF7 or/and IRF3, the VAF level and binding of VAF are clearly increased after Sendai virus infection. Studies with Jak1 kinase inactive 293 cells that were stably transfected with a Jak1 kinase dead dominant negative construct, and the mutant cell lines SAN (IFNalpha-/beta-), U2A (IRF9-), U4A (Jak1-), and DKO (IRF1-/IRF2-) show that the IRF7 transcription activated directly by VAF is distinct from and independent of the IFN signaling pathway. Thus, IRF7 transcription is autoregulated by binding of the IRF7-containing VAF to its own ISRE and IRFE. The results show two distinct mechanisms for the activation of the IRF7 promoter, by IFN and by virus infection. A regulatory network between type I IFNs and IRF7 is proposed. The distinct pathways may reflect special roles for an efficient antiviral response at different stages of virus infection

The Peaceful Atom Comes to Campus

Youthful idealism, institutional ambition, and Cold War sensibilities all helped shape the Michigan Memorial–Phoenix Project, the University of Michigan’s tribute to fallen World War II soldiers.</jats:p

Arachidonate Metabolism and the Signaling Pathway of Induction of Apoptosis by Oxidized LDL/Oxysterol

Owing at least in part to oxysterol components that can induce apoptosis, oxidized LDL (oxLDL) is cytotoxic to mammalian cells with receptors that can internalize it. Vascular cells possess such receptors, and it appears that the apoptotic response of vascular cells to the oxysterols borne by oxLDL is an important part of the atherogenic effects of oxLDL. Thus, an analysis of the signaling pathway of apoptotic induction by oxysterols is of value in understanding the development of atherosclerotic plaque. In a prior study, we demonstrated an induction of calcium ion flux into cells treated with 25-hydroxycholesterol (25-OHC) and showed that this response is essential for 25-OHC-induced apoptosis. One possible signal transduction pathway initiated by calcium ion fluxes is the activation of cytosolic phospholipase A2 (cPLA2). In the current study, we demonstrate that activation of cPLA2 does occur in both macrophages and fibroblasts treated with 25-OHC or oxLDL. Activation is evidenced by 25-OHC-induced relocalization of cPLA2 to the nuclear envelope and arachidonic acid release. Loss of cPLA2 activity, either through genetic knockout in mice, or by treatment with a cPLA2 inhibitor, results in an attenuation of arachidonic acid release as well as of the apoptotic response to oxLDL in peritoneal macrophages or to 25-OHC in cultured fibroblast and macrophage cell lines