Interleukin-6 TGFb Promote Connective Tissue Growth Factor in Chronic Cardiac Allograft Rejection.

Cardiac transplantation is an effective treatment for multiple types of heart failure refractive to therapy. Although immunosuppressive therapeutics have increased survival rates within the first year post-transplant, chronic rejection (CR) remains a significant barrier to long term graft survival. Indicators of CR include patchy interstitial fibrosis, vascular occlusion, and progressive loss of graft function. However, the functional and anatomical changes associated with CR, as well as the factors responsible for the induction and progression of the disease are not understood. These experiments utilized serial echocardiography to assess the progression of chronic rejection in vascularized mouse cardiac allografts. Cardiac allografts in mice transiently depleted of CD4+ cells that develop chronic rejection were compared with those receiving anti-CD40L therapy that do not develop chronic rejection. Echocardiography revealed the development of hypertrophy in grafts undergoing chronic rejection which was confirmed by histologic analysis and coincided with graft fibrosis and elevated intragraft expression of IL-6. To elucidate the role of IL-6 in chronic rejection, cardiac allograft recipients depleted of CD4+ cells were treated with neutralizing anti-IL-6 mAb. IL-6 neutralization ameliorated cardiomyocyte hypertrophy, graft fibrosis, and prevented deterioration of graft contractility associated with chronic rejection. The association of IL-6 with CR prompted us to investigate the relationship between IL-6 and two other factors known to be associated with CR, namely TGFβ and connective tissue growth factor (CTGF). To this end, we utilized forced expression and neutralizing antibody approaches. Transduction of allografts with CTGF significantly increased fibrotic tissue development, though not to levels observed with TGFβ transduction. Further, intragraft CTGF expression was inhibited by IL-6 neutralization while TGFβ expression remained unchanged, indicating that IL-6 effects may potentiate TGFβ-mediated induction of CTGF. Finally, neutralizing CTGF significantly reduced graft fibrosis without reducing TGFβ and IL-6 expression levels. These findings indicate that IL-6 and TGFβ function as promoters of CR while CTGF functions as a downstream mediator of fibrosis in CR. Further, therapeutics targeting IL-6 or CTGF may hold promise in the treatment of CR of cardiac grafts.Ph.D.ImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/64808/1/boothaj_1.pd

Quenched Chiral Perturbation Theory for Vector Mesons

We develop quenched chiral perturbation theory for vector mesons made of light quarks, in the limit where the vector meson masses are much larger than the pion mass. We use this theory to extract the leading nonanalytic dependence of the vector meson masses on the masses of the light quarks. By comparing with analogous quantities computed in ordinary chiral perturbation theory, we estimate the size of quenching effects, observing that in general they can be quite large. This estimate is relevant to lattice simulations, where the $\rho$ mass is often used to set the lattice spacing.Comment: 18 pages, 8 figures, uses REVTeX and epsf.st

A VSM (virtual synchronous machine) convertor control model suitable for RMS studies for resolving system operator/owner challenges

In recent years, it has become clear that reaching the targeted levels of renewable power generation poses problems, not only for basic infrastructure and generation/load balancing, but also in terms of fundamental network stability. In Ireland, the contribution from convertor-connected generation is already constrained to 50-55%, while recent studies of other networks suggest that any "penetration" of convertors above 65% could lead to instability. The phenomena have been observed both in RMS and high-fidelity EMT simulations of convertor-dominated power systems, and appears to be unavoidable when using the dq-axis current-source controllers within conventional grid-connected convertors. The high control bandwidth (>50 Hz) of these convertors also means that they cannot be effectively included within RMS type large-scale network models. The idea of "synthetic inertia" has been proposed in some publications as a mitigating solution but needs to be considered carefully, since if implemented incorrectly it has been shown to further destabilise the network at the critical small timescales and high frequencies. In this paper we present simple versions of a Virtual Synchronous Machine (VSM) model which is implemented and demonstrated in both transient and RMS based simulations. An important aspect of the VSM is that the controller’s bandwidth is low (<<50 Hz). This means that it can be modelled with reasonable accuracy in RMS simulation with time steps of the order of 2ms. From a system operator perspective, large-scale RMS simulations of entire countries or regions containing hundreds of VSM generators can be carried out with reasonable accuracy

Use of an inertia-less virtual synchronous machine within future power networks with high penetrations of converters

Conventional converter models for wind turbines and Voltage Source HVDC links, as submitted to System Operators, typically use dq-axis controllers with current injection (DQCI). Recent work carried out by the authors has proven that for DQCI converter-interfaced sources there are overall penetration limits, i.e. the 'tipping points' beyond which the system will become unstable. Initial investigations of this "tipping point", based on a reduced model of the transmission system of Great Britain using phasor simulation within DIgSILENT PowerFactory, are reviewed briefly in this paper. The 'tipping points' relating to maximum penetration of DQCI converter-interfaced sources are subsequently investigated in this paper using a higher fidelity three-phase dynamic power system model in Matlab Simulink. Additionally, a new converter controller, termed here as Virtual Synchronous Machine Zero Inertia (VSM0H), is described and implemented in the model. It is shown that, in principle, it is possible to significantly increase the penetration of converter based generation (up to 100% of installed capacity) without reaching a stability constraint

Effects of VSM convertor control on penetration limits of non-synchronous generation in the GB power system

2013 saw the presentation of a paper [1][2] to the wind integration workshop, which demonstrated 26 high convertor penetration scenarios, 17 of which introduced a type of instability in RMS models previously unseen by the researchers. It also provided an indication of the constraints necessary if NSG levels where to be limited, potentially placing practical limits on the amount of NSG which could be accommodated. It demonstrated that Synchronous Compensation (SC) could be used to mitigate these and other problems but this is believed to be an expensive solution. Further publications have demonstrated that convertor instability at high NSG extends beyond RMS models and is believed to occur in real systems [3]. In addition, Swing Equation Based Inertial Response (SEBIR) control, sometimes referred to as "Synthetic Inertia", has been shown to be ineffective as a countermeasure against the instability observed in [1][2] and can in some circumstances make it worse [4][5]. Whilst SEBIR improves RoCoF, its inability to address the wider range of problems resulted in the need for more comprehensive solutions. Several authors have proposed converters using principles aligned with VSM and VSM0H concepts and controllers using these concepts exist within marine power networks. This paper returns to the studies presented in [1][2], which used a reduced 36 node GB model in PowerFactory (PF). However here, some of the convertors are replaced with VSM convertor models described in [6] to investigate the effects on Instantaneous Penetration Level (IPL) limit of NSG in terms of transient stability and steady-state stability. These and further results presented demonstrate the potential of VSM, in mitigating the effects of various challenges associated with high NSG, potentially allowing 100% penetration

Instantaneous penetration level limits of non-synchronous devices in the British power system

The installed capacity of non-synchronous devices (NSD), including renewable energy generation and other converter-interfaced equipment such as energy storage, bi-directional transfer links, electric vehicles, etc., is expected to increase and contribute a large proportion of total generation capacity in future power systems. Concerns have been expressed relating to operability and stability of systems with high penetrations of NSD, since NSD are typically decoupled from the grid via power electronic devices and consequently reduce the “natural” inertia, short-circuit levels and damping effects which are inherently provided by synchronous machines. It is therefore crucial to ensure secure and stable operation of power systems with high penetrations of NSD. This paper will show and quantify the instantaneous penetration level (IPL) limits of NSD connected to a simple example power system in terms of steady-state stability beyond which the system can become unstable or unacceptable, defined as “unviable”. The NSD used in this example will be a conventional dq-axis current injection (DQCI) convertor model. The paper will introduce a set of criteria relating to locking signal in converter phase-locked loop, frequency, rate of change of frequency and voltage magnitude, which will be used to determine the system viability and the IPL limit. It will also be shown that there are several factors that can potentially affect the IPL limits. Frequency and voltage droop slopes and filter time-constant for DQCI converter are varied and it is shown how these settings influence the IPL limits. Finally, to provide additional insight into network viability under high penetrations of NSD, a visualisation method referred here as “network frequency perturbation” is introduced to investigate responses of individual generators to a change in network frequency

A new fast-acting backup protection strategy for embedded MVDC links in future distribution networks

This paper presents a new fast-acting backup protection strategy for future hybrid ac-dc distribution networks. By examining the impedance measured by a distance protection relay measuring from the “ac-side” of the network, a unique characteristic is established for faults occurring on the “dc-side” of an embedded medium-voltage dc (MVDC) link, interconnecting two 33 kV distribution network sections. Based on the identified impedance characteristic, appropriate settings are developed and deployed on a verified software model of a commercially available distance protection relay. To remain stable for ac-side faults, it is found that the tripping logic of the device must be altered to provide correct time grading between standard, ac, protection zones and the fast-acting dc region, which can identify faults on the dc system within 40 ms. An additional confirmatory check is also employed to reduce the likelihood of mal-operation. Trials on a test system derived from an actual distribution network, which employs distance protection, are shown to provide stable operation for both ac-side and dc-side pole-pole and pole-pole-ground fault

Connective Tissue Growth Factor Promotes Fibrosis Downstream of TGFΒ and IL-6 in Chronic Cardiac Allograft Rejection

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72574/1/j.1600-6143.2009.02826.x.pd

Topographic signatures and a general transport law for deep-seated landslides in a landscape evolution model

A fundamental goal of studying earth surface processes is to disentangle the complex web of interactions among baselevel, tectonics, climate, and rock properties that generate characteristic landforms. Mechanistic geomorphic transport laws can quantitatively address this goal, but no widely accepted law for landslides exists. Here we propose a transport law for deep-seated landslides in weathered bedrock and demonstrate its utility using a two-dimensional numerical landscape evolution model informed by study areas in the Waipaoa catchment, New Zealand, and the Eel River catchment, California. We define a non-dimensional landslide number, which is the ratio of the horizontal landslide flux to the vertical tectonic flux, that characterizes three distinct landscape types. One is dominated by stochastic landsliding, whereby discrete landslide events episodically erode material at rates exceeding the long-term uplift rate. Another is characterized by steady landsliding, in which the landslide flux at any location remains constant through time and is greatest at the steepest locations in the catchment. The third is not significantly affected by landsliding. In both the “stochastic landsliding” and “steady landsliding” regimes, increases in the non-dimensional landslide number systematically reduce catchment relief and widen valley spacing, producing long, low angle hillslopes despite high uplift rates. The stochastic landsliding regime captures the frequent observation that deep-seated landslides produce large sediment fluxes from small areal extents while being active only a fraction of the time. We suggest that this model is adaptable to a wide range of geologic settings and is useful for interpreting climate-driven changes in landslide behavior

The Presence of Charge Transfer Defect Complexes in Intermediate Band CuAl1−pFepS2

Despite chalcopyrite (CuFeS2) being one of the oldest known copper ores, it exhibits various properties that are still the subject of debate. For example, the relative concentrations of the ionic states of Fe and Cu in CuFeS2 can vary significantly between different studies. The presence of a plasmon-like resonance in the visible absorption spectrum of CuFeS2 nanocrystals has driven a renewed interest in this material over recent years. The successful synthesis of CuAl1−pFepS2 nanocrystals that exhibit a similar optical resonance has recently been demonstrated in the literature. In this study, we use density functional theory to investigate Fe substitution in CuAlS2 and find that the formation energy of neutral [FeCu]2++[CuAl]2− defect complexes is comparable to [FeAl]0 antisites when p≥0.5. Analysis of electron density and density of states reveals that charge transfer within these defect complexes leads to the formation of local Cu2+/Fe2+ ionic states that have previously been associated with the optical resonance in the visible absorption of CuFeS2. Finally, we comment on the nature of the optical resonance in CuAl1−pFepS2 in light of our results and discuss the potential for tuning the optical properties of similar systems