The role of PI3K p110gamma in chronic liver injury

The Phosphatidyl-insitol-3-kinase (PI3K) is a central mediator in many signalling pathways, e.g. in insulin signalling and in proinflammatory signalling via mTOR. Previous studies suggested a critical role of PI3K signalling during hepatic fibrogenesis, however, the role of different PI3K p110 isoforms has not been discriminated. The aim of this project was to assess the expression and function of PI3K p110gamma in chronic liver disease with a focus on hepatic fibrosis. We found that the expression of the PI3K class 1B unit p110gamma is increased in the liver during chronic injury. Further, we found that p110gamma expression is enhanced during the activation of hepatic stellate cells (HSC), a process which plays a key role in hepatic fibrosis. We further discovered that PI3K p110gamma deficiency had divergent effects on the activation of HSC and hepatic fibrosis, respectively, in two different models for chronic liver injury. The bile duct ligation model (BDL) causes chronic injury by inducing hepatocyte apoptosis/necrosis, because of high hepatic concentrations of bile acids. Pro-inflammatory mediators lead to the activation of resident liver macrophages (i.e. Kupffer cells) and infiltrating immune cells. PI3K p110gamma deficient mice revealed significantly diminished liver fibrosis compared to wild-type (WT) mice. In a second model for chronic liver injury, a dietary model for non-alcoholic steatohepatitis (NASH), PI3K p110gamma deficiency surprisingly had no protective effect, but even aggravated liver injury. NASH is primarily caused by a dysregulation of fatty acid (FFA) metabolism, which leads to hepatic lipid accumulation. Free fatty acids then lead to the generation of reactive oxygen species (ROS) and subsequently to lipid peroxidation, which causes hepatic inflammation and fibrosis. Here, we found that PI3K p110gamma deficiency significantly enhanced hepatic FFA accumulation and ROS formation. As potential underlying cause for the enhanced FFA accumulation in the PI3K p110gamma deficient mice we identified impaired FFA transport and enhanced beta-oxidation. In conclusion, we provide experimental evidence that the effect of PI3K p110gamma varies significantly, depending on the cause of liver injury. Particularly, in a model of NAFLD PI3K p110gamma seems to inhibit hepatic steatosis, inflammation and fibrogenesis. Currently, PI3K p110gamma inhibitors are under clinical development for the treatment of inflammatory disorders and cardiovascular dysfunctions. Based on the data of the present study one has to be very cautious regarding harmful effects of a PI3K p110gamma inhibition in patients with the metabolic syndrome or known fatty liver disease, respectively

POWER LINES AS LOCAL AREA NETWORKS FOR MEASURING AND CONTROL SIGNAL TRANSMISSION

Electrical power distribution networks represent the most attractive medium for digital communication purposes due to an ever increasing demand for environmental management of buildings, security monitoring, office automation or remote control of customer appliances and remote meter reading. Power lines are, however, heavily stressed with interference from various sources. Both interference and attenuation are time-variant and frequency-selective in an arbitrary way. The prospective user has to overcome the impairments with a severely restricted level of transmission power, e.g. 5 mW in Germany; the transmission bandwidth, however, exceeds 100 kHz. Obviously simple and inexpensive modulation schemes for digital data transmission such as amplitude shift keying (ASK) or frequency shift keying (FSK) are ruled out. A significant success of band-spreading techniques has been demonstrated by several field trials and extended measurements at different power line networks. Application of spread spectrum techniques generally involves high effort; this is especially true for frequency hopping, which proved advantageous in practical applications. Exploiting the possibilities of modern microelectronics, including design and production of ASICs, recently led to a break-through. A five-year research project based on frequency hopping spread spectrum signaling opened up power lines as local area networks e.g. for office automation or remote meter reading. Transmitter and receiver prototypes were constructed for evaluation of the proposed ideas at various power line networks. Transmitters are based on standard microcontrollers, whereas an application specific integrated circuit (ASIC) with a complexity of about ·5000 gates is the heart of the receiver. Due to completely digital signal processing. the prototypes are useful as a base for series production

REL: a Rapidly Extensible Language System II. REL English

REL, a Rapidly Extensible Language System, is an integrated information system operating in conversational interaction with the computer. It is intended for work with large or small data bases by means of highly individualized languages. The architecture of REL is based on theoretical assumptions about human information dynamics [I], among them the expanding process of conceptualization in working with data, and the idiosyncratic language use of the individual workers. The result of these assumptions is a system which allows the construction of highly individualized languages which are closely knit with the structure of the data and which can be rapidly extended and augmented with new concepts and structures through a facile definitional capability. The REL language processor is designed to accommodate a variety of languages whose structural characteristics may be considerably divergent. The REL English is one of the languages within the REL system. It is intended to facilitate sophisticated work with computers without the need for mastering programming languages. The structural power of REL English matches the extremely flexible organization of data in ring forms. Extensions of the basic REL English language can be achieved either through defining new concepts and structures in terms of the existing ones or through addition of new rules

Software Defined Channel Sounder for Power Line Communications

Most power line channel sounders are based on expensive lab instruments. This work presents an alternative based on software defined radio platforms. These can be later also employed as communication modems, decreasing costs and deployment times. We implemented and evaluated two channel sounding techniques: frequency hopping and sliding correlator. The results suggest that frequency hopping might be a better candidate for power line channels due to the expected low signal-to-noise ratio

Exact semidefinite programming bounds for packing problems

In this paper we give an algorithm to round the floating point output of a semidefinite programming solver to a solution over the rationals or a quadratic extension of the rationals. We apply this to get sharp bounds for packing problems, and we use these sharp bounds to prove that certain optimal packing configurations are unique up to rotations. In particular, we show that the configuration coming from the $\mathsf{E}_8$ root lattice is the unique optimal code with minimal angular distance $\pi/3$ on the hemisphere in $\mathbb R^8$, and we prove that the three-point bound for the $(3, 8, \vartheta)$-spherical code, where $\vartheta$ is such that $\cos \vartheta = (2\sqrt{2}-1)/7$, is sharp by rounding to $\mathbb Q[\sqrt{2}]$. We also use our machinery to compute sharp upper bounds on the number of spheres that can be packed into a larger sphere.Comment: 24 page