Fujitsu (Germany)

Deregulation of apoptosis, the physiological form of cell death, is closely associated with immunological diseases and cancer. Apoptosis is activated either by death receptor-driven or mitochondrial pathways, both of which may provide potential targets for novel anticancer drugs. Although several ligands stimulating death receptors have been described, the actual molecular events triggering the mitochondrial pathway are largely unknown. Here, we show initiation of apoptosis by gradual depletion of the intracellular coenzyme NAD+. We identified the first low molecular weight compound, designated FK866, which induces apoptosis by highly specific, noncompetitive inhibition of nicotinamide phosphoribosyltransferase (NAPRT), a key enzyme in the regulation of NAD+ biosynthesis from the natural precursor nicotinamide. Interference with this enzyme does not primarily intoxicate cells because the mitochondrial respiratory activity and the NAD+ -dependent redox reactions involved remain unaffected as long as NAD+ is not effectively depleted by catabolic reactions. Certain tissues, however, have a high turnover of NAD+ through its cleavage by enzymes like poly(ADP-ribose) polymerase. Such cells often rely on the more readily available nicotinamide pathway for NAD+ synthesis and undergo apoptosis after inhibition of NAPRT, whereas cells effectively using the nicotinic acid pathway for NAD+ synthesis remain unaffected. In support of this concept, FK866 effectively induced delayed cell death by apoptosis in HepG2 human liver carcinoma cells with an IC(50) of approximately 1 nM, did not directly inhibit mitochondrial respiratory activity, but caused gradual NAD+ depletion through specific inhibition of NAPRT. This enzyme, when partially purified from K562 human leukemia cells, was noncompetitively inhibited by FK866, and the inhibitor constants were calculated to be 0.4 nM for the enzyme/substrate complex (K(i)) and 0.3 nM for the free enzyme (K(i)'), respectively. Nicotinic acid and nicotinamide were both found to have antidote potential for the cellular effects of FK866. FK866 may be used for treatment of diseases implicating deregulated apoptosis such as cancer for immunosuppression or as a sensitizer for genotoxic agents. Furthermore, it may provide an important tool for investigation of the molecular triggers of the mitochondrial pathway leading to apoptosis through enabling temporal separation of NAD+ decrease from ATP breakdown and apoptosis by several days.

Tissues must quickly recognize injury to respond to the rapid pace of microbial growth. In skin, dermal microvascular endothelial cells must also react to danger signals from the surrounding tissue and immediately participate by initiating the wound repair process. Components of the extracellular matrix such as hyaluronan are rapidly broken down into smaller molecular weight oligosaccharides in a wound, and these can activate a variety of biological processes. This study set out to determine if hyaluronan fragments released following injury can stimulate endothelial cells and what mechanism is responsible for this response. Using genechip microarray analysis, a response to hyaluronan fragments was detected in endothelial cells with the most significant increase observed for the chemokine IL-8. This observation was verified with qualitative reverse transcriptase-PCR and ELISA in human endothelial cell culture, and in a mouse model by observing serum levels of MIP-2 and KC following hyaluronan fragment administration in vivo. Activation was TLR4-dependent, as shown by use of TLR4 blocking antibody and TLR4-deficient mice, but not due to the presence of undetected contaminants as shown by inactivation following digestion with the hyaluronan-degrading enzyme chondroitinase ABC or incubation with the hyaluronan-specific blocking peptide Pep-1. Inactivation of LPS activity failed to diminish the action of hyaluronan fragments. These observations suggest that endogenous components of the extracellular matrix can stimulate endothelia to trigger recognition of injury in the initial stages of the wound defense and repair response.

BACKGROUND: The increasing use of tacrolimus as a primary immunosuppressant is paralleled by a growing number of pregnancies occurring in mothers receiving tacrolimus systemically. METHODS: In this retrospective analysis during 1992-1998; data sources were case reports from clinical studies, spontaneous reports from health care professionals, routine surveys by transplant registries, and the published literature. RESULTS: One hundred pregnancies in 84 mothers were recorded. Mean maternal age was 28 years. All except one mother (autoimmune disease) were solid organ transplant recipients (66% liver and 27% kid- ci ney). Mean time from transplantation to conception was 26 months. The mean daily dose of tacrolimus (range 11.7-12.8 mg/day) and the mean tacrolimus whole blood level (range 8.5-11.5 ng/ml) remained fairly constant from preconception through the third trimester. The most frequent maternal complications were graft rejection followed by preeclampsia, renal impairment, and infection. All cases of rejection were successfully treated with corticosteroids and did not result in graft loss. Of 100 pregnancies, 71 progressed to delivery (68 live births, 2 neonatal deaths, and 1 stillbirth), 24 were terminated (12 spontaneous and 12 induced), 2 pregnancies were ongoing, and 3 were lost to follow-up. Mean gestation period was 35 weeks with 59% deliveries being premature (<37 weeks). The birth weight (mean 2573 g) was appropriate for gestational age in 90% of cases. Most common complications in the neonate were hypoxia, hyperkalemia, and renal dysfunction. These were transient in nature. Four neonates presented with malformations, without any consistent pattern of affected organs. CONCLUSION: Pregnancy in tacrolimus-treated transplant recipients resulted in a favourable outcome. Complications of the mother and neonate were similar to those previously described with other immunosuppressants.

BACKGROUND: Severely immunocompromised individuals are highly susceptible to Candida infection of the esophagus. This randomized, double-blind study assessed the dose-response relationship of the new echinocandin antifungal, micafungin, compared with that of standard fluconazole treatment. METHODS: A total of 245 patients (age, > or =18 years) with a prior diagnosis of acquired immunodeficiency syndrome/human immunodeficiency virus (HIV) infection and esophageal candidiasis, confirmed by endoscopy and culture, were randomized to receive micafungin (50, 100, or 150 mg per day) or fluconazole (200 mg per day). Both agents were administered once per day by a 1-h intravenous infusion for 14-21 days. The primary efficacy end point was endoscopic cure rate, defined as endoscopy grade of 0 at the end of therapy. RESULTS: The endoscopic cure rate (grade 0) was dose-dependent with 50, 100, and 150 mg of micafungin per day at 68.8%, 77.4%, and 89.8%, respectively. Symptoms improved or resolved rapidly (3-7 days of treatment in the majority of patients). The endoscopic cure rate for 100 and 150 mg of micafungin per day (83.5%) was comparable to that for 200 mg of fluconazole per day (86.7%; 95% confidence interval for the difference in endoscopic cure rate, -14.0% to 7.7%). The overall safety and tolerability was acceptable, with no important differences between micafungin (all doses) and fluconazole. CONCLUSIONS: The dose-response findings demonstrate a greater efficacy with micafungin at 100 and 150 mg per day than at 50 mg per day. This study also indicates that the efficacy of micafungin (at dosages of 100 and 150 mg per day) was comparable to that of fluconazole, suggesting that micafungin represents a valuable new treatment option for esophageal candidiasis in HIV-positive patients.

We report on the dynamic control over the orientation of short oligonucleotide strands which are tethered to gold surfaces in electrolyte solution. By applying alternating electrical bias potentials to the supporting electrodes we are able to induce a switching of the layer conformation between a “lying” and a “standing” state, simultaneously monitored in a contactless mode by fluorescence techniques. We demonstrate that our electrooptical experiments allow for an in-depth investigation of the intriguing molecular dynamics of DNA at surfaces and, moreover, how the dynamic response of these switchable biomolecular layers opens new prospects in label-free biosensing.

BACKGROUND: Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients. METHODS: Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months. RESULTS: At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05). CONCLUSIONS: Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.

This paper reviews the pharmacokinetics of tacrolimus, with special reference to its combination with adjunctive immunosuppressants. Oral bioavailability of tacrolimus, which is variable between patients, averages approximately 25%. This is largely due to extrahepatic metabolism of tacrolimus in the gastrointestinal epithelium. Nevertheless, intra-patient variability is low, as evidenced by the small number of dose changes required to maintain patients within the recommended tacrolimus target levels. Tacrolimus is distributed extensively in the body with most partitioned outside the blood compartment. Concentrations of tacrolimus in blood are used as a surrogate marker of clinically relevant concentration of the drug at the site(s) of action. Convenient whole-blood sampling within a +/-2-h window around 12 h post-dose (C(min)) is highly predictive of systemic exposure to tacrolimus and is thus used to optimise therapy. Sampling at other time-points offers no advantage over C(min) monitoring. The interactions of tacrolimus with other immunosuppressive agents are well characterized. After cessation of concomitant corticosteroid treatment, exposure to tacrolimus increases by approximately 25%. In contrast, there is no pharmacokinetic interaction between mycophenolate mofetil (MMF) and tacrolimus. Therefore, systemic exposure to the active metabolite of MMF, mycophenolic acid, is higher with MMF-tacrolimus combination than with MMF-cyclosporin combination. Therefore, 1 g/day MMF may be an adequate maintenance dose in tacrolimus-based regimens. Co-administration of tacrolimus and sirolimus, while having no effect on exposure to sirolimus, results in reduced exposure to tacrolimus at sirolimus doses of 2 mg/day and above. In conclusion, tacrolimus levels should be monitored when sirolimus is co-administered at doses >2 mg/day and after cessation of corticosteroid treatment.

Although there are experimental reports of cytochrome P450 3A4 iso-enzyme (CYP3A4) induction by glucocorticoids, there are no clinical reports about an interaction between tacrolimus and steroids. Therefore, tacrolimus trough level and dose were compared after dose-normalization before and after withdrawal of prednisolone. After withdrawal of 5 mg prednisolone, the median tacrolimus dose-normalized level increased by 14% in the retrospective ( n=54), and by 11% in the prospective ( n=8) part of the study. After withdrawal of 10 mg, this increase was 33% ( n=30) and 36% ( n=14), respectively. An additional pharmacokinetic part of the study ( n=8) revealed an 18% increase in AUC ( P=0.05) after withdrawal of 5 mg prednisolone, which is compatible with a reduced metabolism after steroid withdrawal. The significant increase in tacrolimus exposure after steroid withdrawal may on the one hand counteract the reduction in immunosuppression intended by steroid withdrawal, and, on the other hand, may result in an increase of serum creatinine which could be misinterpreted as rejection.

We present optical investigations on the conformation of oligonucleotide layers on Au surfaces. Our studies concentrate on the effect of varying surface coverage densities on the structural properties of layers of 12- and 24mer single-stranded DNA, tethered to the Au surface at one end while being labeled with a fluorescent marker at the opposing end. The distance-dependent energy transfer from the marker dye to the metal surface, which causes quenching of the observed fluorescence, is used to provide information on the orientation of the DNA strands relative to the surface. Variations in the oligonucleotide coverage density, as determined from electrochemical quantification, over 2 orders of magnitude are achieved by employing different preparation conditions. The observed enhancement in fluorescence intensity with increasing DNA coverage can be related to a model involving mutual steric interactions of oligonucleotides on the surface, as well as fluorescence quenching theory. Finally, the applicability of the presented concepts for investigations of heterogeneous monolayers is demonstrated by means of studying the coadsorption of mercaptohexanol onto DNA-modified Au surfaces.

Get PDF Email Share Share with Facebook Tweet This Post on reddit Share with LinkedIn Add to CiteULike Add to Mendeley Add to BibSonomy Get Citation Copy Citation Text W. Yan, T. Tanaka, B. Liu, M. Nishihara, L. Li, T. Takahara, Z. Tao, J. C. Rasmussen, and T. Drenski, "100 Gb/s Optical IM-DD Transmission with 10G-Class Devices Enabled by 65 GSamples/s CMOS DAC Core," in Optical Fiber Communication Conference/National Fiber Optic Engineers Conference 2013, OSA Technical Digest (online) (Optica Publishing Group, 2013), paper OM3H.1. Export Citation BibTex Endnote (RIS) HTML Plain Text Get Video Citation alert Save article

In recent years, there is a surge of interest in approaches pertaining to security issues of Internet of Things deployments and applications that leverage machine learning and deep learning techniques. A key prerequisite for enabling such approaches is the development of scalable infrastructures for collecting and processing security-related datasets from IoT systems and devices. This paper introduces such a scalable and configurable data collection infrastructure for data-driven IoT security. It emphasizes the collection of (security) data from different elements of IoT systems, including individual devices and smart objects, edge nodes, IoT platforms, and entire clouds. The scalability of the introduced infrastructure stems from the integration of state of the art technologies for large scale data collection, streaming and storage, while its configurability relies on an extensible approach to modelling security data from a variety of IoT systems and devices. The approach enables the instantiation and deployment of security data collection systems over complex IoT deployments, which is a foundation for applying effective security analytics algorithms towards identifying threats, vulnerabilities and related attack patterns.

The model of a stochastic production/inventory system that is subject to deterioration failures is developed and examined in this paper. Customer interarrival times are assumed to be random and backorders are allowed. The system experiences a number of deterioration stages before it ultimately fails and is rendered inoperable. Repair and maintenance activities restore the system to its initial and previous deterioration state, respectively. The duration of both repair and maintenance is assumed to be stochastic. We address the problem of minimizing the expected sum of two conflicting objective functions: the average inventory level and the average number of backorders. The solution to this problem consists of finding the optimal tradeoff between maintaining a high service level and carrying as low inventory as possible. The primary goal of this research is to obtain optimal or near-optimal joint production/maintenance control policies, by means of a novel reinforcement learning-based approach. Furthermore, we examine parametric production and maintenance policies that are often used in practical situations, namely, Kanban, (s, S), threshold-type condition based maintenance and periodic maintenance. The proposed approach is compared with the parametric policies in an extensive series of simulation experiments and it is found to clearly outperform them in all cases. Based on the numerical results obtained by the experiments, the behavior of the parametric policies as well as the structure of the control policies derived by the Reinforcement Learning-based approach is investigated.

The aim of this paper is to provide a summary of clinical findings regarding the safety of tacrolimus in pregnancy. From 1992 to 1998 data were collected on 100 pregnancies from 84 mothers who received tacrolimus systemically; 83 cases of solid organ transplantation, and 1 case of Behçet's disease. Maternal mean age at conception was 28 years and pregnancy outcome was live birth in 68%, spontaneous abortion in 12%, induced abortion in 12%, stillbirth/perinatal death in 3%, ongoing pregnancy in 2%, and lost to follow up in 3%. Fifty-nine percent of the neonates were delivered prematurely (< 37 weeks of gestation). Birth weight was appropriate for the gestational age in 90% of the cases. Malformations occurred in 4 neonates: case 1, meningocele and urogenital defects; case 2, alcoholic embryopathy; case 3, ear defect, cleft palate and hypospadia; case 4, multicystic dysplastic kidney. There was no consistent pattern of malformations and 2 mothers subsequently delivered a healthy neonate while on tacrolimus therapy. Nearly 70% of pregnancies following systemic tacrolimus administration resulted in a favourable outcome without any significant effect on intrauterine growth. The incidence of malformations was similar to that reported with other immunosuppressants in transplant recipients.

Flexible Job Shop Scheduling is one of the most difficult optimization problems known. In addition, modern production planning and control strategies require continuous and process-parallel optimization of machine allocation and processing sequences. Therefore, this paper presents a new method for process parallel Flexible Job Shop Scheduling using the concept of quantum computing based optimization. A scientific benchmark and the application to a realistic use-case demonstrates the good performance and practicability of this new approach. A managerial insight shows how the approach for process parallel flexible job shop scheduling can be integrated in existing production planning and control IT-infrastructure.

We demonstrate 400Gbit/s data generation using 64QAM at 42.66 GBaud with a reduced oversampling ratio of 1.5 Sample/symbol including digital Nyquist filtering and spectral pre-emphasis. Even at 24% FEC overhead a successful transmission over 300 km ULAF has been shown.

117Gb/s single wavelength and polarization IM-DD transmission over 40km SMF is first enabled by DMT. With an SOA, 101Gb/s over 80km is demonstrated. The nonlinearity management through parameter optimization and digital compensation is discussed.

We introduce a chip-compatible scheme for the label-free detection of proteins in real-time that is based on the electrically driven conformation switching of DNA oligonucleotides on metal surfaces. The switching behavior is a sensitive indicator for the specific recognition of IgG antibodies and antibody fragments, which can be detected in quantities of less than 10(-18) mol on the sensor surface. Moreover, we show how the dynamics of the induced molecular motion can be monitored by measuring the high-frequency switching response. When proteins bind to the layer, the increase in hydrodynamic drag slows the switching dynamics, which allows us to determine the size of the captured proteins. We demonstrate the identification of different antibody fragments by means of their kinetic fingerprint. The switchDNA method represents a generic approach to simultaneously detect and size target molecules using a single analytical platform.

We study the coadsorption of mercaptohexanol onto preimmobilized oligonucleotide layers on gold. Monitoring the position of the DNA relative to the surface by optical means directly shows the mercaptohexanol-induced desorption of DNA and the reorientation of surface-tethered strands in situ and in real time. By simultaneously recording the electrochemical electrode potential, we are able to demonstrate that changes in the layer conformation are predominantly of electrostatic origin and can be reversed by applying external bias to the substrate.

Experimental analysis of computer systems' power consumption has become an integral part of system performance evaluation, efficiency management, and model-based analysis. As with all measurements, repeatability and reproducibility of power measurements are a major challenge. Nominally identical systems can have different power consumption running the same workload under otherwise identical conditions. This behavior can also be observed for individual system components. Specifically, CPU power consumption can vary amongst different samples of nominally identical CPUs. This in turn has a significant impact on the overall system power, considering that a system's processor is the largest and most dynamic power consumer of the overall system. The concrete impact of CPU sample power variations is unknown, as comprehensive studies about differences in power consumption for nominally identical systems are currently missing. We address this lack of studies by conducting measurements on four different processor types from two different architectures. For each of these types, we compare up to 30 physical processor samples with a total sum of 90 samples over all processor types. We analyze the variations in power consumption for the different samples using six different workloads over five load levels. Additionally, we analyze how these variations change for different processor core counts and architectures. The results of this paper show that selection of a processor sample can have a statistically significant impact on power consumption. With no correlation to performance, power consumption for nominally identical processors can differ as much as 29.6% in idle and 19.5% at full load. We also show that these variations change over different architectures and processor types.

Energy efficiency of servers has become a significant research topic over the last years, as server energy consumption varies depending on multiple factors, such as server utilization and workload type. Server energy analysis and estimation must take all relevant factors into account to ensure reliable estimates and conclusions. Thorough system analysis requires benchmarks capable of testing different system resources at different load levels using multiple workload types. Server energy estimation approaches, on the other hand, require knowledge about the interactions of these factors for the creation of accurate power models. Common approaches to energy-aware workload classification categorize workloads depending on the resource types used by the different workloads. However, they rarely take into account differences in workloads targeting the same resources. Industrial energy-efficiency benchmarks typically do not evaluate the system's energy consumption at different resource load levels, and they only provide data for system analysis at maximum system load.