Existence of discrete-time LQG-controllers

Existence results for the LQG-controller are investigated. An infimal Riccati equation based controller may potentially give closed loop eigenvalues on the unit circle. Assuming left and right invertibility it is shown that there exists an optimal controller if and only if the Riccati equation based controller stabilizes the closed loop system after removal of all its unobservable and uncontrollable modes. Furthermore this reduced controller is the optimal controller, and its transfer function is unique. This existence condition is a considerable simplification of the more general geometric condition recently derived by Trentelman and Stoorvogel.     

IT for niche companies: is an ERP system the solution?

Abstract.  Niche companies are per definition idiosyncratic. They survive in a competitive world by mastering a small market niche, providing what their customers need. This often requires a flexible organization, and the ability to customize products. To be more efficient, many of these companies rely on extensive use of IT, often by installing general Enterprise Resource Planning (ERP) systems. These systems have grown from isolated systems that handle planning based on incoming orders and the component structure of the various products, to systems with ambitions to embrace the total functioning of the company including vendor and customer relation management. In this paper, we present four case studies. One company is a part of a large enterprise, but performs niche functions within this enterprise. The other three are small- or medium-sized enterprises. Each of these performs in small niche markets. Common to all is the fact that they encounter problems with the utilization of their ERP systems. The major problem seems to be that the ERP system has an inherent business model that may not conform to the needs of the company. Without a good understanding of the underlying models and the constraints under which the fundamental algorithms operate, it is difficult to use these systems correctly. Even excellent systems may give bad results if they are applied to situations where they are not suited. Further, the monolithic structure of an ERP system, with a rather complicated parameter setting, is often insufficient to mould the system to the needs of a niche company. We discuss these problems based on our four case studies, and offer alternative approaches that may be considered.     

Natural and induced tolerance in an immune network model

It has been proposed that the immune system can be partitioned into central and peripheral immune systems. Recently, Carneiro et al. (1996a, b) proposed a network, model incorporating B and T lymphocytes that explicitly accounts for that partition. This model however, had some limitations that are tackled here. Two main changes were introduced: the average idiotypic connectivity is now an explicit function of time based on empirical evidence; and the activation of T lymphocytes by antigen is described by a log-bell shaped dose response curve. The new model, which also accounts for the CIS and PIS distinction, shows more reasonable results since the frequencies of tolerant, immune or autoimmune responses to an antigen are now correct. The model provides a new interpretation for tolerance induction during the neonatal period, and for the adult tolerance by low or high doses of antigen. It predicts that natural tolerance for antigens available during the neonatal period can be kept indefinitely upon their removal, while tolerance induced in the adult stages is rapidly lost upon transient removal of the antigen. A semiquantitative analysis of the model provides a simple explanation for the different results in terms of the frequency at which a limited set of canonical connectivity structures emerge during ontogenesis.     

Sensitivity to Cisplatin in Head and Neck Cancer Cells Is Significantly Affected by Patient-Derived Cancer-Associated Fibroblasts

Cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor stroma. CAFs can impact many important steps of cancerogenesis and may also influence treatment resistance. Some of these effects need the direct contact of CAFs and cancer cells, while some involve paracrine signals. In this study, we investigated the ability of head and neck squamous cell carcinomas (HNSCC) patient-derived CAFs to promote or inhibit the colony-forming ability of HNSCC cells. The effect of cisplatin on this promoting or inhibiting influence was also studied. The subsequent analysis focused on changes in the expression of genes associated with cancer progression. We found that cisplatin response in model HNSCC cancer cells was modified by coculture with CAFs, was CAF-specific, and different patient-derived CAFs had a different “sensitizing ratio”. Increased expression of VEGFA, PGE2S, COX2, EGFR, and NANOG in cancer cells was characteristic for the increase of resistance. On the other hand, CCL2 expression was associated with sensitizing effect. Significantly higher amounts of cisplatin were found in CAFs derived from patients who subsequently experienced a recurrence. In conclusion, our results showed that CAFs could promote and/or inhibit colony-forming capability and cisplatin resistance in HNSCC cells via paracrine effects and subsequent changes in gene expression of cancer-associated genes in cancer cells.     

GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C Mice

The lysosomal storage disease Niemann–Pick type C (NPC) is caused by impaired cholesterol efflux from lysosomes, which is accompanied by secondary lysosomal accumulation of sphingomyelin and glucosylceramide (GlcCer). Similar to Gaucher disease (GD), patients deficient in glucocerebrosidase (GCase) degrading GlcCer, NPC patients show an elevated glucosylsphingosine and glucosylated cholesterol. In livers of mice lacking the lysosomal cholesterol efflux transporter NPC1, we investigated the expression of established biomarkers of lipid-laden macrophages of GD patients, their GCase status, and content on the cytosol facing glucosylceramidase GBA2 and lysosomal integral membrane protein type B (LIMP2), a transporter of newly formed GCase to lysosomes. Livers of 80-week-old Npc1^−/− mice showed a partially reduced GCase protein and enzymatic activity. In contrast, GBA2 levels tended to be reciprocally increased with the GCase deficiency. In Npc1^−/− liver, increased expression of lysosomal enzymes (cathepsin D, acid ceramidase) was observed as well as increased markers of lipid-stressed macrophages (GPNMB and galectin-3). Immunohistochemistry showed that the latter markers are expressed by lipid laden Kupffer cells. Earlier reported increase of LIMP2 in Npc1^−/− liver was confirmed. Unexpectedly, immunohistochemistry showed that LIMP2 is particularly overexpressed in the hepatocytes of the Npc1^−/− liver. LIMP2 in these hepatocytes seems not to only localize to (endo)lysosomes. The recent recognition that LIMP2 harbors a cholesterol channel prompts the speculation that LIMP2 in Npc1^−/− hepatocytes might mediate export of cholesterol into the bile and thus protects the hepatocytes.     

Gap Junctional Communication via Connexin43 between Purkinje Fibers and Working Myocytes Explains the Epicardial Activation Pattern in the Postnatal Mouse Left Ventricle

The mammalian ventricular myocardium forms a functional syncytium due to flow of electrical current mediated in part by gap junctions localized within intercalated disks. The connexin (Cx) subunit of gap junctions have direct and indirect roles in conduction of electrical impulse from the cardiac pacemaker via the cardiac conduction system (CCS) to working myocytes. Cx43 is the dominant isoform in these channels. We have studied the distribution of Cx43 junctions between the CCS and working myocytes in a transgenic mouse model, which had the His-Purkinje portion of the CCS labeled with green fluorescence protein. The highest number of such connections was found in a region about one-third of ventricular length above the apex, and it correlated with the peak proportion of Purkinje fibers (PFs) to the ventricular myocardium. At this location, on the septal surface of the left ventricle, the insulated left bundle branch split into the uninsulated network of PFs that continued to the free wall anteriorly and posteriorly. The second peak of PF abundance was present in the ventricular apex. Epicardial activation maps correspondingly placed the site of the first activation in the apical region, while some hearts presented more highly located breakthrough sites. Taken together, these results increase our understanding of the physiological pattern of ventricular activation and its morphological underpinning through detailed CCS anatomy and distribution of its gap junctional coupling to the working myocardium.     

Extracellular Vesicles Tune the Immune System in Renal Disease: A Focus on Systemic Lupus Erythematosus,Antiphospholipid Syndrome,Thrombotic Microangiopathy and ANCA-Vasculitis

Extracellular vesicles (EV) are microparticles released in biological fluids by different cell types, both in physiological and pathological conditions. Owing to their ability to carry and transfer biomolecules, EV are mediators of cell-to-cell communication and are involved in the pathogenesis of several diseases. The ability of EV to modulate the immune system, the coagulation cascade, the angiogenetic process, and to drive endothelial dysfunction plays a crucial role in the pathophysiology of both autoimmune and renal diseases. Recent studies have demonstrated the involvement of EV in the control of renal homeostasis by acting as intercellular signaling molecules, mediators of inflammation and tissue regeneration. Moreover, circulating EV and urinary EV secreted by renal cells have been investigated as potential early biomarkers of renal injury. In the present review, we discuss the recent findings on the involvement of EV in autoimmunity and in renal intercellular communication. We focused on EV-mediated interaction between the immune system and the kidney in autoimmune diseases displaying common renal damage, such as antiphospholipid syndrome, systemic lupus erythematosus, thrombotic microangiopathy, and vasculitis. Although further studies are needed to extend our knowledge on EV in renal pathology, a deeper investigation of the impact of EV in kidney autoimmune diseases may also provide insight into renal biological processes. Furthermore, EV may represent promising biomarkers of renal diseases with potential future applications as diagnostic and therapeutic tools.     

Solvent and oxygen effects on the free radical polymerization of 6-O-vinyladipoyl-d-glucopyranose

The vinyl ester-type glycomonomer 6-O-vinyladipoyl-d-glucopyranose was polymerized in water and alcohol solutions. In all cases, long polymerization times were necessary to achieve reasonable conversions. Depending on the nature of the solvent, polydisperse glycopolymers were obtained possessing a molecular weight ranging between 10,000 and 122,000 Da (PS equivalent). Higher alcohols appeared to act as chain transfer agents and oligomers with DP_n between 2 and 6 were indeed obtained when 2-propanol was the solvent. Also, thorough oxygen removal from the reaction mixture proved to be essential for the success of the experiment, plain nitrogen sparging being ineffective in most cases.     

Dietary fish oils and long-term malaria protection in mice

Previous studies indicate a suppressive influence of fish oils on rodent malaria. The present work was carried out to study (i) the dose-effect relation between dietary fish oils and lethality of primary malaria infection in mice; (iii) the modifying influence of vitamin E; and (iii) the effect of previous fish oil feeding on parasitemia and lethality of a rechallenge infection. For two or four weeks, groups of weanling male mice were fed a standard laboratory diet or one of eight purified diets containing various amounts of fish oil (providing 6–21% of energy). The diets were prepared with and without vitamin E. After the two-or four-week feeding period, the mice were injected intraperitoneally withPlasmodium yoelii yoelii-infected erythrocytes. Six months after the primary infection (four months after discontinuing fish oil feeding), the surviving mice were again injected intraperitoneally with parasitized red blood cells (or even better—erythrocytes, erythrocytes are used elsewhere). Primary malaria infection was lethal in mice fed standard diet alone or with fish oil and vitamin E added. In contrast, feeding a fish oil-based diet without vitamin E improved survival to at least 70% if the mice had been fed these diets for four weeks. Protection against malaria did not seem to be related to the fish oil dose used. Regardless of the previous fish oil dose, all the mice surviving the primary infection survived the rechallenge infection with low parasitaemias. The results suggest that the prooxidant nature of highly unsaturated fatty acids in fish oils may beneficially influence malaria infection, and may also increase the resistance against reinfection for some time after discontinuing fish oil intake.     

Plasma desorption mass spectrometry, an analytical tool in protein engineering: characterization of modified insulins

Californium-252 plasma desorption mass spectrometry (PDMS) hasbeen employed for the characterization of a series of humaninsulin derivatives in order to evaluate the performance ofthis technique as an analytical tool in protein engineering.Several of the characterized modifications result in a 1 a.m.u.mass change. The precision in mass determination obtainableby PDMS analysis is not sufficient for unambiguous verificationof such modifications based on the molecular weight alone. Itis, however, possible to carry out in situ enzymatic digestionof the sample. Subsequent PDMS analysis will in most cases revealif the modification has been introduced as intended.