Q-Curves with Complex Multiplication

The Hecke character of an abelian variety A/F is an isogeny invariant and the Galois action is such that A is isogenous to its Galois conjugate A^σ if and only if the corresponding Hecke character is fixed by σ. The quadratic twist of A by an extension L/F corresponds to multiplication of the associated Hecke characters. This leads us to investigate the Galois groups of families of quadratic extensions L/F with restricted ramification which are normal over a given subfield k of F. Our most detailed results are given for the case where k is the field of rational numbers and F is a field of definition for an elliptic curve with complex multiplication by K. In this case the groups which occur as Gal(L/K) are closely related to the 4-torsion of the class group of K. We analyze the structure of the local unit groups of quadratic fields to find conditions for the existence of curves with good reduction everywhere. After discussing the question of finding models for curves of a given Hecke character, we use twists by 3-torsion points to give an algorithm for constructing models of curves with known Hecke character and good reduction outside 3. The endomorphism algebra of the Weil restriction of an abelian variety A may be determined from the Grössencharacter of A. We describe the computation of these algebras and give examples in which A has dimension 1 or 2 and its Weil restriction has simple abelian subvarieties of dimension ranging between 2 and 24

Alter, Technik und Dienstleistungen: Strategien zur Bewältigung des demografischen Wandels

"Ein heute geborener Junge kann damit rechnen, 74,8 Jahre alt zu werden, ein Mädchen hat rein statistisch sogar die Chance, 80,8 Jahre zu leben (vgl. Statistisches Bundesamt 2003: 17). Diese Entwicklung ist begrüßenswert, zeigt sie doch, dass durch medizinischen Fortschritt und verbesserte Lebensbedingungen die Möglichkeit auf ein langes Leben steigt. Resultierend daraus kommt es aber auch zu einer Veränderung des gesellschaftlichen Bildes von älteren Menschen. Während die zunehmende Alterung der Gesellschaft bisher häufig unter dem Gesichtspunkten ökonomischer Belastungen diskutiert wurde, liegen in ihr durchaus positive Aspekte. So hebt der 5. Altenbericht die Chancen hervor, die mit einer längeren Lebenserwartung und guten Gesundheit älter werdender Menschen für sie selbst, aber auch für Gesellschaft und Wirtschaft verbunden sind. Ein Bereich, dem hier besondere Bedeutung zukommt, ist die Seniorenwirtschaft1. Ihr werden große ökonomische Potenziale vorausgesagt, die bisher bei Weitem noch nicht ausgeschöpft sein sollen. Aus diesem breit gefächerten Spektrum wird in dieser Arbeit der Fokus auf den Bereich des Wohnens gelegt. Dem unmittelbaren Wohnbereich kommt mit zunehmendem Alter eine besondere Bedeutung zu. Während Berufstätige neben ihrer Wohnung häufig den Arbeitsraum, Clubräume und Vereine als sog. Freizeiträume zur Verfügung haben, ist für Senioren2 mit zunehmendem Alter immer mehr die Wohnung ihr zentraler Lebensort (vgl. Lehr 2004: 6). Wohnen Zuhause ist immer noch die bevorzugte Wohnform älterer Menschen (vgl. ebd.), doch mit zunehmendem Alter verändern sich die Ansprüche an das Wohnen und die Erfordernisse der räumlichen Gestaltung des Wohnbereiches (vgl. Backes/Clemens 1998: 209)." (Textauszug

Monocyte phenotypes: when local education counts

Monocytes are a heterogeneous population of phagocytic cells that are generated in the bone marrow and released into the bloodstream. There are two main monocyte subsets in mice: “inflammatory” monocytes that are Ly6Chi CCR2hi CX3 CR1low and “alternative” or “patrolling” monocytes that are Ly6Clow CCR2low CX3 CR1hi. The process of monocyte recruitment and differentiation is still a matter of controversy. In this issue, Dal-Secco et al. report in situ monocyte reprogramming in the liver, from proinflammatory CCR2hi CX3 CR1low cells into reparative CCR2low CX3 CR1hi cells and show, for the first time, that this occurs at the site of injury.Fil: Quintar, Amado Alfredo. la Jolla Institute For Allergy And Immunology; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hedrick, Catherine C. . la Jolla Institute For Allergy And Immunology; Estados UnidosFil: Ley, Klaus. la Jolla Institute For Allergy And Immunology; Estados Unido

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice.

Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes 1 . Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL2-4. Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr-/- background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling. Compared to Ldlr-/- mice, Ldlr -/- E06-scFv mice had 57-28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo. These studies suggest that therapies inactivating OxPL may be beneficial for reducing generalized inflammation, including the progression of atherosclerosis, aortic stenosis and hepatic steatosis

Neuroinflammation Plays a Critical Role in Cerebral Cavernous Malformation Disease

BackgroundCerebral cavernous malformations (CCMs) are neurovascular lesions caused by loss of function mutations in 1 of 3 genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3). CCMs affect ≈1 out of 200 children and adults, and no pharmacologic therapy is available. CCM lesion count, size, and aggressiveness vary widely among patients of similar ages with the same mutation or even within members of the same family. However, what determines the transition from quiescent lesions into mature and active (aggressive) CCM lesions is unknown.MethodsWe use genetic, RNA-sequencing, histology, flow cytometry, and imaging techniques to report the interaction between CCM endothelium, astrocytes, leukocytes, microglia/macrophages, neutrophils (CCM endothelium, astrocytes, leukocytes, microglia/macrophages, neutrophils interaction) during the pathogenesis of CCMs in the brain tissue.ResultsExpression profile of astrocytes in adult mouse brains using translated mRNAs obtained from the purification of EGFP (enhanced green fluorescent protein)-tagged ribosomes (Aldh1l1-EGFP/Rpl10a) in the presence or absence of CCM lesions (Slco1c1-iCreERT2;Pdcd10fl/fl; Pdcd10BECKO) identifies a novel gene signature for neuroinflammatory astrocytes. CCM-induced reactive astrocytes have a neuroinflammatory capacity by expressing genes involved in angiogenesis, chemotaxis, hypoxia signaling, and inflammation. RNA-sequencing analysis on RNA isolated from brain endothelial cells in chronic Pdcd10BECKO mice (CCM endothelium), identified crucial genes involved in recruiting inflammatory cells and thrombus formation through chemotaxis and coagulation pathways. In addition, CCM endothelium was associated with increased expression of Nlrp3 and Il1b. Pharmacological inhibition of NLRP3 (NOD [nucleotide-binding oligomerization domain]-' LRR [leucine-rich repeat]- and pyrin domain-containing protein 3) significantly decreased inflammasome activity as assessed by quantification of a fluorescent indicator of caspase-1 activity (FAM-FLICA [carboxyfluorescein-fluorochrome-labeled inhibitors of caspases] caspase-1) in brain endothelial cells from Pdcd10BECKO in chronic stage. Importantly, our results support the hypothesis of the crosstalk between astrocytes and CCM endothelium that can trigger recruitment of inflammatory cells arising from brain parenchyma (microglia) and the peripheral immune system (leukocytes) into mature active CCM lesions that propagate lesion growth, immunothrombosis, and bleedings. Unexpectedly, partial or total loss of brain endothelial NF-κB (nuclear factor κB) activity (using Ikkbfl/fl mice) in chronic Pdcd10BECKO mice does not prevent lesion genesis or neuroinflammation. Instead, this resulted in a trend increase in the number of lesions and immunothrombosis, suggesting that therapeutic approaches designed to target inflammation through endothelial NF-κB inhibition may contribute to detrimental side effects.ConclusionsOur study reveals previously unknown links between neuroinflammatory astrocytes and inflamed CCM endothelium as contributors that trigger leukocyte recruitment and precipitate immunothrombosis in CCM lesions. However, therapeutic approaches targeting brain endothelial NF-κB activity may contribute to detrimental side effects

Next-generation sequencing identifies the natural killer cell microRNA transcriptome

Natural killer (NK) cells are innate lymphocytes important for early host defense against infectious pathogens and surveillance against malignant transformation. Resting murine NK cells regulate the translation of effector molecule mRNAs (e.g., granzyme B, GzmB) through unclear molecular mechanisms. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate the translation of their mRNA targets, and are therefore candidates for mediating this control process. While the expression and importance of miRNAs in T and B lymphocytes have been established, little is known about miRNAs in NK cells. Here, we used two next-generation sequencing (NGS) platforms to define the miRNA transcriptomes of resting and cytokine-activated primary murine NK cells, with confirmation by quantitative real-time PCR (qRT-PCR) and microarrays. We delineate a bioinformatics analysis pipeline that identified 302 known and 21 novel mature miRNAs from sequences obtained from NK cell small RNA libraries. These miRNAs are expressed over a broad range and exhibit isomiR complexity, and a subset is differentially expressed following cytokine activation. Using these miRNA NGS data, miR-223 was identified as a mature miRNA present in resting NK cells with decreased expression following cytokine activation. Furthermore, we demonstrate that miR-223 specifically targets the 3′ untranslated region of murine GzmB in vitro, indicating that this miRNA may contribute to control of GzmB translation in resting NK cells. Thus, the sequenced NK cell miRNA transcriptome provides a valuable framework for further elucidation of miRNA expression and function in NK cell biology

Adverse Cerebral Outcomes after Coronary Bypass Surgery

ABSTRACT Background Acute changes in cerebral function after elective coronary bypass surgery are a difficult clinical problem. We carried out a multicenter study to determine the incidence and predictors of — and the use of resources associated with — perioperative adverse neurologic events, including cerebral injury. Methods In a prospective study, we evaluated 2108 patients from 24 U.S. institutions for two general categories of neurologic outcome: type I (focal injury, or stupor or coma at discharge) and type II (deterioration in intellectual function, memory deficit, or seizures). Results Adverse cerebral outcomes occurred in 129 patients (6.1 percent). A total of 3.1 percent had type I neurologic outcomes (8 died of cerebral injury, 55 had nonfatal strokes, 2 had transient ischemic attacks, and 1 had stupor), and 3.0 percent had type II outcomes (55 had deterioration of intellectual function and 8 had seizures). Patients with adverse cerebral outcomes had higher in-hospital mortality (21 percent of patients with type I outcomes died, vs. 10 percent of those with type II and 2 percent of those with no adverse cerebral outcome; P0.001 for all comparisons), longer hospitalization (25 days with type I outcomes, 21 days with type II, and 10 days with no adverse outcome; P0.001), and a higher rate of discharge to facilities for intermediate- or long-term care (47 percent, 30 percent, and 8 percent; P0.001). Predictors of type I outcomes were proximal aortic atherosclerosis, a history of neurologic disease, and older age; predictors of type II outcomes were older age, systolic hypertension on admission, pulmonary disease, and excessive consumption of alcohol. Conclusions Adverse cerebral outcomes after coronary bypass surgery are relatively common and serious; they are associated with substantial increases in mortality, length of hospitalization, and use of intermediate- or long-term care facilities. New diagnostic and therapeutic strategies must be developed to lessen such injury. (N Engl J Med 1996;335:1857-63.)

Evolution of Symbiotic Bacteria in the Distal Human Intestine

The adult human intestine contains trillions of bacteria, representing hundreds of species and thousands of subspecies. Little is known about the selective pressures that have shaped and are shaping this community's component species, which are dominated by members of the Bacteroidetes and Firmicutes divisions. To examine how the intestinal environment affects microbial genome evolution, we have sequenced the genomes of two members of the normal distal human gut microbiota, Bacteroides vulgatus and Bacteroides distasonis, and by comparison with the few other sequenced gut and non-gut Bacteroidetes, analyzed their niche and habitat adaptations. The results show that lateral gene transfer, mobile elements, and gene amplification have played important roles in affecting the ability of gut-dwelling Bacteroidetes to vary their cell surface, sense their environment, and harvest nutrient resources present in the distal intestine. Our findings show that these processes have been a driving force in the adaptation of Bacteroidetes to the distal gut environment, and emphasize the importance of considering the evolution of humans from an additional perspective, namely the evolution of our microbiomes

Health care costs, utilization and patterns of care following Lyme disease

BACKGROUND:Lyme disease is the most frequently reported vector borne infection in the United States. The Centers for Disease Control have estimated that approximately 10% to 20% of individuals may experience Post-Treatment Lyme Disease Syndrome - a set of symptoms including fatigue, musculoskeletal pain, and neurocognitive complaints that persist after initial antibiotic treatment of Lyme disease. Little is known about the impact of Lyme disease or post-treatment Lyme disease symptoms (PTLDS) on health care costs and utilization in the United States. OBJECTIVES:1) to examine the impact of Lyme disease on health care costs and utilization, 2) to understand the relationship between Lyme disease and the probability of developing PTLDS, 3) to understand how PTLDS may impact health care costs and utilization. METHODS:This study utilizes retrospective data on medical claims and member enrollment for persons aged 0-64 years who were enrolled in commercial health insurance plans in the United States between 2006-2010. 52,795 individuals treated for Lyme disease were compared to 263,975 matched controls with no evidence of Lyme disease exposure. RESULTS:Lyme disease is associated with $2,968 higher total health care costs (95$3,798 higher total health care costs (95% CI: 3,542-4,055, p<.001) and 66% more outpatient visits (95% CI: 64%-69%, p<.001) over a 12-month period, relative to those with no PTLDS-related diagnoses. CONCLUSIONS:Lyme disease is associated with increased costs above what would be expected for an easy to treat infection. The presence of PTLDS-related diagnoses after treatment is associated with significant health care costs and utilization