Minimal-dimensional representations of reduced enveloping algebras for gln_n

Let g=gl$_N$(k), where k is an algebraically closed field of characteristic p>0, and N∈Z$_{⩾1}$. Let χ∈g∗ and denote by Uχ(g) the corresponding reduced enveloping algebra. The Kac–Weisfeiler conjecture, which was proved by Premet, asserts that any finite-dimensional Uχ(g) -module has dimension divisible by p$^d$χ , where dχ is half the dimension of the coadjoint orbit of χ . Our main theorem gives a classification of Uχ(g) -modules of dimension p$^d$χ. As a consequence, we deduce that they are all parabolically induced from a one-dimensional module for U$_0$(h) for a certain Levi subalgebra h of g ; we view this as a modular analogue of Mœglin’s theorem on completely primitive ideals in U(gl$_N$(C)) . To obtain these results, we reduce to the case where χ is nilpotent, and then classify the one-dimensional modules for the corresponding restricted W -algebra

Modular finite <i>W</i>-algebras

Abstract Let ${\mathbb{k}}$ be an algebraically closed field of characteristic p &gt; 0 and let G be a connected reductive algebraic group over ${\mathbb{k}}$. Under some standard hypothesis on G, we give a direct approach to the finite W-algebra $U(\mathfrak{g},e)$ associated to a nilpotent element $e \in \mathfrak{g} = \textrm{Lie}\ G$. We prove a PBW theorem and deduce a number of consequences, then move on to define and study the p-centre of $U(\mathfrak{g},e)$, which allows us to define reduced finite W-algebras $U_{\eta}(\mathfrak{g},e)$ and we verify that they coincide with those previously appearing in the work of Premet. Finally, we prove a modular version of Skryabin’s equivalence of categories, generalizing recent work of the second author.</jats:p

miR-21 Promotes Fibrogenesis in Peritoneal Dialysis.

Peritoneal dialysis (PD) is a life-saving form of renal replacement therapy for those with end-stage kidney disease. Mesothelial cells (MCs) line the peritoneal cavity and help define peritoneal response to treatment-associated injury, a major reason for treatment failure. miRNAs are important regulators, but their roles in peritoneal fibrosis are largely unknown. In this study, miR-21 was one of the most abundant miRNAs in primary MCs, and was up-regulated by the profibrotic cytokine transforming growth factor-β1 and in PD effluent-derived MCs exhibiting mesenchymal phenotypic change. Increased miR-21 was found in peritoneal membrane biopsy specimens from PD patients compared to healthy controls (PD biocompatible, 5.86×, P = 0.0001; PD conventional, 7.09×, P < 0.0001, n = 11 per group). In PD effluent from a cohort of 230 patients, miR-21 was higher in those receiving the therapy long-term compared to new starters (n = 230, miR-21 3.26×, P = 0.001) and associated with icodextrin use (R = 0.52; 95% CI, 0.20-0.84), peritonitis count (R = 0.16; 95% CI, 0.03-0.29), and dialysate cytokines. miR-21 down-regulated programmed cell death 4 and programmed cell death 4 protein was decreased in peritoneal membrane biopsy specimens from PD patients compared to healthy controls. New miR-21 targets were identified that may be important during PD fibrogenesis. These data identify miR-21 as an important effector of fibrosis in the peritoneal membrane, and a promising biomarker in the dialysis effluent for membrane change in patients receiving PD

Interferon-γ inhibits interleukin-1β-induced matrix metalloproteinase production by synovial fibroblasts and protects articular cartilage in early arthritis

Introduction: The first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA). We used relevant experimental models to define the pathological role of interferon-γ (IFN-γ) during early inflammatory arthritis. Methods: We studied IFN-γ's capacity to modulate interleukin-1β (IL-1β) induced degenerative responses using RA fibroblast-like synoviocytes (FLS), a bovine articular cartilage explant (BACE)/RA-FLS co-culture model and an experimental inflammatory arthritis model (murine antigen-induced arthritis (AIA)). Results: IFN-γ modulated IL-1β driven matrix metalloproteinases (MMP) synthesis resulting in the down-regulation of MMP-1 and MMP-3 production in vitro. IFN-γ did not affect IL-1β induced tissue inhibitor of metalloproteinase-1 (TIMP-1) production by RA FLS but skewed the MMP/TIMP-1 balance sufficiently to attenuate glycosaminoglycan-depletion in our BACE model. IFN-γ reduced IL-1β expression in the arthritic joint and prevented cartilage degeneration on Day 3 of AIA. Conclusions: Early therapeutic intervention with IFN-γ may be critical to orchestrate tissue-protective responses during inflammatory arthritis

Longitudinal evaluation of peritoneal macrophage function and activation during CAPD: Maturity, cytokine synthesis and arachidonic acid metabolism

Longitudinal evaluation of peritoneal macrophage function and activation during CAPD: Maturity, cytokine synthesis and arachidonic acid metabolism. The release of cytokines and prostaglandins (PG) by peritoneal macrophages (PMØ) may influence the cytokine network controlling peritoneal inflammation and in the long-term the function of the peritoneum as a dialysis membrane. In the present study, an evaluation of the long-term effects of peritoneal dialysis on the release of cytokines and prostaglandins, and the expression of surface markers of cellular maturation on blood and mononuclear cells has been performed in patients during their first year on CAPD. Spontaneous release of tumour necrosis factor α (TNFα) and interleukin 6 (IL-6) by PMØ, after 4 or 24 hours in culture, increased significantly with time on CAPD, while there was a small but significant decrease in release of prostaglandin E2 (PGE2). Production of TNFα and IL-6 was enhanced following incubation of the cells with lipopolysaccharide (LPS), but the effect of LPS was proportionally greater on blood monocytes than on PMØ. There was a significant increase in the concentrations of PGE2 and 6-keto-prostaglandin F1α in overnight dwell peritoneal dialysis effluent with time on CAPD. The levels of TNFα and IL-6 in uninfected PDE were below the detection limit of the immunoassay over the whole time period studied. Expression of CD15, which correlates with immaturity, by PMØ and blood monocytes increased with time on CAPD, while expression of CD11c, a marker of maturation, decreased on blood monocytes, but did not change significantly on PMØ. There was also a slight increase in expression of transferrin receptor in both PMØ and monocytes, but this did not reach statistical significance. These findings suggest that peritoneal macrophages and blood monocytes isolated from CAPD patients over a one year period become increasingly immature with time, and this is accompanied by a significant modulation of their ability to secrete inflammatory cytokines. Dysregulation of macrophage function may have important consequences with respect to inflammatory processes and the long-term function of the peritoneal membrane in CAPD patients

Type-1 fimbriate escherichia-coli stimulates a unique pattern of de-granulation by human polymorphonuclear leukocytes

Uropathogenic strains of Escherichia coli bearing mannose-sensitive (type 1) fimbriae promote a unique pattern of degranulation from human polymorphonuclear leukocytes (PMN). Significant quantities of the primary (1 degree) and tertiary (3 degree) granule markers, neutral protease-myeloperoxidase and N-acetyl-beta-D-glucosaminidase, respectively, were released by PMN in a dose- and time-dependent manner when stimulated by these defined bacterial strains. Organisms bearing mannose-resistant (P) fimbriae promoted release of only the secondary (2 degree) granule marker, vitamin B12-binding protein. When this pattern of degranulation was compared to that produced by PMN in response to a variety of soluble and particulate stimuli, only the calcium ionophore A23187 similarly triggered 1 degree and 3 degree granule marker release. All the other stimuli tested--zymosan, serum-treated and unopsonized; n-formylmethionyl-leucyl-phenylalanine; and phorbol myristate acetate--promoted release of only the 2 degree granule marker. These results demonstrate selectivity of PMN degranulation in response to a number of transmembrane signals. In addition, the capacity of E. coli to promote PMN degranulation is dependent on its phenotypic fimbrial expression, a surface characteristic which correlates significantly with its relative surface hydrophobicity as measured by binding to octyl Sepharose. Those bacteria demonstrating the greatest hydrophobicity were capable of triggering discharge of all three granule marker proteins. Thus, the mannose-sensitive fimbriae of uropathogenic E. coli may contribute significantly to their potential pathophysiologic role in renal scarring

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber

Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation

Mutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are very limited. Most mtDNA diseases show heteroplasmy – tissues express both wild-type and mutant mtDNA. While the level of heteroplasmy broadly correlates with disease severity, the relationships between specific mtDNA mutations, heteroplasmy, disease phenotype and severity are poorly understood. We have carried out extensive bioenergetic, metabolomic and RNAseq studies on heteroplasmic patient-derived cells carrying the most prevalent disease related mtDNA mutation, the m.3243 A &gt; G. These studies reveal that the mutation promotes changes in metabolites which are associated with the upregulation of the PI3K-Akt-mTORC1 axis in patient-derived cells and tissues. Remarkably, pharmacological inhibition of PI3K, Akt, or mTORC1 reduced mtDNA mutant load and partially rescued cellular bioenergetic function. The PI3K-Akt-mTORC1 axis thus represents a potential therapeutic target that may benefit people suffering from the consequences of the m.3243 A &gt; G mutation