Changes in lymphocyte subsets, interleukin 2, and soluble interleukin 2 receptor in old and very old age

In this study, the changes in some of the cellular components of the immune system and the activity of the cytokine interleukin 2, important for immune activation and lymphocyte proliferation, were measured in a large cross-sectional study of all age groups including octogenarian and nonagenarian subjects. In 206 apparently well community-living subjects, the absolute lymphocyte count and T and B cell numbers fell a little in old and very old subjects. Within the T cell compartment, helper/inducer CD4+ T cells, together with their subsets identified as 'naive' (CD4+/CD45RA+) and 'memory' (CD4+/CD45RO+) cells, also showed a decline with increased age. The suppressor/cytotoxic CD8+ subset showed no age-related change. The levels of the cytokine interleukin 2 were very low in octogenarian and nonagenarian subjects, while the soluble interleukin 2 receptor levels increased with increasing age. The interleukin 2 levels were associated with number and percentage of the 'memory' (CD4+/CD45RO+) subset of T cells which mediates the host response to previously met antigens. Since the interleukin 2 values were very low in the oldest groups and were associated with a reduced 'memory' (CD4+/CD45RO+) compartment, this suggests a possible mechanism of why the very elderly subject is more susceptible to morbidity and mortality from infectious or other agents.

Immunophenotypic shift in a case of mycosis fungoides with vitreous invasion

The case of an 82-year-old man who developed intraocular extension from mycosis fungoides, a cutaneous T-cell lymphoma, is presented. The patient died soon after intra-ocular involvement occurred. Immunohistochemistry of a skin biopsy, taken early in the course of the disease, disclosed a predominance of T cells with a helper/inducer phenotype (CD4). However, an intraocular infiltrate obtained 7 years later contained mostly T cells with a suppressor/cytotoxic phenotype (CD8). The occurrence of ocular invasion, the change in immunophenotype, and the predominant proliferation of CD8 lymphocytes may have been related to the poor outcome in this patient.

An Investigation of Compressor Map Width Enhancement and a Detailed Analysis of Inducer Flow Field

This paper describes an investigation of various shroud bleed slot configurations of a centrifugal compressor using CFD with a manual multi-block structured grid generation method. The compressor under investigation is used in a turbocharger application for a heavy duty diesel engine of approximately 400 hp. The baseline numerical model has been developed and validated against experimental performance measurements. The influence of the bleed slot flow field on a range of operating conditions between surge and choke has been analysed in detail.
The impact of the returning bleed flow on the incidence at the impeller blade leading edge due to its mixing with the main through-flow has also been studied. From the baseline geometry, a number of modifications to the bleed slot width have been proposed, and a detailed comparison of the flow characteristics performed. The impact of slot variations on the inlet incidence angle has been investigated, highlighting the improvement in surge and choked flow capability. Along with this, the influence of the bleed slot on stabilising the blade passage flow by the suction of the tip and over-tip vortex flow by the slot has been considered near surge.

SOCS2 regulates T helper type 2 differentiation and the generation of type 2 allergic responses

The incidence of allergy and asthma in developed countries is on the increase and this trend looks likely to continue. CD4(+) T helper 2 (Th2) cells are major drivers of these diseases and their commitment is controlled by cytokines such as interleukin 4, which are in turn regulated by the suppressor of cytokine signaling (SOCS) proteins. We report that SOCS2(-/-) CD4(+) T cells show markedly enhanced Th2 differentiation. SOCS2(-/-) mice, as well as RAG1(-/-) mice transferred with SOCS2(-/-) CD4(+) T cells, exhibit elevated type 2 responses after helminth antigen challenge. Moreover, in in vivo models of atopic dermatitis and allergen-induced airway inflammation, SOCS2(-/-) mice show significantly elevated IgE, eosinophilia, type 2 responses, and inflammatory pathology relative to wild-type mice. Finally, after T cell activation, markedly enhanced STAT6 and STAT5 phosphorylation is observed in SOCS2(-/-) T cells, whereas STAT3 phosphorylation is blunted. Thus, we provide the first evidence that SOCS2 plays an important role in regulating Th2 cell expansion and development of the type 2 allergic responses.

An Impact Of Various Shroud Bleed Slot Configurations And Cavity Vanes On Compressor Map Width And The Inducer Flow Field

This paper describes an investigation of map width enhancement and a detailed analysis of the inducer flow field due to various bleed slot configurations and vanes in the annular cavity of a turbocharger centrifugal compressor. The compressor under investigation is used in a turbocharger application for a heavy duty diesel engine of approximately 400 hp. This investigation has been undertaken using a computational fluid dynamics (CFD) model of the full compressor stage, which includes a manual multiblock-structured grid generation method. The influence of the bleed slot flow on the inducer flow field at a range of operating conditions has been analyzed, highlighting the improvement in surge and choked flow capability. The impact of the bleed slot geometry variations and the inclusion of cavity vanes on the inlet incidence angle have been studied in detail by considering the swirl component introduced at the leading edge by the recirculating flow through the slot. Further, the overall stage efficiency and the nonuniform flow field at the inducer inlet have been also analyzed. The analysis revealed that increasing the slot width has increased the map width by about 17%. However, it has a small impact on the efficiency, due to the frictional and mixing losses. Moreover, adding vanes in the cavity improved the pressure ratio and compressor performance noticeably. A detail analysis of the compressor with cavity vanes has also been presented.

In Helicobacter pylori auto-inducer-2, but not LuxS/MccAB catalysed reverse transsulphuration, regulates motility through modulation of flagellar gene transcription

BACKGROUND: LuxS may function as a metabolic enzyme or as the synthase of a quorum sensing signalling molecule, auto-inducer-2 (AI-2); hence, the mechanism underlying phenotypic changes upon luxS inactivation is not always clear. In Helicobacter pylori, we have recently shown that, rather than functioning in recycling methionine as in most bacteria, LuxS (along with newly-characterised MccA and MccB), synthesises cysteine via reverse transsulphuration. In this study, we investigated whether and how LuxS controls motility of H. pylori, specifically if it has its effects via luxS-required cysteine metabolism or via AI-2 synthesis only.

RESULTS: We report that disruption of luxS renders H. pylori non-motile in soft agar and by microscopy, whereas disruption of mccAHp or mccBHp (other genes in the cysteine provision pathway) does not, implying that the lost phenotype is not due to disrupted cysteine provision. The motility defect of the DeltaluxSHp mutant was complemented genetically by luxSHp and also by addition of in vitro synthesised AI-2 or 4, 5-dihydroxy-2, 3-pentanedione (DPD, the precursor of AI-2). In contrast, exogenously added cysteine could not restore motility to the DeltaluxSHp mutant, confirming that AI-2 synthesis, but not the metabolic effect of LuxS was important. Microscopy showed reduced number and length of flagella in the DeltaluxSHp mutant. Immunoblotting identified decreased levels of FlaA and FlgE but not FlaB in the DeltaluxSHp mutant, and RT-PCR showed that the expression of flaA, flgE, motA, motB, flhA and fliI but not flaB was reduced. Addition of DPD but not cysteine to the DeltaluxSHp mutant restored flagellar gene transcription, and the number and length of flagella.

CONCLUSIONS: Our data show that as well as being a metabolic enzyme, H. pylori LuxS has an alternative role in regulation of motility by modulating flagellar transcripts and flagellar biosynthesis through production of the signalling molecule AI-2.

An Investigation of Compressor Map Width Enhancement and the Inducer Flow Field Using Various Configurations of Shroud Bleed Slot

This paper describes an investigation of various shroud bleed slot configurations of a centrifugal compressor using CFD with a manual multi-block structured grid generation method. The compressor under investigation is used in a turbocharger application for a heavy duty diesel engine of approximately 400hp. The baseline numerical model has been developed and validated against experimental performance measurements. The influence of the bleed slot flow field on a range of operating conditions between surge and choke has been analysed in detail. The impact of the returning bleed flow on the incidence at the impeller blade leading edge due to its mixing with the main through-flow has also been studied. From the baseline geometry, a number of modifications to the bleed slot width have been proposed, and a detailed comparison of the flow characteristics performed. The impact of slot variations on the inlet incidence angle has been investigated, highlighting the improvement in surge and choked flow capability. Along with this, the influence of the bleed slot on stabilizing the blade passage flow by the suction of the tip and over-tip vortex flow by the slot has been considered near surge.

SOCS3 regulates onset and maintenance of TH2- mediated allergic responses

Members of the suppressor of cytokine signaling (SOCS) family are involved in the pathogenesis of many inflammatory diseases. SOCS-3 is predominantly expressed in T-helper type 2 (TH2) cells, but its role in TH2-related allergic diseases remains to be investigated. In this study we provide a strong correlation between SOCS-3 expression and the pathology of asthma and atopic dermatitis, as well as serum IgE levels in allergic human patients. SOCS-3 transgenic mice showed increased TH2 responses and multiple pathological features characteristic of asthma in an airway hypersensitivity model system. In contrast, dominant-negative mutant SOCS-3 transgenic mice, as well as mice with a heterozygous deletion of Socs3, had decreased TH2 development. These data indicate that SOCS-3 has an important role in regulating the onset and maintenance of TH2-mediated allergic immune disease, and suggest that SOCS-3 may be a new therapeutic target for the development of antiallergic drugs.

A role of cellular prion protein in programming T-cell cytokine responses in disease.

The cellular prion protein (PrPC) is widely expressed in neural and non-neural tissues, but its function is unknown. Elucidation of the part played by PrPC in adaptive immunity has been a particular conundrum: increased expression of cell surface PrPC has been documented during T-cell activation, yet the functional significance of this activation remains unclear, with conflicting data on the effects of Prnp gene knockout on various parameters of T-cell immunity. We show here that Prnp mRNA is highly inducible within 8–24 h of T-cell activation, with surface protein levels rising from 24 h. When measured in parallel with CD69 and CD25, PrPC is a late activation antigen. Consistent with its up-regulation being a late activation event, PrP deletion did not alter T-cell-antigen presenting cell conjugate formation. Most important, activated PrP0/0 T cells demonstrated much reduced induction of several T helper (Th) 1, Th2, and Th17 cytokines, whereas others, such as TNF- and IL-9, were unaffected. These changes were investigated in the context of an autoimmune model and a bacterial challenge model. In experimental autoimmune encephalomyelitis, PrP-knockout mice showed enhanced disease in the face of reduced IL-17 responses. In a streptococcal sepsis model, this constrained cytokine program was associated with poorer local control of infection, although with reduced bacteremia. The findings indicate that PrPC is a potentially important molecule influencing T-cell activation and effector function.

Insulin-stimulated protein kinase B phosphorylation on Ser-473 is independent of its activity and occurs through a staurosporine-insensitive kinase

Full activation of protein kinase B (PKB, also called Akt) requires phosphorylation on two regulatory sites, Thr-308 in the activation loop and Ser-473 in the hydrophobic C-terminal regulatory domain (numbering for PKB alpha /Akt-1), Although 3 ' -phosphoinositide-dependent protein kinase 1 (PDK1) has now been identified as the Thr-308 kinase, the mechanism of the Ser-473 phosphorylation remains controversial. As a step to further characterize the Ser-473 kinase, we examined the effects of a range of protein kinase inhibitors on the activation and phosphorylation of PKB. We found that staurosporine, a broad-specificity kinase inhibitor and inducer of cell apoptosis, attenuated PKB activation exclusively through the inhibition of Thr-308 phosphorylation, with Ser-473 phosphorylation unaffected. The increase in Thr-308 phosphorylation because of overexpression of PDK1 was also inhibited by staurosporine, We further show that staurosporine (CGP 39360) potently inhibited PDK1 activity in vitro with an IC50 of similar to0.22 muM. These data indicate that agonist-induced phosphorylation of Ser-473 of PKB is independent of PDK1 or PKB activity and occurs through a distinct Ser-473 kinase that is not inhibited by staurosporine, Moreover, our results suggest that inhibition of PKB signaling is involved in the proapoptotic action of staurosporine.

‘Doing it with men’: feminist research practice and patriarchal inheritance practices in Welsh family farming

Internationally, the gender relations of the family farming ‘way of life’ have beenshown to be stubbornly persistent in their adherence to patriarchal inheritancepractices. This article demonstrates how such ‘agri-cultural’ practices are situated bothwithin the subjective sphere of farming individuals’ and within global agri-economics,bringing new challenges to patrilineal farm survival. It is suggested here that the recenttendency for post-structuralist theorisation in rural studies has underestimated theexistence and impact of patrilineal patterns in family farming. Such patterns mean thatwomen are shown to largely occupy relational gender identities as the ‘helper’, whilstmen are strongly identified as the ‘farmer’. Drawing on repeated life-history interviewsconducted with farming men and women from Powys, Mid Wales, the aim of thisarticle is to generate debate as to the extent to which men can be brought into feministresearch practice in order to reveal patriarchy to a greater degree. The article begins bysituating the near-exclusion of men from feminist research practice within theoreticaldevelopments in feminist geography. This discussion also assists in deriving issues ofresearch methods, positionality and interpretive power which focus the integration ofempirical material in the methodological reflections provided in section three. In sectiontwo, the rationale for the epistemological stance taken in the research is provided. Thearticle provides an example of the successful integration of men into a feminist researchframe, suggests avenues for theoretical development and identifies future researchdirections which can be informed by ‘doing it with men’.

Keywords: epistemology; family farming; feminist res

RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization

Loss of RUNX3 expression is suggested to be causally related to gastric cancer as 45% to 60% of gastric cancers do not express RUNX3 mainly due to hypermethylation of the RUNX3 promoter. Here, we examined for other defects in the properties of RUNX3 in gastric cancers that express RUNX3. Ninety-seven gastric cancer tumor specimens and 21 gastric cancer cell lines were examined by immunohistochemistry using novel anti-RUNX3 monoclonal antibodies. In normal gastric mucosa, RUNX3 was expressed most strongly in the nuclei of chief cells as well as in surface epithelial cells. In chief cells, a significant portion of the protein was also found in the cytoplasm. RUNX3 was not detectable in 43 of 97 (44%) cases of gastric cancers tested and a further 38% showed exclusive cytoplasmic localization, whereas only 18% showed nuclear localization. Evidence is presented suggesting that transforming growth factor-beta is an inducer of nuclear translocation of RUNX3, and RUNX3 in the cytoplasm of cancer cells is inactive as a tumor suppressor. RUNX3 was found to be inactive in 82% of gastric cancers through either gene silencing or protein mislocalization to the cytoplasm. In addition to the deregulation of mechanisms controlling gene expression, there would also seem to be at least one other mechanism controlling nuclear translocation of RUNX3 that is impaired frequently in gastric cancer.