Counter-Regulation of Interleukin-1α (IL-1α) and IL-1 Receptor Antagonist in Murine Keratinocytes

Interleukin-1α (IL-1α) is a potent proinflammatory cytokine constitutively expressed by keratinocytes, which also synthesize a specific inhibitor of IL-1 activity, intracellular IL-1 receptor antagonist (IL-1ra). Although homeostatic regulation of the IL-1 system in keratinocytes has long been suspected, there is currently little evidence for this. To explore this issue, the PAM212 murine keratinocyte cell line was exposed to increasing concentrations of either IL-1α or IL-1ra and the opposing ligand was assessed by ELISA. Release of IL-1ra was induced following stimulation by murine IL-1α in a concentration-dependent manner and, conversely, IL-1ra stimulation increased IL-1α release. To determine whether a similar homeostatic circuit operates in vivo, epidermis from transgenic mice in which overexpression of IL-1α or IL-1ra was targeted to keratinocytes was analyzed. Epidermal sheets derived from IL-1α transgenic mice released eight times more IL-1ra than those from wild-type mice following ex vivo culture and similarly, IL-1α release was increased 3–4-fold in epidermal sheets derived from IL-1ra transgenic epidermis, Use of specific neutralizing antibodies against type I and type II IL-1 receptors indicated that the counter-regulation mechanism is mediated extracellularly through the type I IL-1 receptor alone. Taken together, these observations provide the first demonstration of mutual counter-regulation of IL-1 receptor ligands in keratinocytes

Integrin Expression by Human Epidermal Keratinocytes Can Be Modulated by Interferon-γ, Transforming Growth Factor-β, Tumor Necrosis Factor-α, and Culture on a Dermal Equivalent

Receptors of the integrin family are largely confined to the basal layer of keratinocytes, both in human epidermis and in stratified cultures of human keratinocytes. However, suprabasal integrin expression is observed during epidermal wound healing and in psoriatic lesions. We have investigated potential stimuli of suprabasal expression. Addition of transforming growth factor-β (TGF-β), interferon-γ (IFN-γ or tumor necrosis factor-α (TNF-α) to keratinocytes cultured with a 3T3 feeder layer did not induce suprabasal expression. The cytokines caused small changes in the levels of α2β1 or α3β1 on the surface of basal keratinocytes but had no significant effect on the proportion of cells adhering to fibronectin, type IV collagen, and laminin, and did not cause changes in the mobility of integrin subunits on polyacrylamide gels. Injection of TNF-α or IFN-γ intradermally into healthy human volunteers induced an inflammatory response but did not induce suprabasal integrin expression. However, we did observe transient suprabasal Integrin expression when keratinocytes were grown on a dermal equivalent consisting of fibroblasts in a collagen gel. One week after raising the cultures to the air-liquid interface, β1 integrins were found in all the viable cell layers, with suprabasal cells co-expressing integrins and involucrin; 1 week later integrins were confined to the basal layer. Addition of TGF-β, IFN-γ, or TNF-α to the dermal equivalents neither induced nor inhibited suprabasal integrin expression. We conclude that suprabasal integrin expression is not induced by the inflammatory cytokines tested, and instead may reflect the proliferation/differentiation status of the epidermis

The prosequence of procaricain forms an α-helical domain that prevents access to the substrate-binding cleft

AbstractBackground Cysteine proteases are involved in a variety of cellular processes including cartilage degradation in arthritis, the progression of Alzheimer's disease and cancer invasion: these enzymes are therefore of immense biological importance. Caricain is the most basic of the cysteine proteases found in the latex of Carica papaya. It is a member of the papain superfamily and is homologous to other plant and animal cysteine proteases. Caricain is naturally expressed as an inactive zymogen called procaricain. The inactive form of the protease contains an inhibitory proregion which consists of an additional 106 N-terminal amino acids; the proregion is removed upon activation.Results The crystal structure of procaricain has been refined to 3.2 å resolution; the final model consists of three non-crystallographically related molecules. The proregion of caricain forms a separate globular domain which binds to the C-terminal domain of mature caricain. The proregion also contains an extended polypeptide chain which runs through the substrate-binding cleft, in the opposite direction to that of the substrate, and connects to the N terminus of the mature region. The mature region does not undergo any conformational change on activation.Conclusions We conclude that the rate-limiting step in the in vitro activation of procaricain is the dissociation of the prodomain, which is then followed by proteolytic cleavage of the extended polypeptide chain of the proregion. The prodomain provides a stable scaffold which may facilitate the folding of the C-terminal lobe of procaricain

The multidimensional causal factors of ‘wet litter’ in chicken-meat production

The problem of ‘wet litter’, which occurs primarily in grow-out sheds for meat chickens (broilers), has been recognised for nearly a century. Nevertheless, it is an increasingly important problem in contemporary chicken-meat production as wet litter and associated conditions, especially footpad dermatitis, have developed into tangible welfare issues. This is only compounded by the market demand for chicken paws and compromised bird performance. This review considers the multidimensional causal factors of wet litter. While many causal factors can be listed it is evident that the critical ones could be described as micro-environmental factors and chief amongst them is proper management of drinking systems and adequate shed ventilation. Thus, this review focuses on these environmental factors and pays less attention to issues stemming from health and nutrition. Clearly, there are times when related avian health issues of coccidiosis and necrotic enteritis cannot be overlooked and the development of efficacious vaccines for the latter disease would be advantageous. Presently, the inclusion of phytate-degrading enzymes in meat chicken diets is routine and, therefore, the implication that exogenous phytases may contribute to wet litter is given consideration. Opinion is somewhat divided as how best to counter the problem of wet litter as some see education and extension as being more beneficial than furthering research efforts. However, it may prove instructive to assess the practice of whole grain feeding in relation to litter quality and the incidence of footpad dermatitis. Additional research could investigate the relationships between dietary concentrations of key minerals and the application of exogenous enzymes with litter quality

Human marginal zone B cell development from early T2 progenitors.

B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2, and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of α4β7 integrin and lower expression of IL-4 receptor (IL4R) compared with the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZBs). Lineage progression from T1 cells to MZBs via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut-homing T2 cells is observed in severe SLE and is associated with reduction of MZBs and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence in health

Phylogenetic Relationships among the Colobine Monkeys Revisited: New Insights from Analyses of Complete mt Genomes and 44 Nuclear Non-Coding Markers

Background: Phylogenetic relationships among Asian and African colobine genera have been disputed and are not yet well established. In the present study, we revisit the contentious relationships within the Asian and African Colobinae by analyzing 44 nuclear non-coding genes (.23 kb) and mitochondrial (mt) genome sequences from 14 colobine and 4 noncolobine primates. Principal Findings: The combined nuclear gene and the mt genome as well as the combined nuclear and mt gene analyses yielded different phylogenetic relationships among colobine genera with the exception of a monophyletic ‘odd-nosed’ group consisting of Rhinopithecus, Pygathrix and Nasalis, and a monophyletic African group consisting of Colobus and Piliocolobus. The combined nuclear data analyses supported a sister-grouping between Semnopithecus and Trachypithecus, and between Presbytis and the odd-nosed monkey group, as well as a sister-taxon association of Pygathrix and Rhinopithecus within the odd-nosed monkey group. In contrast, mt genome data analyses revealed that Semnopithecus diverged earliest among the Asian colobines and that the odd-nosed monkey group is sister to a Presbytis and Trachypithecus clade, as well as a close association of Pygathrix with Nasalis. The relationships among these genera inferred from the analyses of combined nuclear and mt genes, however, varied with the tree-building methods used. Another remarkable finding of the present study is that all of our analyses rejected the recently proposed African colobine paraphyl

Polymorphisms near EXOC4 and LRGUK on chromosome 7q32 are associated with Type 2 Diabetes and fasting glucose; The NHLBI Family Heart Study

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The SAMI Galaxy Survey : spatially resolving the main sequence of star formation

We present the ∼800 star formation rate maps for the Sydney-AAO Multi-object Integral field spectrograph (SAMI) Galaxy Survey based on H α emission maps, corrected for dust attenuation via the Balmer decrement, that are included in the SAMI Public Data Release 1. We mask out spaxels contaminated by non-stellar emission using the [O iii]/H β, [N ii]/H α, [S ii]/H α, and [O i]/H α line ratios. Using these maps, we examine the global and resolved star-forming main sequences of SAMI galaxies as a function of morphology, environmental density, and stellar mass. Galaxies further below the star-forming main sequence are more likely to have flatter star formation profiles. Early-type galaxies split into two populations with similar stellar masses and central stellar mass surface densities. The main-sequence population has centrally concentrated star formation similar to late-type galaxies, while galaxies >3σ below the main sequence show significantly reduced star formation most strikingly in the nuclear regions. The split populations support a two-step quenching mechanism, wherein halo mass first cuts off the gas supply and remaining gas continues to form stars until the local stellar mass surface density can stabilize the reduced remaining fuel against further star formation. Across all morphologies, galaxies in denser environments show a decreased specific star formation rate from the outside in, supporting an environmental cause for quenching, such as ram-pressure stripping or galaxy interactions.Publisher PDFPeer reviewe

The multidimensional causal factors of ‘wet litter’ in chicken-meat production

The problem of ‘wet litter’, which occurs primarily in grow-out sheds for meat chickens (broilers), has been recognised for nearly a century. Nevertheless, it is an increasingly important problem in contemporary chicken-meat production as wet litter and associated conditions, especially footpad dermatitis, have developed into tangible welfare issues. This is only compounded by the market demand for chicken paws and compromised bird performance. This review considers the multidimensional causal factors of wet litter. While many causal factors can be listed it is evident that the critical ones could be described as micro-environmental factors and chief amongst them is proper management of drinking systems and adequate shed ventilation. Thus, this review focuses on these environmental factors and pays less attention to issues stemming from health and nutrition. Clearly, there are times when related avian health issues of coccidiosis and necrotic enteritis cannot be overlooked and the development of efficacious vaccines for the latter disease would be advantageous. Presently, the inclusion of phytate-degrading enzymes in meat chicken diets is routine and, therefore, the implication that exogenous phytases may contribute to wet litter is given consideration. Opinion is somewhat divided as how best to counter the problem of wet litter as some see education and extension as being more beneficial than furthering research efforts. However, it may prove instructive to assess the practice of whole grain feeding in relation to litter quality and the incidence of footpad dermatitis. Additional research could investigate the relationships between dietary concentrations of key minerals and the application of exogenous enzymes with litter quality