Regulating STING in health and disease.

The presence of cytosolic double-stranded DNA molecules can trigger multiple innate immune signalling pathways which converge on the activation of an ER-resident innate immune adaptor named "STimulator of INterferon Genes (STING)". STING has been found to mediate type I interferon response downstream of cyclic dinucleotides and a number of DNA and RNA inducing signalling pathway. In addition to its physiological function, a rapidly increasing body of literature highlights the role for STING in human disease where variants of the STING proteins, as well as dysregulated STING signalling, have been implicated in a number of inflammatory diseases. This review will summarise the recent structural and functional findings of STING, and discuss how STING research has promoted the development of novel therapeutic approaches and experimental tools to improve treatment of tumour and autoimmune diseases

Możliwości optymalizacji technologii suchej fermentacji

The paper describes a perspective technology socalled dry fermentation for biogas production. The authors discuss its weaknesses and strengths, determine parameters defining possibilities of the process optimizing and describe experimental equipment for the optimal parameter verification. As an example they present results of an experiment based on the utilization of the straw cattle manure for the biogas production by the dry fermentation technology.Artykuł stanowi opis perspektywicznej technologii tzw. suchej fermentacji, która może być wykorzystywana w produkcji biogazu. Oceniane są pozytywne i negatywne właściwości technologii, określone parametry definiujące możliwości optymalizacji procesu oraz opis eksperymentalnego urządzenia umożliwiającego sprawdzenie optymalnych parametrów. Jako przykład zostały podane wyniki eksperymentów z zastosowaniem słomianego obornika końskiego do produkcji biogazu technologią suchej fermentacji

A novel missense mutation in the factor VIII gene identified by analysis of amplified hemophilia DNA sequences.

To date the only point mutations demonstrated to cause hemophilia are C to T transitions in TaqI sites. These were detected by screening Southern blots with cloned factor VIII probes. During the development of improved methods for detecting and analyzing mutations in genomic DNA, a novel G to C transversion mutation has been identified. This rare transversion results in a missense mutation, with proline being substituted for arginine in one of the active domains of the factor VIII molecule. The results suggest that the improved methods will be useful for detecting mutations in hemophilia as well as in other genetic disorders. In this method, specific DNA sequences in genomic DNA are amplified using oligonucleotide primers and a heat-resistant DNA polymerase. Mutations are detected and localized in the amplified samples by RNase A cleavage, and the altered region is then sequenced

A cross-sectional study comparing the rates of osteoarthritis, laxity, and quality of life in primary and revision anterior cruciate ligament reconstructions

The purpose of this study was to assess the degree of osteoarthritis, degree of laxity, and quality-of-life (QOL) scores in primary and revision anterior cruciate ligament (ACL) reconstruction. This was a cross-sectional study; 25 patients who had undergone revision ACL reconstruction with allografts were identified and compared with 27 randomly selected primary ACL reconstruction patients operated on in the same hospital in the same period with the same technique. The main outcome measure was the International Knee Documentation Committee (IKDC) radiographic osteoarthritis sum score, and secondary outcome measures were Knee injury and Osteoarthritis Outcome Score, IKDC functional outcome measures, anterior laxity, and QOL at follow-up. The median follow-up was 5.3 years for revision reconstruction patients and 5.1 years for primary reconstruction patients. Radiographic IKDC sum scores for osteoarthritis were found to be significantly worse in revision patients, with a median of 4, compared with primary patients, with a median of 1 (P = .016). Differences were found in meniscal injury (P = .02) and cartilage status (P < .001) before or at the index operation. Significantly worse outcomes were found in the following subscores of the Knee injury and Osteoarthritis Outcome Score: pain (median, 92 v 97; P = .032), symptom (median, 86 v 96; P = .015), activities of daily living (median, 94 v 100; P = .020), sport (median, 50 v 85; P = .006), and QOL (median, 56 v 81; P = .001). IKDC functional outcome measures were the same in both groups except for the pivot-shift test (P = .007). No differences were found in anterior drawer, Lachman, or KT-1000 arthrometer (MEDmetric, San Diego, CA) testing. Present-day health scores on the EQ-5D were worse for revision reconstruction patients (median, 70 v 80; P = .009). Revision reconstruction patients have more signs of osteoarthritis and worse QOL than primary reconstruction patients, even though they have comparable IKDC success rates and KT-1000 arthrometer laxity test results. Level III, retrospective comparative stud

Partial inhibition of human neutrophil activation by FK-506 at supratherapeutic concentrations

The macrolide, FK-506, is a potent and effective inhibitor of lymphocyte activation. We studied the effects of FK-506 on human neutrophil activation induced by chemoattractants and by various substances which circumvent receptor stimulation. After preincubation for 5 min at 37 degrees C, FK-506 (1 microM) inhibited N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe)- or platelet-activating factor-induced superoxide production in neutrophils by about 30%. At therapeutic concentrations (0.1-1 nM) FK-506 was ineffective. FK-506 did not inhibit exocytosis and rises in cytosolic Ca2+ concentration [Ca2+]i mediated by these stimuli, and it did not at all inhibit neutrophil activation induced by C5a, leukotriene B4 and 4 beta-phorbol 12-myristate 13-acetate. FK-506 (1 microM) inhibited A23187-induced exocytosis by about 35%, but A23187-induced superoxide production was unaffected. After preincubation for 5 min at 37 degrees C, FK-506 inhibited fMet-Leu-Phe-induced superoxide production in dibutyryl cAMP-differentiated HL-60 cells by about 20%; preincubation with the drug for 24 h did not result in inhibition of superoxide production. FK-506 did not inhibit agonist-binding to formyl peptide receptors and fMet-Leu-Phe-stimulated GTP hydrolysis of heterotrimeric regulatory guanine nucleotide-binding proteins (G-proteins) in membranes from dibutyryl cAMP-differentiated HL-60 cells. FK-506 did not change steady-state and differential polarized phase fluorescence in HL-60 membranes using 1,6-diphenylhexa-1,3,5-triene and 12-(9-anthroyloxy)-stearate as probes. Our results show that FK-506 at supratherapeutic concentrations partially inhibits neutrophil activation. Inhibition by FK-506 of fMet-Leu-Phe-induced superoxide production is rapid in onset and is not due to inhibition of agonist-binding to receptors, interference with G-proteins or protein kinase C, reduction of rises in [Ca2+]i or alteration in physical membrane state

Molecular integration of the anti-tropomyosin compound ATM-3507 into the coiled coil overlap region of the cancer-associated Tpm3.1

Tropomyosins (Tpm) determine the functional capacity of actin filaments in an isoform-specific manner. The primary isoform in cancer cells is Tpm3.1 and compounds that target Tpm3.1 show promising results as anti-cancer agents both in vivo and in vitro. We have determined the molecular mechanism of interaction of the lead compound ATM-3507 with Tpm3.1-containing actin filaments. When present during co-polymerization of Tpm3.1 with actin, 3H-ATM-3507 is incorporated into the filaments and saturates at approximately one molecule per Tpm3.1 dimer and with an apparent binding affinity of approximately 2 µM. In contrast, 3H-ATM-3507 is poorly incorporated into preformed Tpm3.1/actin co-polymers. CD spectroscopy and thermal melts using Tpm3.1 peptides containing the C-terminus, the N-terminus, and a combination of the two forming the overlap junction at the interface of adjacent Tpm3.1 dimers, show that ATM-3507 shifts the melting temperature of the C-terminus and the overlap junction, but not the N-terminus. Molecular dynamic simulation (MDS) analysis predicts that ATM-3507 integrates into the 4-helix coiled coil overlap junction and in doing so, likely changes the lateral movement of Tpm3.1 across the actin surface resulting in an alteration of filament interactions with actin binding proteins and myosin motors, consistent with the cellular impact of ATM-3507