B cells from rheumatoid arthritis patients show important alterations in the expression of CD86 and FcγRIIb,which are modulated by anti-tumor necrosis factor therapy

Introduction  

Several molecules help preserve peripheral B cell tolerance, but when altered, they may predispose to autoimmunity. This work studied the expression of the costimulatory molecule CD86 and the inhibitory receptor for IgG immune complexes FcγRIIb (CD32b), on B cells from rheumatoid arthritis (RA) patients, and the influence of anti-tumor necrosis factor (TNF) therapy.     

Low prevalence of hepatitis C virus infection in Amerindians from Western Venezuela

Previous studies have not found hepatitis C virus (HCV) infection in Amerindians from Western Venezuela. A survey of 254 Bari and Yukpa natives aged 10-60 years (mean +/- SD age = 35 +/- 5.4 years) from four communities, two Bari and two Yukpa, in this area were studied to assess the prevalence of antibodies to HCV (anti-HCV) and HCV RNA among these indigenous populations. Serum samples were examined initially for anti-HCV by a four generation enzyme-linked immunosorbent assay (ELISA). Reactive samples were then tested using a third generation recombinant immunoblot assay (RIBA-3). Viral RNA was investigated in all immunoblot-reactive samples by a nested polymerase chain reaction (PCR) method. Six (2.3%) of 254 natives were positive by ELISA, one (2.2%) of these reactive samples were positive by RIBA, and four (1.5%) were indeterminate. Only two (0.8%) were positive by PCR, corresponding to 1 (2.1%) of 47 inhabitants of a Yukpa community and to 1 (2.2%) of 45 subjects of a Bari community. Iatrogenic is thought to play a role in acquisition of the infection. The findings indicate a HCV focus of low endemicity and are compatible with a low degree of exposures of the natives to the virus. Studies are necessary to assess the risk factors for infection in these Amerindians.     

Metalloproteases and γ‐secretase: new membrane partners regulating p75 neurotrophin receptor signaling?

Signaling by the p75 neurotrophin receptor (p75) has been implicated in diverse neuronal responses, including the control of neuronal survival versus death and axonal regeneration and growth cone collapse, involving p75 in different neuropathological conditions. There are different levels of complexity regulating p75-mediated signaling. First, p75 can interact with different ligands and co-receptors in the plasma membrane, forming tripartite complexes, whose activation result in different cellular outcomes. Moreover, it was recently described that trafficking capacities of p75 in neurons are regulating, in addition to p75 downstream interactions, also the sequential cleavage of p75. The proteolytical processing of p75 involves, first, a shedding event that releases a membrane-bound carboxiterminal fragment (p75-CTF), followed by a gamma-secretase mediated cleavage, generating a soluble intracellular domain (p75-ICD) with signaling capabilities. The first shedding event, generating a p75-CTF, is the key step to regulating the production of p75-ICD, and although the generation of p75-ICD is important for both p75-mediated control of neuronal survival and the control of neurite outgrowth, little is known how both cleavage events are regulated. In this review, we argue that both sheddases and gamma-secretase are key membrane components regulating p75-mediated signaling transduction; therefore, further attention should be paid to their roles as p75 signaling regulators.     

Phosphatidylinositol 3-kinase, MEK-1 and p38 mediate leptin/interferon-gamma synergistic NOS type II induction in chondrocytes

In a previous study, we established that leptin acts synergistically with interferon-gamma in inducing nitric oxide synthase type II in cultured chondrocytes via Janus kinase-2 activation. However, the exact molecular mechanism that accounts for this synergism is not completely understood. The aim of the present study was to further delineate the signalling pathway used by leptin/interferon-gamma in the nitric oxide synthase type II induction in chondrocytes. Consequently, the roles of PI-3 kinase, MEK1 and p38 kinase were investigated using specific pharmacological inhibitors (Wortmannin, LY 294002, PD 098,059 and SB 203580). For this purpose, the amount of stable nitrite, the end product of NO generation by activated chondrocytes, has been evaluated by Griess colorimetric reaction in culture medium of human primary chondrocytes and in the murine ATDC5 cell line stimulated with leptin (400 nM) and interferon-gamma (1 ng/ml), alone or in combination. Specific inhibitors for PI-3K, MEK1 and p38 were added 1 h before stimulation. Nitric oxide synthase type II mRNA was investigated by real-time RT-PCR and NOS type II protein expression has been evaluated by western blot analysis. Our results showed that, as expected, leptin synergizes with IFN-gamma in inducing NO accumulation in the supernatant of co-stimulated cells. Pre-treatment with Wortmannin, LY 294002, PD 098,059 and SB 203580 caused a significant decrease in nitrite production, NOS type II protein expression and NOS type II mRNA expression induced by leptin and interferon-gamma co-stimulation. These findings were confirmed in 15 and 21-day differentiated ATDC5 cells, and in normal human primary chondrocytes. This is the first report showing that NOS type II induction triggered by co-stimulation with leptin and interferon-gamma is mediated by a signaling pathway involving PI-3K, MEK1 and p38.     

Harvest prediction in ‘Algerie’ loquat

Plant phenology is in great measure driven by air temperature. To forecast harvest time for ‘Algerie’ loquat accurately, the growing degree days (GDD) needed from bloom to ripening were determined using data from nine seasons. The methods proposed by Zalom et al. (Zalom FG, Goodell PB, Wilson LT, Barnett WW, Bentley W, Degree-days: the calculation and use of heat units in pest management, leaflet no 21373, Division Agriculture and Natural Resources, University of California 10 pp, 1983) were compared as regards their ability to estimate heat summation based on hourly records. All the methods gave remarkably similar results for our cultivation area, although the double-sine method showed higher performance when temperatures were low. A base temperature of 3°C is proposed for ‘Algerie’ loquat because it provides a coefficient of variation in GDD among seasons of below 5%, and because of its compatibility with loquat growth. Based on these determinations, ‘Algerie’ loquat requires 1,715 GDD from bloom to harvest; under our conditions this heat is accumulated over an average of 159 days. Our procedure permits the ‘Algerie’ harvest date to be estimated with a mean error of 4.4 days (<3% for the bloom-harvest period). GDD summation did not prove superior to the use of the number of calendar days for predicting ‘Algerie’ harvest under non-limiting growing conditions. However, GDD reflects the developmental rate in water-stressed trees better than calendar days. Trees under deficit irrigation during flower development required more time and more heat to ripen their fruits.     

Effectiveness of imazalil to control the effect of fungal deterioration on mummies at the Mexico City Museum "El Carmen"

We present a study on the control and elimination of the fungi affecting the mummies specifically at the museum "El Carmen", in San Angel, Mexico City. Twelve analysed mummies presented an important deterioration attributed to colonizing fungi. The degree of fungal contamination and the efficacy of imazalil were evaluated. Two samplings were performed in order to isolate and identify the fungal genera, one for control and the other after the treatment. Isolation was done by the carpet-square technique and identification was performed by morphological features. Each sampling gave a total of 100 samples as follows: 17 from the air, 23 from the walls and 60 from the mummies. Samples were cultured on Sabouraud dextrose agar. From the first sampling a total of 649 colonies corresponding to 24 genera were obtained being the most frequent Penicillium, Cladophialophora and Aspergillus. From the second sampling, after the imazalil treatment, which was applied by means of lit candles containing the antifungal drug, 57 colonies were recovered, representing a 91.2% fungal reduction; 18 genera were eliminated. In spite of resistance showed by many Penicillium strains, the imazalil is an alternative drug for the control of fungal colonization on these studied materials.     

Systemic inflammatory markers in patients with aortic sclerosis

The aim of the study was to evaluate several mediators of inflammation in patients with aortic sclerosis in relation to severity of cardiovascular disease. Serum level of cytokines, soluble intracellular adhesion molecule 1, matrix metalloproteinase (MMP) 2 and 9 and their tissue inhibitor TIMP-1, were measured by ELISA and MMPs activity by zymography in 51 aortic sclerosis patients. The increase in MMPs expression positively correlated with their gelatinase activity; also there was a positive correlation between MMP-9 and TIMP-1 serum levels. Moreover, IL-6 concentration positively correlated with both serum level and activity of MMP-9. The level of IL-6 and IL-1Ra were higher in patients with a great burden of atherosclerosis. Noteworthy, statistically significant higher levels of IL-6 were noticed for patients with coronary artery disease. There was a significant increase in IL-6 serum level as well as a significant decrease in IL-1Ra for patients with a history of myocardial infarction. A trend toward higher concentration of inflammatory mediators was noticed in relation to the increase in severity of the aortic valve disease. Our results support the hypothesis of an "inflammatory pattern" associated with AS pathology and suggest the persistence of a chronic inflammation in patients who experienced acute coronary events.     

<Emphasis Type="Italic">Slc11a1</Emphasis> (<Emphasis Type="Italic">Nramp1</Emphasis>) alleles interact with acute inflammation loci to modulate wound-healing traits in mice

Lines of mice were obtained by selective breeding for maximum (AIRmax) or minimum (AIRmin) acute inflammation. They present distinct neutrophil influx and show frequency disequilibrium of the solute carrier family 11a member 1 (Slc11a1) alleles. This gene is involved in ion transport at the endosomes within macrophages and neutrophils, interfering in their activation. Homozygous AIRmax and AIRmin sublines for the Slc11a1 gene were produced to examine the interaction of this gene with the acute inflammatory loci. The present work investigated wound-healing traits in AIRmax and AIRmin mice, in F₁ and F₂ intercrosses, and in Slc11a1 sublines. Two-millimeter ear punches were made in the mice and hole closure was measured during 40 days. AIRmax mice demonstrated significant tissue repair while AIRmin mice did not. Significant differences between the responses of male and female mice were also observed. Wound-healing traits demonstrated a correlation with neutrophil influx in F₂ populations. AIRmax ^SS showed higher ear-wound closure than AIRmax ^RR mice, suggesting that the Slc11a1 S allele favored ear tissue repair. QTL analysis has detected two inflammatory loci modulating ear wound healing on chromosomes 1 and 14. These results suggest the involvement of the acute inflammation modifier QTL in the wound-healing phenotype.     

Dominant Mutations in KAT6A Cause Intellectual Disability with Recognizable Syndromic Features

Through a multi-center collaboration study, we here report six individuals from five unrelated families, with mutations in KAT6A/MOZ detected by whole-exome sequencing. All five different de novo heterozygous truncating mutations were located in the C-terminal transactivation domain of KAT6A: {"type":"entrez-nucleotide","attrs":{"text":"NM_001099412.1","term_id":"150378462","term_text":"NM_001099412.1"}}NM_001099412.1: c.3116_3117 delCT, p.(Ser1039^∗); c.3830_3831insTT, p.(Arg1278Serfs^∗17); c.3879 dupA, p.(Glu1294Argfs^∗19); c.4108G>T p.(Glu1370^∗) and c.4292 dupT, p.(Leu1431Phefs^∗8). An additional subject with a 0.23 MB microdeletion including the entire KAT6A reading frame was identified with genome-wide array comparative genomic hybridization. Finally, by detailed clinical characterization we provide evidence that heterozygous mutations in KAT6A cause a distinct intellectual disability syndrome. The common phenotype includes hypotonia, intellectual disability, early feeding and oromotor difficulties, microcephaly and/or craniosynostosis, and cardiac defects in combination with subtle facial features such as bitemporal narrowing, broad nasal tip, thin upper lip, posteriorly rotated or low-set ears, and microretrognathia. The identification of human subjects complements previous work from mice and zebrafish where knockouts of Kat6a/kat6a lead to developmental defects.