Secretory Leukocyte Protease Inhibitor Binds to Annexin II, a Cofactor for Macrophage HIV-1 Infection

The distribution of secretory leukocyte protease inhibitor (SLPI) at entry portals indicates its involvement in defending the host from pathogens, consistent with the ability of SLPI to inhibit human immunodeficiency virus (HIV)-1 infection by an unknown mechanism. We now demonstrate that SLPI binds to the membrane of human macrophages through the phospholipid-binding protein, annexin II. Based on the recent identification of human cell membrane phosphatidylserine (PS) in the outer coat of HIV-1, we define a novel role for annexin II, a PS-binding moiety, as a cellular cofactor supporting macrophage HIV-1 infection. Moreover, this HIV-1 PS interaction with annexin II can be disrupted by SLPI or other annexin II–specific inhibitors. The PS–annexin II connection may represent a new target to prevent HIV-1 infection

Measurements of CaII absorption, metals, and dust in a sample of z~1 DLAs and subDLAs

We present observations of CaII, ZnII, and CrII absorption lines in 16 DLAs and 6 subDLAs at 0.6 < z < 1.3, obtained for the dual purposes of: (i) clarifying the relationship between DLAs and absorbers selected via strong CaII lines, and (ii) increasing the still limited sample of Zn and Cr abundances in this redshift range. We find only partial overlap between current samples of intermediate-z DLAs (which are drawn from magnitude limited surveys) and strong CaII absorbers: approximately 25% of known DLAs at these redshifts have an associated CaII 3935 line with REW>0.35A, the threshold of the SDSS sample assembled by Wild and her collaborators. The lack of the strongest systems (with REW>0.5A) is consistent with these authors' conclusion that such absorbers are often missed in current DLA surveys because they redden/dim the light of the background QSOs. We rule out the suggestion that strong CaII absorption is associated exclusively with the highest-N(HI) DLAs. Furthermore, we find no correlation between the strength of the CaII lines and either the metallicity or depletion, although the strongest CaII absorber in our sample is also the most metal-rich DLA yet discovered, with [Zn/H] ~ solar. We conclude that a complex mix of parameters determine the strengths of the CaII lines, including the density of particles and UV photons in the ISM of the galaxies hosting the DLAs. We find tentative evidence (given the small size of our sample) that strong CaII systems may preferentially sample regions of high gas density, perhaps akin to the DLAs exhibiting molecular hydrogen absorption at redshifts z>2. If this connection is confirmed, strong CaII absorbers would trace possibly metal-rich, H2-bearing columns of cool, dense gas at distances up to tens of kpc from normal galaxies. (abridged)Comment: Accepted for publication in MNRAS; 15 pages, 10 figure

A shared frequency set between the historical mid-latitude aurora records and the global surface temperature

Herein we show that the historical records of mid-latitude auroras from 1700 to 1966 present oscillations with periods of about 9, 10-11, 20-21, 30 and 60 years. The same frequencies are found in proxy and instrumental global surface temperature records since 1650 and 1850, respectively and in several planetary and solar records. Thus, the aurora records reveal a physical link between climate change and astronomical oscillations. Likely, there exists a modulation of the cosmic ray flux reaching the Earth and/or of the electric properties of the ionosphere. The latter, in turn, have the potentiality of modulating the global cloud cover that ultimately drives the climate oscillations through albedo oscillations. In particular, a quasi 60-year large cycle is quite evident since 1650 in all climate and astronomical records herein studied, which also include an historical record of meteorite fall in China from 619 to 1943. These findings support the thesis that climate oscillations have an astronomical origin. We show that a harmonic constituent model based on the major astronomical frequencies revealed in the aurora records is able to forecast with a reasonable accuracy the decadal and multidecadal temperature oscillations from 1950 to 2010 using the temperature data before 1950, and vice versa. The existence of a natural 60-year modulation of the global surface temperature induced by astronomical mechanisms, by alone, would imply that at least 60-70% of the warming observed since 1970 has been naturally induced. Moreover, the climate may stay approximately stable during the next decades because the 60-year cycle has entered in its cooling phase.Comment: 18 pages, 11 figure

Frequency of single nucleotide polymorphisms in NOD1 gene of ulcerative colitis patients: a case-control study in the Indian population

<p>Abstract</p> <p>Background</p> <p>Epidemiological studies have provided enough evidence that genetic factors have an important role in determining susceptibility to IBD. The most significant finding in the IBD research has been identification of mutations in the gene that encodes Nod2 (nucleotide-binding oligomerization domain 2) protein in a subgroup of patients with Crohn's disease. However, a very similar gene encoding Nod1 protein still has not been well documented for its association with Ulcerative colitis patients. Detection of polymorphism in <it>NOD1 </it>gene using SNP analysis has been attempted in the present study. We evaluated frequency and significance of mutations present in the nucleotide-binding domain (NBD) of <it>NOD1 </it>gene in context to Indian population.</p> <p>Methods</p> <p>A total of 95 patients with ulcerative colitis and 102 controls enrolled in the Gastroenterology department of All India Institute of Medical Sciences, New Delhi were screened for SNPs by DHPLC and RFLP techniques. Exon 6 locus in the NBD domain of <it>NOD1 </it>gene was amplified and sequenced. Genotype and allele frequencies of the patients and controls were calculated by the Pearson's χ²test, Fisher's exact test and ANOVA with Bonferroni's correction using SPSS software version 12.</p> <p>Results</p> <p>We have demonstrated DHPLC screening technique to show the presence of SNPs in Exon 6 locus of NBD domain of <it>NOD1 </it>gene. The DHPLC analysis has proven suitable for rapid detection of base pair changes. The data was validated by sequencing of clones and subsequently by RFLP analysis. Analyses of SNP data revealed 3 significant mutations (W219R, <it>p </it>= 0.002; L349P, <it>p </it>= 0.002 and L370R, <it>p </it>= 0.039) out of 5 in the Exon 6 locus of NBD domain of the gene that encompasses ATP and Mg²⁺binding sites. No significant association was observed within different sub phenotypes.</p> <p>Conclusion</p> <p>We propose that the location of mutations in the Exon 6 spanning the ATP and Mg²⁺binding site of NBD in <it>NOD1 </it>gene may affect the process of oligomerization and subsequent function of the LRR domain. Further studies are been conducted at the protein level to prove this possibility.</p

Interleukin-6 and Cyclooxygenase-2 downregulation by fatty-acid fractions of Ranunculus constantinopolitanus

<p>Abstract</p> <p>Background</p> <p>Medicinal plants represent alternative means for the treatment of several chronic diseases, including inflammation. The genus <it>Ranunculus</it>, a representative of the Ranunculaceae family, has been reported to possess anti-inflammatory, analgesic, antiviral, antibacterial, antiparasitic and antifungal activities, possibly due to the presence of anemonin and other. Different studies have shown the occurrence of unusual fatty acids (FAs) in Ranunculaceae; however, their therapeutic role has not been investigated. The purpose of this study is to characterize potential anti-inflammatory bioactivities in <it>Ranunculus constantinopolitanus </it>D'Urv., traditionally used in Eastern Mediterranean folk medicine.</p> <p>Methods</p> <p>The aerial part of <it>R. constantinopolitanus </it>was subjected to methanol (MeOH) extraction and solvent fractionation. The bioactive fraction (I.2) was further fractionated using column chromatography, and the biologically active subfraction (Y₂₊₃) was identified using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC-MS). The effects of I.2 and Y₂₊₃on cell viability were studied in mouse mammary epithelial SCp2 cells using trypan blue exclusion method. To study the anti-inflammatory activities of I.2 and Y₂₊₃, their ability to reduce interleukin (IL)-6 levels was assessed in endotoxin (ET)-stimulated SCp2 cells using enzyme-linked immunosorbent assay (ELISA). In addition, the ability of Y₂₊₃to reduce cyclooxygenase (COX)-2 expression was studied in IL-1-treated mouse intestinal epithelial Mode-K cells via western blotting. Data were analyzed by one-way analysis of variance (ANOVA), Student-Newman-Keuls (SNK), Tukey HSD, two-sample t-test and Dunnett t-tests for multiple comparisons.</p> <p>Results</p> <p>The chloroform fraction (I.2) derived from crude MeOH extract of the plant, in addition to Y₂₊₃, a FA mix isolated from this fraction and containing palmitic acid, C18:2 and C18:1 isomers and stearic acid (1:5:8:1 ratio), reduced ET-induced IL-6 levels in SCp2 cells without affecting cell viability or morphology. When compared to fish oil, conjugated linoleic acid (CLA) and to individual FAs as palmitic, linoleic, oleic and stearic acid or to a mix of these FAs (1:5:8:1 ratio), Y₂₊₃exhibited higher potency in reducing ET-induced IL-6 levels within a shorter period of time. Y₂₊₃ also reduced COX-2 expression in IL-1-treated Mode-K cells.</p> <p>Conclusion</p> <p>Our studies demonstrate the existence of potential anti-inflammatory bioactivities in <it>R. constantinopolitanus </it>and attribute them to a FA mix in this plant.</p

Past changes in the vertical distribution of ozone - Part 3: Analysis and interpretation of trends

This is the final version of the article. It first appeared from Copernicus Publications via http://dx.doi.org/10.5194/acp-15-9965-2015Abstract. Trends in the vertical distribution of ozone are reported and compared for a number of new and recently revised data sets. The amount of ozone-depleting compounds in the stratosphere (as measured by equivalent effective stratospheric chlorine – EESC) was maximised in the second half of the 1990s. We examine the periods before and after the peak to see if any change in trend is discernible in the ozone record that might be attributable to a change in the EESC trend, though no attribution is attempted. Prior to 1998, trends in the upper stratosphere (~ 45 km, 4 hPa) are found to be −5 to −10 % per decade at mid-latitudes and closer to −5 % per decade in the tropics. No trends are found in the mid-stratosphere (28 km, 30 hPa). Negative trends are seen in the lower stratosphere at mid-latitudes in both hemispheres and in the deep tropics. However, it is hard to be categorical about the trends in the lower stratosphere for three reasons: (i) there are fewer measurements, (ii) the data quality is poorer, and (iii) the measurements in the 1990s are perturbed by aerosols from the Mt Pinatubo eruption in 1991. These findings are similar to those reported previously even though the measurements for the main satellite and ground-based records have been revised. There is no sign of a continued negative trend in the upper stratosphere since 1998: instead there is a hint of an average positive trend of ~ 2 % per decade in mid-latitudes and ~ 3 % per decade in the tropics. The significance of these upward trends is investigated using different assumptions of the independence of the trend estimates found from different data sets. The averaged upward trends are significant if the trends derived from various data sets are assumed to be independent (as in Pawson et al., 2014) but are generally not significant if the trends are not independent. This occurs because many of the underlying measurement records are used in more than one merged data set. At this point it is not possible to say which assumption is best. Including an estimate of the drift of the overall ozone observing system decreases the significance of the trends. The significance will become clearer as (i) more years are added to the observational record, (ii) further improvements are made to the historic ozone record (e.g. through algorithm development), and (iii) the data merging techniques are refined, particularly through a more rigorous treatment of uncertainties. The support of SPARC, IO3C, IGACO-O3 and NDACC was essential to the success of the initiative. Neil Harris thanks the UK Natural Environment Research Council for an Advanced Research Fellowship. Work at the Jet Propulsion Laboratory was performed under contract with the National Aeronautics and Space Administration. Measurements at Lauder are core funded through New Zealand’s Ministry of Business, Innovation and Employment, while those at Woolongong are supported by the Australian Research Council

Obesity related methylation changes in DNA of peripheral blood leukocytes

<p>Abstract</p> <p>Background</p> <p>Despite evidence linking obesity to impaired immune function, little is known about the specific mechanisms. Because of emerging evidence that immune responses are epigenetically regulated, we hypothesized that DNA methylation changes are involved in obesity induced immune dysfunction and aimed to identify these changes.</p> <p>Method</p> <p>We conducted a genome wide methylation analysis on seven obese cases and seven lean controls aged 14 to 18 years from extreme ends of the obesity distribution and performed further validation of six CpG sites from six genes in 46 obese cases and 46 lean controls aged 14 to 30 years.</p> <p>Results</p> <p>In comparison with the lean controls, we observed one CpG site in the UBASH3A gene showing higher methylation levels and one CpG site in the TRIM3 gene showing lower methylation levels in the obese cases in both the genome wide step (<it>P </it>= 5 × 10^-6and <it>P </it>= 2 × 10^-5for the UBASH3A and the TRIM3 gene respectively) and the validation step (<it>P </it>= 0.008 and <it>P </it>= 0.001 for the UBASH3A and the TRIM3 gene respectively).</p> <p>Conclusions</p> <p>Our results provide evidence that obesity is associated with methylation changes in blood leukocyte DNA. Further studies are warranted to determine the causal direction of this relationship as well as whether such methylation changes can lead to immune dysfunction.</p> <p>See commentary: <url>http://www.biomedcentral.com/1741-7015/8/88/abstract</url></p

Structural Optimization and De Novo Design of Dengue Virus Entry Inhibitory Peptides

Viral fusogenic envelope proteins are important targets for the development of inhibitors of viral entry. We report an approach for the computational design of peptide inhibitors of the dengue 2 virus (DENV-2) envelope (E) protein using high-resolution structural data from a pre-entry dimeric form of the protein. By using predictive strategies together with computational optimization of binding “pseudoenergies”, we were able to design multiple peptide sequences that showed low micromolar viral entry inhibitory activity. The two most active peptides, DN57opt and 1OAN1, were designed to displace regions in the domain II hinge, and the first domain I/domain II beta sheet connection, respectively, and show fifty percent inhibitory concentrations of 8 and 7 µM respectively in a focus forming unit assay. The antiviral peptides were shown to interfere with virus:cell binding, interact directly with the E proteins and also cause changes to the viral surface using biolayer interferometry and cryo-electron microscopy, respectively. These peptides may be useful for characterization of intermediate states in the membrane fusion process, investigation of DENV receptor molecules, and as lead compounds for drug discovery

Clinical significance of circulating anti-p53 antibodies in European patients with hepatocellular carcinoma

p53 alterations are considered to be predictive of poor prognosis in hepatocellular carcinoma (HCC) and may induce a humoral response. Anti-p53 serum antibodies were assessed by enzyme-linked immunosorbent assay (ELISA) using purified recombinant human p53 on 130 European HCC patients before treatment and during the clinical course of the disease. p53 immunohistochemistry was performed on tumours from the 52 patients who underwent surgery, and DNA sequencing analysis was initiated when circulating anti-p53 antibodies were detected. Nine (7%) HCC patients had anti-p53 serum antibodies before treatment. During a mean period of 30 months of follow-up, all the negative patients remained negative, even when recurrence was observed. Of the nine positive patients, eight were still positive 12–30 months after surgery. The presence of anti-p53 serum antibodies was correlated neither with mutation of the p53 gene nor the serum alpha-fetoprotein levels and clinicopathological characterics of the tumours. However, a greater incidence of vascular invasion and accumulation of p53 protein were observed in the tumours of these patients (P < 0.03 and P < 0.01 respectively) as well as a better survival rate without recurrence (P = 0.05). In conclusion, as was recently shown in pancreatic cancer, anti-p53 serum antibodies may constitute a marker of relative ‘good prognosis’ in a subgroup of patients exhibiting one or several markers traditionally thought to be of bad prognosis. © 1999 Cancer Research Campaig

Introduction to Special Issue - In-depth study of air pollution sources and processes within Beijing and its surrounding region (APHH-2 Beijing)

Abstract. The Atmospheric Pollution and Human Health in a Chinese Megacity (APHH-Beijing) programme is an international collaborative project focusing on understanding the sources, processes and health effects of air pollution in the Beijing megacity. APHH-Beijing brings together leading China and UK research groups, state-of-the-art infrastructure and air quality models to work on four research themes: (1) sources and emissions of air pollutants; (2) atmospheric processes affecting urban air pollution; (3) air pollution exposure and health impacts; and (4) interventions and solutions. Themes 1 and 2 are closely integrated and support Theme 3, while Themes 1-3 provide scientific data for Theme 4 to develop cost-effective air pollution mitigation solutions. This paper provides an introduction to (i) the rationale of the APHH-Beijing programme, and (ii) the measurement and modelling activities performed as part of it. In addition, this paper introduces the meteorology and air quality conditions during two joint intensive field campaigns - a core integration activity in APHH-Beijing. The coordinated campaigns provided observations of the atmospheric chemistry and physics at two sites: (i) the Institute of Atmospheric Physics in central Beijing, and (ii) Pinggu in rural Beijing during 10 November – 10 December 2016 (winter) and 21 May- 22 June 2017 (summer). The campaigns were complemented by numerical modelling and automatic air quality and low-cost sensor observations in the Beijing megacity. In summary, the paper provides background information on the APHH-Beijing programme, and sets the scene for more focussed papers addressing specific aspects, processes and effects of air pollution in Beijing