Talking about the genes for cancer. A study of lay and professional knowledge of cancer genetics

This paper is concerned with the ways in which people who work in and use a cancer genetics clinic in the UK talk about the ‘gene for cancer’. By conceptualising such a gene as a boundary object, and using empirical data derived from clinic consultations, observations in a genetics laboratory and interviews with patients, the author seeks to illustrate how the various parties involved adopt different discursive strategies to appropriate, describe and understand what is apparently the ‘same’ thing. The consequent focus on the ways in which the rhetorical and syntactical features of lay and professional talk interlink and diverge, illustrates not merely how our contemporary knowledge of genes and genetics is structured, but also how different publics position themselves with respect to the biochemistry of life.

Vasodilator-Stimulated Phosphoprotein Regulates Inside-Out Signaling of beta(2) Integrins in Neutrophils

The monomeric GTPase Rap1 controls functional activation of beta2 integrins in leukocytes. In this article, we describe a novel mechanism by which the chemoattractant fMLP activates Rap1 and inside-out signaling of beta2 integrins. We found that fMLP-induced activation of Rap1 in human polymorphonuclear leukocytes or neutrophils and differentiated PLB-985 cells was blocked by inhibitors of the NO/guanosine-3',5'-cyclic monophosphate-dependent protein kinase (cGKI) pathway [N-(3-(aminomethyl)benzyl)acetamidine, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, DT-3 peptide, 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphothioate, Rp-isomer triethylammonium salt-guanosine-3',5'-cyclic monophosphate], indicating that the downstream signaling events in Rap1 activation involve the production of NO and guanosine-3',5'-cyclic monophosphate, as well as the activation of cGKI. Silencing the expression of vasodilator-stimulated phosphoprotein (VASP), a substrate of cGKI, in resting PLB-985 cells or mice neutrophils led to constitutive activation of Rap1. In parallel, silencing VASP in differentiated PLB-985 cells led to recruitment of C3G, a guanine nucleotide exchange factor for Rap1, to the plasma membrane. Expression of murine GFP-tagged phosphodeficient VASP Ser235Ala mutant (murine serine 235 of VASP corresponds to human serine 239) in PLB-985 cells blunted fMLP-induced translocation of C3G to the membrane and activation of Rap1. Thus, bacterial fMLP triggers cGKI-dependent phosphorylation of human VASP on serine 239 and, thereby, controls membrane recruitment of C3G, which is required for activation of Rap1 and beta2 integrin-dependent antibacterial functions of neutrophils.

Recurrent lower gastrointestinal bleeding secondary to cytomegalovirus-associated colonic ulcer in a non human immunodeficiency virus infected patient:Timely diagnosis and treatment averted surgery

Mr C, a 68-year-old Chinese male with diabetes mellitus, previous stroke and ischaemic cardiomyopathy on clopidogrel, presented with haematochezia. Colonoscopy showed a sigmoid ulcer, which was treated endoscopically. Histology of the biopsy from the ulcer revealed non-specific changes. However, he presented with recurrent bleeding from this non-healing sigmoid ulcer. A review of the histologic specimen revealed CMV intranuclear inclusion bodies. He was treated with intravenous ganciclovir, with no further hematochezia.

Keywords Hematochezia, cytomegalovirus, ulcer

Exchange protein directly activated by cAMP 1 (Epac1) is expressed in human neutrophils and mediates cAMP-dependent activation of the monomeric GTPase Rap1

Epac1 and Epac2 bind cAMP and mediate cAMP-dependent activation of Rap1. cAMP is produced in neutrophils in response to many chemoattractants. This second messenger plays a key role in the regulation of the functions of neutrophils. However, it is still not known whether Epacs are expressed in human neutrophils. We found that stimulation of PLB-985 cells differentiated into neutrophil-like cells, human neutrophils with 8CPT-2Me-cAMP (a selective activator of Epacs), or FK (a diterpene that augments the intracellular level of cAMP) led to GTP-loading of Rap1. Epac1 mRNA was expressed in UND and DF PLB-985 cells, but Epac1 protein was only detected in DF PLB-985 cells. In human neutrophils, the Epac1 transcript was present, and Epac1 protein could be detected by Western blot analysis if the cells had been treated with the serine protease inhibitor PMSF. FK induced adhesion of PLB-985 cells and human neutrophils on fibrinogen, a ligand for beta 2 integrins. Interestingly, in DF PLB-985 cells, but not in human neutrophils, 8CPT-2Me-cAMP induced beta 2 integrin-dependent adhesion. The failure of 8CPT-2Me-cAMP to induce beta 2 integrin-dependent human neutrophil adhesion could be explained by the fact that this compound did not induce a switch of the beta 2 integrins from a low-affinity to a high-affinity ligand-binding conformation. We concluded that Epac1 is expressed in human neutrophils and is involved in cAMP-dependent regulation of Rap1. However, the loading of GTP on Rap1 per se is not sufficient to promote activation of beta 2 integrins. J. Leukoc. Biol. 90: 741-749; 2011.

Contact, trust and social capital in Northern Ireland: a qualitative study of three mixed communities

In a recent paper, Robert Putnam (2007) challenges the contact hypothesis by arguing that ethnic diversity causes people to ‘hunker down’ and essentially withdraw themselves from society. Drawing on
qualitative data collected from three mixed communities in Northern Ireland, this paper explores the extent and quality of contact experienced by Protestants and Catholics in their everyday lives. Themes emerging from our data are generally consistent with the contact hypothesis. There is also some support for Putnam’s theory that mixed environments can induce ‘hunkering down’ and that inter-group trust may be compromised. However, our data challenge Putnam’s argument that these responses are a consequence of ‘anomie’ or ‘social malaise’. Rather, we find that withdrawal from social activity in the neighbourhoods we observed was a calculated response at times of threat, often aimed at protecting existent positive inter-ethnic relations.

Delayed lethality, apoptosis and micronucleus formation in human fibroblasts irradiated with X-rays or alpha-particles

Purpose: To determine the yields of cell lethality and micronucleus formation measured immediately after irradiation or at delayed times in primary human fibroblasts exposed to X-rays or alpha-particles.

Principal Component Analysis of Wide Area Phasor Measurements for Islanding Detection – A Geometric View

This paper presents a new technique for the detectionof islanding conditions in electrical power systems. This problem isespecially prevalent in systems with significant penetrations of distributedrenewable generation. The proposed technique is based onthe application of principal component analysis (PCA) to data setsof wide-area frequency measurements, recorded by phasor measurementunits. The PCA approach was able to detect islandingaccurately and quickly when compared with conventional RoCoFtechniques, as well as with the frequency difference and change-ofangledifference methods recently proposed in the literature. Thereliability and accuracy of the proposed PCA approach is demonstratedby using a number of test cases, which consider islandingand nonislanding events. The test cases are based on real data,recorded from several phasor measurement units located in theU.K. power system.

The histamine H4 receptor is a potent inhibitor of adhesion-dependent degranulation in human neutrophils

The histamine H4 receptor regulates the inflammatory response. However, it is not known whether this receptor has a functional role in human neutrophils. We found that fMLP (1 μM), but not histamine (0.1-1 μM), induced Mac-1-dependent adhesion, polarization, and degranulation (release of lactoferrin). A pretreatment of neutrophils with histamine (0.001-1 μM) or JNJ 28610244 (0.1-10 μM), a specific H4 receptor agonist, led to inhibition of degranulation. Total inhibition of degranulation was obtained with 0.1 μM histamine and 10 μM JNJ 28610244. Furthermore, such inhibition by histamine of degranulation was reversed by JNJ 7777120 and JNJ 28307474, two selective H4 receptor antagonists. However, neither histamine nor the H4 receptor agonist JNJ 28610244 prevented fMLP-induced, Mac-1-dependent adhesion, indicating that the H4 receptor may block signals emanating from Mac-1-controlling degranulation. Likewise, engagement of the H4 receptor by the selective agonist JNJ 28610244 blocked Mac-1-dependent activation of p38 MAPK, the kinase that controls neutrophil degranulation. We also show expression of the H4 receptor at the mRNA level in ultrapure human neutrophils and myeloid leukemia PLB-985 cells. We concluded that engagement of this receptor by selective H4 receptor agonists may represent a good, therapeutic approach to accelerate resolution of inflammation.