Maternal coding variants in complement receptor 1 and spontaneous idiopathic preterm birth

Preterm birth (PTB) is a major global public health concern. However, little is known about the pathophysiology of spontaneous idiopathic PTB. We tested the hypothesis that rare variants in families would target specific genes and pathways that contribute to PTB risk in the general population. Whole-exome sequencing was performed on 10 PTB mothers from densely affected families including two mother–daughter pairs. We identified novel variants shared between the two mother–daughter pairs when compared to a 1000 Genomes Project background exome file and investigated these genes for pathway aggregation using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Genes in enriched pathways were then surveyed in the other six PTB exomes and tested for association in a larger number of nuclear families. The KEGG complement and coagulation cascade was one of the most enriched pathways in our two mother–daughter pairs. When the six genes found in this pathway (CFH, CR1, F13B, F5, CR2, and C4BPA) were examined for novel missense variants, half of all the exomes harbored at least one. Association analysis of variants in these six gene regions in nuclear families from Finland (237 cases and 328 controls) found statistically significant associations after multiple test corrections in three CR1 SNPs; the strongest in an exonic missense SNP, rs6691117, p value = 6.91e?5, OR = 1.71. Our results demonstrate the importance of the complement and coagulation cascades in the pathophysiology of PTB, and suggest potential screening and intervention approaches to prevent prematurity that target this pathway.     

Host genetic risk factors for community-acquired pneumonia

This study was conducted to establish the contribution of genetic host factors in the susceptibility to community acquired pneumonia (CAP) in the Russian population. Patients with CAP (n = 334), volunteers without a previous history of CAP, constantly exposed to infectious agents, control A group (n = 141) and a second control group B consisted of healthy persons (n = 314) were included in the study. All subjects were genotyped for 13 polymorphic variants in the genes of xenobiotics detoxification CYP1A1 (rs2606345, rs4646903, and rs1048943), GSTM1 (Ins/del), GSTT1 (Ins/del), ABCB1 rs1045642); immune and inflammation response IL-6 (rs1800795), TNF-a (rs1800629), MBL2 (rs7096206), CCR5 (rs333), NOS3 (rs1799983), angiotensin-converting enzyme ACE (rs4340), and occlusive vascular disease/hyperhomocysteinemia MTHFR (rs1801133). Seven polymorphic variants in genes CYP1A1, GSTM1, ABCB1, NOS3, IL6, CCR5 and ACE were associated with CAP. For two genes CYP1A1 and GSTM1 associations remained significant after correction for multiple comparisons. Multiple analysis by the number of all risk genotypes showed a highly significant association with CAP (P = 2.4 × 10^− 7, OR = 3.03, 95% CI 1.98–4.64) with the threshold for three risk genotypes. Using the ROC-analysis, the AUC value for multi-locus model was estimated as 68.38.     

Birch pollen-associated peanut allergies in children

Panallergens show structural similarities, and they are responsible for many cross-reactions between pollen and plant food sources. The aim of the present study was to investigate IgE reactivity to peanut allergen components in children with birch pollen allergy. Patients experienced symptoms of allergic asthma, allergic rhinitis, and urticaria, and they underwent a complete diagnostic evaluation, including skin prick test (SPT), specific IgE (sIgE) to birch pollen allergen (t3), peanut allergen (f13). In addition, measurement of sIgE to the major birch allergen components, Betula verrucosa (Bet v1, Bet v2), and to peanut allergen components, Arachis hypogaea (genuine componens: Ara h1, Ara h2, Ara h3, and cross-reactive Ara h8) was performed, by using a microarray technique (component resolved diagnosis, CRD). SPT to birch extract was positive in all children, and SPT to peanut extract was positive in 51 % of them. sIgE to both allergens was increased in 39 % of children, 55 % of them had increased sIgE (t3), and one child had increased sIgE (f13). CRD results confirmed that some children were sensitized to Bet v1 only, and some children to genuine Ara h only. Bet v1/Ara h8 cross-reactivity was found in 16 % of children. Results of the present study reveal that SPT, sIgE, and CRD may detect sensitization and co-sensitization with birch and peanut allergens/allergen components, and CRD may help to differentiate sensitization to genuine peanut components from sensitization to peanut cross-reactive component in birch-sensitive children. Diagnostic approach has to be individualized for each patient.     

Attempted Integration of Multiple Species of Turaco Into a Mixed‐Species Aviary

Mixed‐species exhibits offer a variety of benefits but can be challenging to maintain due to difficulty in managing interspecific interactions. This is particularly true when little has been documented on the behavior of the species being mixed. This was the case when we attempted to house three species of turaco (family: Musophagidae) together with other species in a walk‐through aviary. To learn more about the behavior of great blue turacos, violaceous turacos, and white‐bellied gray go‐away birds, we supplemented opportunistic keeper observations with systematic data collection on their behavior, location, distance from other birds, and visibility to visitors. Keepers reported high levels of aggression among turacos, usually initiated by a go‐away bird or a violaceous turaco. Most aggression occurred during feedings or when pairs were defending nest sites. Attempts to reduce aggression by temporarily removing birds to holding areas and reintroducing them days later were ineffective. Systematic data collection revealed increased social behavior, including aggression, during breeding season in the violaceous turacos, as well as greater location fidelity. These behavioral cues may be useful in predicting breeding behavior in the future. Ultimately, we were only able to house three species of turaco together for a short time, and prohibitively high levels of conflict occurred when pairs were breeding. We conclude that mixing these three turaco species is challenging and may not be the most appropriate housing situation for them, particularly during breeding season. However, changes in turaco species composition, sex composition, or exhibit design may result in more compatible mixed‐turaco species groups. Zoo Biol. 32:216–221, 2013. © 2012 Wiley Periodicals, Inc.     

Political competition,relative deprivation,and perceived threat: a research note on anti-Christian violence in India

A preliminary subnational statistical analysis of violence against Christians in contemporary India, this article suggests that whereas the data provide very little support for simple, demographic explanations of this violence, they do more robustly support theories emphasizing the relative status of ethnic and religious minorities (vis-à-vis majorities) and the perception, among Hindus, that Christians (and other minorities) represent a threat to their numerical, political and economic strength.     

Book reviews

Stephen Cornell, THE RETURN OF THE NATIVE: AMERICAN INDIAN POLITICAL RESURGENCE, New York and Oxford: Oxford University Press, 1988, 278 pp., $29.95.

Jack D. Forbes, BLACK AFRICANS AND NATIVE AMERICANS: COLOR, RACE AND CASTE IN THE EVOLUTION OF RED‐BLACK PEOPLES, Oxford and New York: Basil Blackwell, 1988, 334 pp., £35.00.

Maryon McDonald, ’WE ARE NOT FRENCH!’: LANGUAGE, CULTURE AND IDENTITY IN BRITTANY, London: Routledge, 1989, 384 pp., £40.00.

Ronald Grigor Suny, THE MAKING OF THE GEORGIAN NATION, London: I. B. Taurus and Co. Ltd., 1989, ix‐395 pp., £29.50.

Shlomo Deshen, THE MELLAH SOCIETY: JEWISH COMMUNITY LIFE IN SHERIFIAN MOROCCO, translated and revised from the Hebrew by the author. Chicago: The University of Chicago Press, 1989, xii + 152 pp., £23.95 and £9.50 (paper).

Roger Waldinger, Howard Aldrich, Robin Ward and Associates, ETHNIC ENTREPRENEURS: IMMIGRANT BUSINESS IN INDUSTRIAL SOCIETIES, Sage Series on Race and Ethnic Relations, vol. 1., Newbury Park, CA: Sage Publications, 1990, 226 pp., £29.25 and £13.95 (paper).

Saul Dubow, RACIAL SEGREGATION AND THE ORIGINS OF APARTHEID IN SOUTH AFRICA, 1919–36, St Antony's and Macmillan, London, 1989, xi and 250 pp., £35.00.

Mark Duffield, BLACK RADICALISM AND THE POLITICS OF DE‐INDUSTRIALISATION: THE HIDDEN HISTORY OF INDIAN FOUNDRY WORKERS, Avebury, 1988, 226 pp., £24.50.

John Eade, THE POLITICS OF COMMUNITY: THE BANGLADESHI COMMUNITY IN EAST LONDON, Avebury, 1989, 213 pp., £24.00.

Nicole Hahn Rafter (ed.), WHITE TRASH: THE EUGENICS FAMILY STUDIES 1877–1919, Boston: Northeastern University Press, 1988, 382 pp., £36.00.

Neil R. McMillen, DARK JOURNEY ‐ BLACK MISSISSIPPIANS IN THE AGE OF JIM CROW, Urbana, Ill: University of Illinois Press, 1989, N.P.L.     

Coarse Architecture of the Transient Receptor Potential Vanilloid 1 (TRPV1) Ion Channel Determined by Fluorescence Resonance Energy Transfer

The transient receptor potential vanilloid 1 ion channel is responsible for the perception of high temperatures and low extracellular pH, and it is also involved in the response to some pungent compounds. Importantly, it is also associated with the perception of pain and noxious stimuli. Here, we attempt to discern the molecular organization and location of the N and C termini of the transient receptor potential vanilloid 1 ion channel by measuring FRET between genetically attached enhanced yellow and cyan fluorescent protein to the N or C terminus of the channel protein, expressed in transfected HEK 293 cells or Xenopus laevis oocytes. The static measurements of the domain organization were mapped into an available cryo-electron microscopy density of the channel with good agreement. These measurements also provide novel insights into the organization of terminal domains and their proximity to the plasma membrane.     

Reciprocal epithelial:endothelial paracrine interactions during thyroid development govern follicular organization and C-cells differentiation

The thyroid is a highly vascularized endocrine gland, displaying a characteristic epithelial organization in closed spheres, called follicles. Here we investigate how endothelial cells are recruited into the developing thyroid and if they control glandular organization as well as thyrocytes and C-cells differentiation. We show that endothelial cells closely surround, and then invade the expanding thyroid epithelial cell mass to become closely associated with nascent polarized follicles. This close and sustained endothelial:epithelial interaction depends on epithelial production of the angiogenic factor, Vascular Endothelial Growth Factor-A (VEGF-A), as its thyroid-specific genetic inactivation reduced the endothelial cell pool of the thyroid by >90%. Vegfa KO also displayed decreased C-cells differentiation and impaired organization of the epithelial cell mass into follicles. We developed an ex vivo model of thyroid explants that faithfully mimicks bilobation of the thyroid anlagen, endothelial and C-cells invasion, folliculogenesis and differentiation. Treatment of thyroid explants at e12.5 with a VEGFR2 inhibitor ablated the endothelial pool and reproduced ex vivo folliculogenesis defects observed in conditional Vegfa KO. In the absence of any blood supply, rescue by embryonic endothelial progenitor cells restored folliculogenesis, accelerated lumen expansion and stimulated calcitonin expression by C-cells. In conclusion, our data demonstrate that, in developing mouse thyroid, epithelial production of VEGF-A is necessary for endothelial cells recruitment and expansion. In turn, endothelial cells control epithelial reorganization in follicles and C-cells differentiation.     

Cathepsin L silencing enhances arsenic trioxide mediated in vitro cytotoxicity and apoptosis in glioblastoma U87MG spheroids

Despite improved treatment options, glioblastoma multiforme (GBM) remains the most aggressive brain tumour with the shortest post-diagnostic survival. Arsenite (As₂O₃) is already being used in the treatment of acute promyelocytic leukaemia (APL), yet its effects on GBM have not been evaluated in detail. In U87MG cell monolayers, we have previously shown that arsenite cytotoxicity significantly increases upon transient inhibition of lysosomal protease Cathepsin L (CatL). As multicellular spheroids more closely represent in vivo tumours, we aimed to evaluate the impact of permanent CatL silencing on arsenite treatment in U87MG spheroids. CatL was stably silenced using shRNA expression plasmid packed lentiviruses. By using metabolic- and cell viability assays, we demonstrated that long-term CatL silencing significantly increased arsenite cytotoxicity in U87MG spheroids. Silenced CatL also increased arsenite-mediated apoptosis in spheroids via elevated p53 expression, Bax/Bcl2 ratio and caspase 3/7 activity, though with lower efficacy than in monolayers. Arsenite cytotoxicity was enhanced by lower CatL activity, since similar cytotoxicity increase was also observed using the novel CatL inhibitor AT094. The results have significant translational impact, since stable CatL silencing would enable the application of lower systemic doses of arsenite to achieve the desired cytotoxic effects on GBMs in vivo.