Modulation of human lymphocyte function by C3a and C3a(70-77).

Human C3a and the synthetic octapeptide C3a (70-77), which retains the activities of an anaphylatoxin, inhibit in a concentration-dependent manner the generation of leukocyte inhibitory factor (LIF) activity by human mononuclear leukocytes and T lymphocytes cultured with the mitogens phytohemagglutinin (PHA) or concanavalin A (Con A) or the antigen streptokinase-streptodornase (SK-SD). The generation of LIF activity was inhibited by 50% by 10(-8) M C3a or C3a(70-77) with PHA or Con A as the stimulus, whereas a more than 10-fold higher concentration of C3a(70-77) than C3a was required to achieve the same level of suppression with SK-SD as the stimulus. Similar concentrations of C3a(70-77) inhibited to the same extent the migration of T lymphocytes stimulated by alpha-thioglycerol of Con A. Neither C3a nor C3a(70-77) altered significantly the uptake of [3H]thymidine by human mononuclear cells exposed to PHA, Con A, or SK-SD. The capacity of C3a(70-77)-Sepharose,m but not Sepharose alone, to adsorb or inactivate mononuclear leukocytes required for the generation of LIF activity established a direct interaction. Analysis of the lymphocytes in the effluent from C3a(70-77)-Sepharose columns, using monoclonal antibodies to surface antigens, showed a selective depletion of the helper/inducer population of lymphocytes. C3a might represent an important mediator of the functionally selective regulation of human T lymphocyte activities by the complement system

Demography and disorders of the French Bulldog population under primary veterinary care in the UK in 2013

Abstract Background Despite its Gallic name, the French Bulldog is a breed of both British and French origin that was first recognised by The Kennel Club in 1906. The French Bulldog has demonstrated recent rapid rises in Kennel Club registrations and is now (2017) the second most commonly registered pedigree breed in the UK. However, the breed has been reported to be predisposed to several disorders including ocular, respiratory, neurological and dermatological problems. The VetCompass™ Programme collates de-identified clinical data from primary-care veterinary practices in the UK for epidemiological research. Using VetCompass™ clinical data, this study aimed to characterise the demography and common disorders of the general population of French Bulldogs under veterinary care in the UK. Results French Bulldogs comprised 2228 (0.49%) of 445,557 study dogs under veterinary care during 2013. Annual proportional birth rates showed that the proportional ownership of French Bulldog puppies rose steeply from 0.02% of the annual birth cohort attending VetCompass™ practices in 2003 to 1.46% in 2013. The median age of the French Bulldogs overall was 1.3 years (IQR 0.6–2.5, range 0.0–13.0). The most common colours of French Bulldogs were brindle (solid or main) (32.36%) and fawn (solid or main) (29.9%). Of the 2228 French Bulldogs under veterinary care during 2013, 1612 (72.4%) had at least one disorder recorded. The most prevalent fine-level precision disorders recorded were otitis externa (14.0%, 95% CI: 12.6–15.5), diarrhoea (7.5%, 95% CI: 6.4–8.7), conjunctivitis (3.2%, 95% CI: 2.5–4.0), nails overlong (3.1%, 95% CI% 2.4–3.9) and skin fold dermatitis (3.0%, 95% CI% 2.3–3.8). The most prevalent disorder groups were cutaneous (17.9%, 95% CI: 16.3–19.6), enteropathy (16.7%, 95% CI: 15.2–18.3), aural (16.3%, 95% CI: 14.8–17.9), upper respiratory tract (12.7%, 95% CI: 11.3–14.1) and ophthalmological (10.5%, 95% CI: 9.3–11.9). Conclusions Ownership of French Bulldogs in the UK is rising steeply. This means that the disorder profiles reported in this study reflect a current young UK population and are likely to shift as this cohort ages. Otitis externa, diarrhoea and conjunctivitis were the most common disorders in French Bulldogs. Identification of health priorities based on VetCompass™ data can support evidence–based reforms to improve health and welfare within the breed

Conserved intron positions in ancient protein modules

BACKGROUND: The timing of the origin of introns is of crucial importance for an understanding of early genome architecture. The Exon theory of genes proposed a role for introns in the formation of multi-exon proteins by exon shuffling and predicts the presence of conserved splice sites in ancient genes. In this study, large-scale analysis of potential conserved splice sites was performed using an intron-exon database (ExInt) derived from GenBank. RESULTS: A set of conserved intron positions was found by matching identical splice sites sequences from distantly-related eukaryotic kingdoms. Most amino acid sequences with conserved introns were homologous to consensus sequences of functional domains from conserved proteins including kinases, phosphatases, small GTPases, transporters and matrix proteins. These included ancient proteins that originated before the eukaryote-prokaryote split, for instance the catalytic domain of protein phosphatase 2A where a total of eleven conserved introns were found. Using an experimental setup in which the relation between a splice site and the ancientness of its surrounding sequence could be studied, it was found that the presence of an intron was positively correlated to the ancientness of its surrounding sequence. Intron phase conservation was linked to the conservation of the gene sequence and not to the splice site sequence itself. However, no apparent differences in phase distribution were found between introns in conserved versus non-conserved sequences. CONCLUSION: The data confirm an origin of introns deep in the eukaryotic branch and is in concordance with the presence of introns in the first functional protein modules in an 'Exon theory of genes' scenario. A model is proposed in which shuffling of primordial short exonic sequences led to the formation of the first functional protein modules, in line with hypotheses that see the formation of introns integral to the origins of genome evolution. REVIEWERS: This article was reviewed by Scott Roy (nominated by Anthony Poole), Sandro de Souza (nominated by Manyuan Long), and Gáspár Jékely

Modelling evolution on design-by-contract predicts an origin of Life through an abiotic double-stranded RNA world

BACKGROUND: It is generally believed that life first evolved from single-stranded RNA (ssRNA) that both stored genetic information and catalyzed the reactions required for self-replication. PRESENTATION OF THE HYPOTHESIS: By modeling early genome evolution on the engineering paradigm design-by-contract, an alternative scenario is presented in which life started with the appearance of double-stranded RNA (dsRNA) as an informational storage molecule while catalytic single-stranded RNA was derived from this dsRNA template later in evolution. TESTING THE HYPOTHESIS: It was investigated whether this scenario could be implemented mechanistically by starting with abiotic processes. Double-stranded RNA could be formed abiotically by hybridization of oligoribonucleotides that are subsequently non-enzymatically ligated into a double-stranded chain. Thermal cycling driven by the diurnal temperature cycles could then replicate this dsRNA when strands of dsRNA separate and later rehybridize and ligate to reform dsRNA. A temperature-dependent partial replication of specific regions of dsRNA could produce the first template-based generation of catalytic ssRNA, similar to the developmental gene transcription process. Replacement of these abiotic processes by enzymatic processes would guarantee functional continuity. Further transition from a dsRNA to a dsDNA world could be based on minor mutations in template and substrate recognition sites of an RNA polymerase and would leave all existing processes intact. IMPLICATIONS OF THE HYPOTHESIS: Modeling evolution on a design pattern, the 'dsRNA first' hypothesis can provide an alternative mechanistic evolutionary scenario for the origin of our genome that preserves functional continuity. REVIEWERS: This article was reviewed by Anthony Poole, Eugene Koonin and Eugene Shakhnovic

Age-dependent sensitization to the 7S-vicilin-like protein Cor a 11 from hazelnut (Corylus avellana) in a birch-endemic region

Background: Hazelnut (Corylus avellana) allergy exhibits age and geographically distinct sensitization patterns that have not yet been fully resolved. Objective: To study sensitization to Cor a 11 in different age groups of hazelnut-allergic patients and infants with atopic dermatitis (AD) sensitized to hazelnut in a birch-endemic region. Methods: Sera from 80 hazelnut-allergic patients, 33 infants under 1 year of age with AD (24 sensitized and 9 not sensitized to hazelnut), 32 healthy control individuals, and 29 birch pollen–allergic but hazelnut-tolerant individuals were tested for immunoglobulin (Ig) E reactivity to Cor a 11 by ImmunoCAP. IgE reactivity to Cor a 1.01, Cor a 1.04, Cor a 8, and Cor a 9 was studied by ISAC microarray. Results: Forty patients (22 preschool children, 10 schoolchildren, and 8 adults) with systemic reactions on consumption of hazelnut were sensitized to Cor a 11 (respective rates of 36%, 40%, and 12.5%). Forty patients (6 preschool children, 10 schoolchildren, and 24 adults) reported oral allergy syndrome but only 2 of them (of preschool age) were sensitized to Cor a 11. Two (8%) of the AD infants sensitized to hazelnut showed IgE reactivity to Cor a 11. This reactivity was not observed in any of the AD infants without sensitization to hazelnut, in any of the birch-pollen allergic patients without hazelnut allergy, or in any of the healthy control individuals. Conclusion: Sensitization to Cor a 11 in a birch-endemic region is predominantly found in children with severe hazelnut allergy, a finding that is consistent with observations concerning sensitization to Cor a 9

Massive Gravity Simplified: A Quadratic Action

We present a simplified formulation of massive gravity where the Higgs fields have quadratic kinetic term. This new formulation allows us to prove in a very explicit way that all massive gravity theories considered so far inevitably have Boulware-Deser ghost in non-trivial fluctuations of background metric.Comment: 8 pages, paragraph added proving that Bianchi identity does not imply vanishing of linearized curvatur

Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey.

Antibodies directed against fetal brain proteins of 37 and 73 kDa molecular weight are found in approximately 12% of mothers who have children with autism spectrum disorder (ASD), but not in mothers of typically developing children. This finding has raised the possibility that these immunoglobulin G (IgG) class antibodies cross the placenta during pregnancy and impact brain development, leading to one form of ASD. We evaluated the pathogenic potential of these antibodies by using a nonhuman primate model. IgG was isolated from mothers of children with ASD (IgG-ASD) and of typically developing children (IgG-CON). The purified IgG was administered to two groups of female rhesus monkeys (IgG-ASD; n=8 and IgG-CON; n=8) during the first and second trimesters of pregnancy. Another control group of pregnant monkeys (n=8) was untreated. Brain and behavioral development of the offspring were assessed for 2 years. Behavioral differences were first detected when the macaque mothers responded to their IgG-ASD offspring with heightened protectiveness during early development. As they matured, IgG-ASD offspring consistently deviated from species-typical social norms by more frequently approaching familiar peers. The increased approach was not reciprocated and did not lead to sustained social interactions. Even more striking, IgG-ASD offspring displayed inappropriate approach behavior to unfamiliar peers, clearly deviating from normal macaque social behavior. Longitudinal magnetic resonance imaging analyses revealed that male IgG-ASD offspring had enlarged brain volume compared with controls. White matter volume increases appeared to be driving the brain differences in the IgG-ASD offspring and these differences were most pronounced in the frontal lobes

Megaprojects as niches of sociotechnical transitions: The case of digitalization in UK construction

Transitions are processes of systemic change where niches peripheral to a sociotechnical regime accumulate momentum, scale up and eventually transform its core. In contrast to this dominant narrative in transitions research, infrastructure systems exhibit the reverse process as change propagates from the regime core to its periphery. We explore this under-researched process in the case of digitalization in UK construction. We analyse six UK megaprojects that span more than 30 years as a single longitudinal embedded case, and show how the adoption of digital technologies driven by regime incumbents, seeds the processes of technology adaptation, aggregation, and system transformation. The adoption of digital technologies by incumbents is necessary to cope with megaproject scale and scope. Their adaptation to technology instigates organizational level change that starts at the regime core, accumulates with each project and makes these changes ripple across the industry and transform it

Cell biology:Collagen secretion explained

Cells package proteins into vesicles for secretion to the extracellular milieu. A study shows that an enzyme modifies the packaging machinery to encapsulate unusually large proteins such as collagen

Collaborative research and development (R&D) for climate technology transfer and uptake in developing countries: Towards a needs driven approach

While international cooperation to facilitate the transfer and uptake of climate technologies in developing countries is an ongoing part of climate policy conversations, international collaborative R&D has received comparatively little attention. Collaborative R&D, however, could be a potentially important contributor to facilitating the transfer and uptake of climate technologies in developing countries. But the complexities of international collaborative R&D options and their distributional consequences have been given little attention to date. This paper develops a systematic approach to informing future empirical research and policy analysis on this topic. Building on insights from relevant literature and analysis of empirical data based on a sample of existing international climate technology R&D initiatives, three contributions are made. First, the paper analyses the coverage of existing collaborative R&D efforts in relation to climate technologies, highlighting some important concerns, such as a lack of coverage of lower-income countries or adaptation technologies. Second, it provides a starting point for further systematic research and policy thinking via the development of a taxonomic approach for analysing collaborative designs. Finally, it matches characteristics of R&D collaborations against developing countries’ climate technology needs to provide policymakers with guidance on how to Configure R&D collaborations to meet these needs