Evidence in Sheep for Pre-Natal Transmission of Scrapie to Lambs from Infected Mothers

Natural scrapie transmission from infected ewes to their lambs is thought to occur by the oral route around the time of birth. However the hypothesis that scrapie transmission can also occur before birth (in utero) is not currently favoured by most researchers. As scrapie is an opportunistic infection with multiple infection routes likely to be functional in sheep, definitive evidence for or against transmission from ewe to her developing fetus has been difficult to achieve. In addition the very early literature on maternal transmission of scrapie in sheep was compromised by lack of knowledge of the role of the PRNP (prion protein) gene in control of susceptibility to scrapie. In this study we experimentally infected pregnant ewes of known PRNP genotype with a distinctive scrapie strain (SSBP/1) and looked for evidence of transmission of SSBP/1 to the offspring. The sheep were from the NPU Cheviot flock, which has endemic natural scrapie from which SSBP/1 can be differentiated on the basis of histology, genetics of disease incidence and strain typing bioassay in mice. We used embryo transfer techniques to allow sheep fetuses of scrapie-susceptible PRNP genotypes to develop in a range of scrapie-resistant and susceptible recipient mothers and challenged the recipients with SSBP/1. Scrapie clinical disease, caused by both natural scrapie and SSBP/1, occurred in the progeny but evidence (including mouse strain typing) of SSBP/1 infection was found only in lambs born to fully susceptible recipient mothers. Progeny were not protected from transmission of natural scrapie or SSBP/1 by washing of embryos to International Embryo Transfer Society standards or by caesarean derivation and complete separation from their birth mothers. Our results strongly suggest that pre-natal (in utero) transmission of scrapie may have occurred in these sheep.     

IBC’s 23rd Annual Antibody Engineering, 10th Annual Antibody Therapeutics International Conferences and the 2012 Annual Meeting of The Antibody Society

The 23rd Annual Antibody Engineering, 10th Annual Antibody Therapeutics international conferences, and the 2012 Annual Meeting of The Antibody Society, organized by IBC Life Sciences with contributions from The Antibody Society and two Scientific Advisory Boards, were held December 3–6, 2012 in San Diego, CA. The meeting drew over 800 participants who attended sessions on a wide variety of topics relevant to antibody research and development. As a prelude to the main events, a pre-conference workshop held on December 2, 2012 focused on intellectual property issues that impact antibody engineering. The Antibody Engineering Conference was composed of six sessions held December 3–5, 2012: (1) From Receptor Biology to Therapy; (2) Antibodies in a Complex Environment; (3) Antibody Targeted CNS Therapy: Beyond the Blood Brain Barrier; (4) Deep Sequencing in B Cell Biology and Antibody Libraries; (5) Systems Medicine in the Development of Antibody Therapies/Systematic Validation of Novel Antibody Targets; and (6) Antibody Activity and Animal Models. The Antibody Therapeutics conference comprised four sessions held December 4–5, 2012: (1) Clinical and Preclinical Updates of Antibody-Drug Conjugates; (2) Multifunctional Antibodies and Antibody Combinations: Clinical Focus; (3) Development Status of Immunomodulatory Therapeutic Antibodies; and (4) Modulating the Half-Life of Antibody Therapeutics. The Antibody Society’s special session on applications for recording and sharing data based on GIATE was held on December 5, 2012, and the conferences concluded with two combined sessions on December 5–6, 2012: (1) Development Status of Early Stage Therapeutic Antibodies; and (2) Immunomodulatory Antibodies for Cancer Therapy.     

Roux-en-Y Gastric Bypass Increases Intravenous Ethanol Self-Administration in Dietary Obese Rats

Roux-en-Y gastric bypass surgery (RYGB) is an effective treatment for severe obesity. Clinical studies however have reported susceptibility to increased alcohol use after RYGB, and preclinical studies have shown increased alcohol intake in obese rats after RYGB. This could reflect a direct enhancement of alcohol’s rewarding effects in the brain or an indirect effect due to increased alcohol absorption after RGYB. To rule out the contribution that changes in alcohol absorption have on its rewarding effects, here we assessed the effects of RYGB on intravenously (IV) administered ethanol (1%). For this purpose, high fat (60% kcal from fat) diet-induced obese male Sprague Dawley rats were tested ∼2 months after RYGB or sham surgery (SHAM) using both fixed and progressive ratio schedules of reinforcement to evaluate if RGYB modified the reinforcing effects of IV ethanol. Compared to SHAM, RYGB rats made significantly more active spout responses to earn IV ethanol during the fixed ratio schedule, and achieved higher breakpoints during the progressive ratio schedule. Although additional studies are needed, our results provide preliminary evidence that RYGB increases the rewarding effects of alcohol independent of its effects on alcohol absorption.     

Ecological Modeling from Time-Series Inference: Insight into Dynamics and Stability of Intestinal Microbiota

The intestinal microbiota is a microbial ecosystem of crucial importance to human health. Understanding how the microbiota confers resistance against enteric pathogens and how antibiotics disrupt that resistance is key to the prevention and cure of intestinal infections. We present a novel method to infer microbial community ecology directly from time-resolved metagenomics. This method extends generalized Lotka–Volterra dynamics to account for external perturbations. Data from recent experiments on antibiotic-mediated Clostridium difficile infection is analyzed to quantify microbial interactions, commensal-pathogen interactions, and the effect of the antibiotic on the community. Stability analysis reveals that the microbiota is intrinsically stable, explaining how antibiotic perturbations and C. difficile inoculation can produce catastrophic shifts that persist even after removal of the perturbations. Importantly, the analysis suggests a subnetwork of bacterial groups implicated in protection against C. difficile. Due to its generality, our method can be applied to any high-resolution ecological time-series data to infer community structure and response to external stimuli.     

Interferon-Inducible Mechanism of Dendritic Cell-Mediated HIV-1 Dissemination Is Dependent on Siglec-1/CD169

Human immunodeficiency virus type 1 (HIV-1) interactions with myeloid dendritic cells (DCs) can result in virus dissemination to CD4⁺ T cells via a trans infection pathway dependent on virion incorporation of the host cell derived glycosphingolipid (GSL), GM3. The mechanism of DC-mediated trans infection is extremely efficacious and can result in infection of multiple CD4⁺ T cells as these cells make exploratory contacts on the DC surface. While it has long been appreciated that activation of DCs with ligands that induce type I IFN signaling pathway dramatically enhances DC-mediated T cell trans infection, the mechanism by which this occurs has remained unclear until now. Here, we demonstrate that the type I IFN-inducible Siglec-1, CD169, is the DC receptor that captures HIV in a GM3-dependent manner. Selective downregulation of CD169 expression, neutralizing CD169 function, or depletion of GSLs from virions, abrogated DC-mediated HIV-1 capture and trans infection, while exogenous expression of CD169 in receptor-naïve cells rescued GSL-dependent capture and trans infection. HIV-1 particles co-localized with CD169 on DC surface immediately following capture and subsequently within non-lysosomal compartments that redistributed to the DC – T cell infectious synapses upon initiation of T cell contact. Together, these findings describe a novel mechanism of pathogen parasitization of host encoded cellular recognition machinery (GM3 – CD169 interaction) for DC-dependent HIV dissemination.     

Wild fledgling tits do not mob in response to conspecific or heterospecific mobbing calls

Mobbing, where birds harass a predator through a combination of vocalizations and stereotyped behaviours, is an effective anti-predator behaviour for many species. Mobbing may be particularly important for juveniles, as these individuals are often more vulnerable than adults. Although the component behaviours of mobbing are often considered to be un-learned, there are few confirmatory data, and the developmental trajectory of mobbing is unknown. In this study, we tested whether conspecific or heterospecific mobbing calls initiated mobbing behaviour in juvenile Blue Tits Cyanistes caeruleus. We located wild adult and recently fledged juvenile Blue Tits and presented them with playback recordings of adult conspecific (Blue Tit) and heterospecific (Great Tit Parus major) mobbing alarm calls. Although adult birds readily mob in response to these types of playbacks, juveniles did not exhibit characteristic mobbing behaviour. Some juveniles did, however, exhibit individual components of mobbing behaviour found in mobbing, despite not producing adult-like mobbing behaviour in response to either conspecific or heterospecific playback. These results suggest that, although birds might be capable of mobbing as juveniles, the associations between the non-vocal stereotyped mobbing behaviours and mobbing calls may be learned.     

The Four Canonical TPR Subunits of Human APC/C Form Related Homo-Dimeric Structures and Stack in Parallel to Form a TPR Suprahelix

The anaphase-promoting complex or cyclosome (APC/C) is a large E3 RING-cullin ubiquitin ligase composed of between 14 and 15 individual proteins. A striking feature of the APC/C is that only four proteins are involved in directly recognizing target proteins and catalyzing the assembly of a polyubiquitin chain. All other subunits, which account for > 80% of the mass of the APC/C, provide scaffolding functions. A major proportion of these scaffolding subunits are structurally related. In metazoans, there are four canonical tetratricopeptide repeat (TPR) proteins that form homo-dimers (Apc3/Cdc27, Apc6/Cdc16, Apc7 and Apc8/Cdc23). Here, we describe the crystal structure of the N-terminal homo-dimerization domain of Schizosaccharomyces pombe Cdc23 (Cdc23^Nterm). Cdc23^Nterm is composed of seven contiguous TPR motifs that self-associate through a related mechanism to those of Cdc16 and Cdc27. Using the Cdc23^Nterm structure, we generated a model of full-length Cdc23. The resultant “V”-shaped molecule docks into the Cdc23-assigned density of the human APC/C structure determined using negative stain electron microscopy (EM). Based on sequence conservation, we propose that Apc7 forms a homo-dimeric structure equivalent to those of Cdc16, Cdc23 and Cdc27. The model is consistent with the Apc7-assigned density of the human APC/C EM structure. The four canonical homo-dimeric TPR proteins of human APC/C stack in parallel on one side of the complex. Remarkably, the uniform relative packing of neighboring TPR proteins generates a novel left-handed suprahelical TPR assembly. This finding has implications for understanding the assembly of other TPR-containing multimeric complexes.     

Pellet contents of the Barn Owl,Tyto alba,near Samandag,Turkey

Summary

Weights and standard measurements are given of 568 individuals of 52 bird species ringed in various localities in Turkey in July and August 1973. The Melodious Warbler, Hippolais polyglotta, was recorded in Turkey for the first time.