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Xenotransplantation from pigs could alleviate the shortage of human tissues and organs for transplantation. Means have been identified to overcome hyperacute rejection and acute vascular rejection mechanisms mounted by the recipient. The challenge is to combine multiple genetic modifications to enable normal animal breeding and meet the demand for transplants. We used two methods to colocate xenoprotective transgenes at one locus, sequential targeted transgene placement - ‘gene stacking’ and cointegration of multiple engineered large vectors - ‘combineering’, to generate pigs carrying modifications considered necessary to inhibit short to mid-term xenograft rejection. Pigs were generated by serial nuclear transfer and analysed at intermediate stages. Human complement inhibitors CD46, CD55 and CD59 were abundantly expressed in all tissues examined, human HO1 and human A20 were widely expressed. ZFN or CRISPR/Cas9 mediated homozygous GGTA1 and CMAH knockout abolished α-Gal and Neu5Gc epitopes. Cells from multi-transgenic piglets showed complete protection against human complement-mediated lysis, even before GGTA1 knockout. Blockade of endothelial activation reduced TNFα-induced E-selectin expression, IFNγ-induced MHC class-II upregulation and TNFα/cycloheximide caspase induction. Microbial analysis found no PERV-C, PCMV or 13 other infectious agents. These animals are a major advance towards clinical porcine xenotransplantation and demonstrate that livestock engineering has come of age.

Mutation of the tumor suppressor p53 plays a major role in human carcinogenesis. Here we describe gene-targeted porcine mesenchymal stem cells (MSCs) and live pigs carrying a latent TP53(R167H) mutant allele, orthologous to oncogenic human mutant TP53(R175H) and mouse Trp53(R172H), that can be activated by Cre recombination. MSCs carrying the latent TP53(R167H) mutant allele were analyzed in vitro. Homozygous cells were p53 deficient, and on continued culture exhibited more rapid proliferation, anchorage independent growth, and resistance to the apoptosis-inducing chemotherapeutic drug doxorubicin, all characteristic of cellular transformation. Cre mediated recombination activated the latent TP53(R167H) allele as predicted, and in homozygous cells expressed mutant p53-R167H protein at a level ten-fold greater than wild-type MSCs, consistent with the elevated levels found in human cancer cells. Gene targeted MSCs were used for nuclear transfer and fifteen viable piglets were produced carrying the latent TP53(R167H) mutant allele in heterozygous form. These animals will allow study of p53 deficiency and expression of mutant p53-R167H to model human germline, or spontaneous somatic p53 mutation. This work represents the first inactivation and mutation of the gatekeeper tumor suppressor gene TP53 in a non-rodent mammal.

Oncogenic mutations of KRAS play a major role in human carcinogenesis. Here we describe viable gene-targeted pigs carrying a latent KRAS G12D mutant allele that can be activated by Cre recombination. These have been produced as part of a program to model human cancers in pigs by replicating genetic lesions known to initiate and drive human disease. Cre-activated KRAS G12D animals add to a growing set of gene-targeted pigs that includes a Cre-activated oncogenic mutant TP53 , a Cre-responsive dual fluorescent reporter and two truncating mutations of APC (adenomatous polyposis coli). These alleles can be combined and activated in various tissues to produce new models for cancer research.

Objectives The VIBRANT SOUNDBRIDGE is a widely used active middle ear implant to treat hearing loss. The floating mass transducer is surgically coupled to the ossicles, the round or oval window. A reliable method to monitor the coupling efficiency intraoperatively is highly desired. Research groups have developed several methods, but limitations remain. This study aims to evaluate the clinical feasibility of a new research setup for auditory brainstem response measurement to evaluate the coupling efficiency. Method In 14 subjects, the new tool was used to record VSB‐evoked ABR thresholds during surgery. The intra‐op ABR thresholds were compared to pre‐op bone conduction (BC) thresholds and post‐op vibrogram thresholds to evaluate the feasibility of the method as a tool to monitor coupling efficiency. Results The mean pre‐op BC threshold average at 1, 2, and 4 kHz (PTA3) was 47 dB HL, the mean intra‐op ABR threshold was 54 dB nHL, and the mean post‐op vibrogram PTA3 was 60 dB HLeq. ABR was measurable in all subjects using the new tool. Correlation between pre‐op BC thresholds and intra‐op ABR thresholds was statistically significant; however, one outlier was present. Conclusion Intra‐op hearing threshold detection through ABR and direct stimulation of the VSB implant was reliable using this new tool. Despite some individual variability, first results correlate well with pre‐op BC and post‐op vibrogram thresholds. The VIBRANT SOUNDBRIDGE couples the floating mass transducer to the ossicles to treat mild to severe sensorineural, conductive, or mixed hearing loss. A reliable method to monitor the coupling efficiency intraoperatively is highly desired. This study aims to evaluate the clinical feasibility of a new research setup for auditory brainstem response measurement to evaluate the coupling efficiency.

Purpose - Based on an in-depth comparison of 20 multicultural university curricula, this article aims to provide practical and implementable suggestions about how to improve such curricula in order to ensure highest and globally compatible academic quality. The recently founded developmental Master's curriculum \"Global Studies\" (GS) at the University of Graz, Austria serves as a case study.Design methodology approach - Through an academic web-based process of authoring and reviewing, over a dozen students and practitioners in Global Studies have compiled this analysis. Such an approach shows that education technologies significantly enhance peer-oriented scientific culture. Further networking among universities from every continent, and their students, is also facilitated.Findings - Analyses conducted by over 50 contributors during 2010-2013 show first that the Graz-based curriculum has achieved international quality standards by spanning multiple faculties, disciplines, professional roles, and perspectives regarding globalisation. Secondly, suggestions for improvements pertaining to nine aggregated issues are provided: partner universities, semester abroad, interdisciplinarity, didactics & lectures, practicals, languages, electives, admission of students, and exams.Practical implications - The present specific recommendations serve as valuable evidence-based and authentic input for quality assessment procedures at Graz University, and similarly for other academic curricula elsewhere.Social implications - Peer-oriented higher education profits greatly from student input that has undergone an academic peer review procedure. Such quality assurance is favourably implemented via collaborative education technologies such as web platforms with discussion fora.Originality value - Students as the core target group in higher education institutions express their own opinion and are valued as experts and stakeholders in a genuinely democratic procedure.