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Forced to leave New York City to move in with her aunt in South Dakota, once-wealthy orphan June comes across her mother's coin collection and determines to find a rare penny worth one million dollars so she can return to her life of privilege.

Before they are used in the clinical setting, the effectiveness of artificially produced human-derived tissue-engineered medical products should be verified in an immunodeficient animal model, such as severe combined immunodeficient mice. However, small animal models are not sufficient to evaluate large-sized products for human use. Thus, an immunodeficient large animal model is necessary in order to properly evaluate the clinical efficacy of human-derived tissue-engineered products, such as artificial grafts. Here we report the development of an immunodeficient pig model, the operational immunodeficient pig (OIDP), by surgically removing the thymus and spleen, and creating a controlled immunosuppressive protocol using a combination of drugs commonly used in the clinical setting. We find that this model allows the long-term accommodation of artificial human vascular grafts. The development of the OIDP is an essential step towards a comprehensive and clinically relevant evaluation of human cell regeneration strategies at the preclinical stage. The development of tissue-engineered vascular grafts heavily relies on the availability of large animal models that allow long-term assessment of graft patency. Here Itoh et al. propose a novel model of immunodeficient pigs that allows long-term accommodation of human cell-derived three-dimensional bioprinted vascular tubes.

Birds and bees are just the beginning for a burgeoning technology.

Pandemic virus characterized Analysis of a series of clinical isolates of the swine-origin H1N1 influenza virus reveals that in mammalian models (mice, ferrets and macaques) the current pandemic virus is associated with more severe disease than a seasonal H1N1 strain. The viruses can also infect pigs but do not cause clinical signs. All antivirus drugs tested, including Tamiflu, were effective in cell culture against the new virus, lending support to the use of these compounds as a first line of defence against the pandemic. On 11 June 2009 the World Health Organization declared that the infections caused by a new strain of influenza A virus closely related to swine viruses had reached pandemic levels. Here, one of the first US isolates of the new swine-origin H1N1 influenza virus (S-OIV) is characterized, as well as several other S-OIV isolates, both in vitro and in vivo . Influenza A viruses cause recurrent outbreaks at local or global scale with potentially severe consequences for human health and the global economy. Recently, a new strain of influenza A virus was detected that causes disease in and transmits among humans, probably owing to little or no pre-existing immunity to the new strain. On 11 June 2009 the World Health Organization declared that the infections caused by the new strain had reached pandemic proportion. Characterized as an influenza A virus of the H1N1 subtype, the genomic segments of the new strain were most closely related to swine viruses 1 . Most human infections with swine-origin H1N1 influenza viruses (S-OIVs) seem to be mild; however, a substantial number of hospitalized individuals do not have underlying health issues, attesting to the pathogenic potential of S-OIVs. To achieve a better assessment of the risk posed by the new virus, we characterized one of the first US S-OIV isolates, A/California/04/09 (H1N1; hereafter referred to as CA04), as well as several other S-OIV isolates, in vitro and in vivo . In mice and ferrets, CA04 and other S-OIV isolates tested replicate more efficiently than a currently circulating human H1N1 virus. In addition, CA04 replicates efficiently in non-human primates, causes more severe pathological lesions in the lungs of infected mice, ferrets and non-human primates than a currently circulating human H1N1 virus, and transmits among ferrets. In specific-pathogen-free miniature pigs, CA04 replicates without clinical symptoms. The assessment of human sera from different age groups suggests that infection with human H1N1 viruses antigenically closely related to viruses circulating in 1918 confers neutralizing antibody activity to CA04. Finally, we show that CA04 is sensitive to approved and experimental antiviral drugs, suggesting that these compounds could function as a first line of defence against the recently declared S-OIV pandemic.

Since being domesticated about 10,000-12,000 years ago, domestic pigs (Sus scrofa domesticus) have been selected for traits of economic importance, in particular large body size. However, Yucatan miniature pigs have been selected for small body size to withstand high temperature environment and for laboratory use. This renders the Yucatan miniature pig a valuable model for understanding the evolution of body size. We investigate the genetic signature for selection of body size in the Yucatan miniature pig. Phylogenetic distance of Yucatan miniature pig was compared to other large swine breeds (Yorkshire, Landrace, Duroc and wild boar). By estimating the XP-EHH statistic using re-sequencing data derived from 70 pigs, we were able to unravel the signatures of selection of body size. We found that both selections at the level of organism, and at the cellular level have occurred. Selection at the higher levels include feed intake, regulation of body weight and increase in mass while selection at the molecular level includes cell cycle and cell proliferation. Positively selected genes probed by XP-EHH may provide insight into the docile character and innate immunity as well as body size of Yucatan miniature pig.

Animal experimentation is necessary to characterize human diseases and design adequate therapeutic interventions. In renal transplantation research, the limited number of in vitro models involves a crucial role for in vivo models and particularly for the porcine model. Pig and human kidneys are anatomically similar (characterized by multilobular structure in contrast to rodent and dog kidneys unilobular). The human proximity of porcine physiology and immune systems provides a basic knowledge of graft recovery and inflammatory physiopathology through in vivo studies. In addition, pig large body size allows surgical procedures similar to humans, repeated collections of peripheral blood or renal biopsies making pigs ideal for medical training and for the assessment of preclinical technologies. However, its size is also its main drawback implying expensive housing. Nevertheless, pig models are relevant alternatives to primate models, offering promising perspectives with developments of transgenic modulation and marginal donor models facilitating data extrapolation to human conditions.

Here, biological attributes of two early human isolates of the newly emerged H7N9 influenza viruses are characterized: the potential of these viruses to infect and/or transmit within various animal models is discussed, as is their relative sensitivity to neuraminidase inhibitors and experimental polymerase inhibitors compared to an H1N1 pandemic strain. Transmission of emerging H7N9 virus By 20 July 2013, there had been 134 laboratory-confirmed human cases of infection with avian influenza A H7N9 virus infection, including 43 deaths. Yoshihiro Kawaoka and colleagues characterize the biology of two recent isolates of the virus. They provide a wealth of data from infections in mice, pigs, macaques and ferrets. H7N9 virus is shown to be less sensitive to neuraminidase inhibitors than pandemic H1N1 virus, but equally susceptible to an experimental polymerase inhibitor. Terrence Tumpey and colleagues determine the capacity of two clinical H7N9 isolates to cause disease and transmit between mammals. They show that the virus can replicate in human airway cells and in the respiratory tract of ferrets to a higher level than can seasonal H3N2 virus, and show higher lethality in mice than genetically related H7N9 and H9N2 viruses. In transmission studies, the H7N9 virus showed limited transmission in ferrets by respiratory droplets. Ron Fouchier and colleagues investigate the transmissibility of H7N9 virus between ferrets. They show that airborne transmission can occur, but inefficiently. They also show that on passage in ferrets, virus variants that have higher avian receptor binding, higher pH of fusion and lower thermostability are selected, and they suggest that these characteristics may result in reduced transmissibility. Avian influenza A viruses rarely infect humans; however, when human infection and subsequent human-to-human transmission occurs, worldwide outbreaks (pandemics) can result. The recent sporadic infections of humans in China with a previously unrecognized avian influenza A virus of the H7N9 subtype (A(H7N9)) have caused concern owing to the appreciable case fatality rate associated with these infections (more than 25%), potential instances of human-to-human transmission 1 , and the lack of pre-existing immunity among humans to viruses of this subtype. Here we characterize two early human A(H7N9) isolates, A/Anhui/1/2013 (H7N9) and A/Shanghai/1/2013 (H7N9); hereafter referred to as Anhui/1 and Shanghai/1, respectively. In mice, Anhui/1 and Shanghai/1 were more pathogenic than a control avian H7N9 virus (A/duck/Gunma/466/2011 (H7N9); Dk/GM466) and a representative pandemic 2009 H1N1 virus (A/California/4/2009 (H1N1pdm09); CA04). Anhui/1, Shanghai/1 and Dk/GM466 replicated well in the nasal turbinates of ferrets. In nonhuman primates, Anhui/1 and Dk/GM466 replicated efficiently in the upper and lower respiratory tracts, whereas the replicative ability of conventional human influenza viruses is typically restricted to the upper respiratory tract of infected primates. By contrast, Anhui/1 did not replicate well in miniature pigs after intranasal inoculation. Critically, Anhui/1 transmitted through respiratory droplets in one of three pairs of ferrets. Glycan arrays showed that Anhui/1, Shanghai/1 and A/Hangzhou/1/2013 (H7N9) (a third human A(H7N9) virus tested in this assay) bind to human virus-type receptors, a property that may be critical for virus transmissibility in ferrets. Anhui/1 was found to be less sensitive in mice to neuraminidase inhibitors than a pandemic H1N1 2009 virus, although both viruses were equally susceptible to an experimental antiviral polymerase inhibitor. The robust replicative ability in mice, ferrets and nonhuman primates and the limited transmissibility in ferrets of Anhui/1 suggest that A(H7N9) viruses have pandemic potential.

Induced pluripotent stem cells (iPS cells) are considered a promising source of cell-based therapy for the treatment of Parkinson’s disease (PD). Recent studies have shown forebrain GABA interneurons have crucial roles in many psychiatric disorders, and secondary changes in the GABA system play a directly effect on the pathogenesis of PD. Here, we first describe an efficient differentiation procedure of GABA progenitors (MiPSC-iGABAPs) from miniature-swine iPSCs through two major developmental stages. Then, the MiPSC-iGABAPs were stereotactically transplanted into the right medial forebrain bundle (MFB) of 6-hydroxydopamine (OHDA)-lesioned PD model rats to confirm their feasibility for the neural transplantation as a donor material. Furthermore, the grafted MiPSC-iGABAPs could survive and migrate from the graft site into the surrounding brain tissue including striatum (ST) and substantia nigra (SN) for at least 32 weeks, and significantly improved functional recovery of PD rats from their parkinsonian behavioral defects. Histological studies showed that the grafted cells could migrate and differentiate into various neurocytes, including GABAergic, dopaminergic neurons, and glial cells in vivo, and many induced dopaminergic neurons extended dense neurites into the host striatum. Moreover, over 50% of the grafted MiPSC-iGABAPs could express GABA, and these GABAergic neurons might be responsible for modifying the balance of excitatory and inhibitory signals in the striatum to promote behavioral recovery. Thus, the present study confirmed that the MiPSC-iGABAPs can be used as an attractive donor material for the neural grafting to remodel basal ganglia circuitry in neurodegenerative diseases, avoiding tumorigenicity of iPSCs and the nonproliferative and nondifferentiated potential of mature neurons.

In mammals, testis and epididymis are critical components of the male reproductive system for androgen production, spermatogenesis, sperm transportation, as well as sperm maturation. Here, we report single-molecule real-time sequencing data from the testis and epididymis of the Banna mini-pig inbred line (BMI), a promising laboratory animal for medical research. We obtained high-quality full-length transcriptomes and identified 9879 isoforms and 8761 isoforms in the BMI testis and epididymis, respectively. Most of the isoforms we identified have novel exon structures that will greatly improve the annotation of testis- and epididymis-expressed genes in pigs. We also found that 3055 genes (over 50%) were shared between BMI testis and epididymis, indicating widespread expression profiles of genes related to reproduction. We characterized extensive alternative splicing events in BMI testis and epididymis and showed that 96 testis-expressed genes and 79 epididymis-expressed genes have more than six isoforms, revealing the complexity of alternative splicing. We accurately defined the transcribed isoforms in BMI testis and epididymis by combining Pacific Biotechnology Isoform-sequencing (PacBio Iso-Seq) and Illumina RNA Sequencing (RNA-seq) techniques. The refined annotation of some key genes governing male reproduction will facilitate further understanding of the molecular mechanisms underlying BMI male sterility. In addition, the high-confident identification of 548 and 669 long noncoding RNAs (lncRNAs) in these two tissues has established a candidate gene set for future functional investigations. Overall, our study provides new insights into the role of the testis and epididymis during BMI reproduction, paving the path for further studies on BMI male infertility. Summary Sentence Transcriptomic analysis from testis and epididymis of BMI by combining PacBio Iso-Seq and RNA-seq provides a comprehensive set of reference transcripts and improves the annotation of pig testis and epididymis isoforms, which will offer a valuable resource for further studying the spermatogenesis disorder in BMI caused by inbreeding. Graphical Abstract

Hepatitis E virus (HEV) is a major cause of viral hepatitis worldwide. Pigs are the natural host of HEV genotype 3 and the main reservoir of HEV. As the host range of HEV genotype 3 expands, the possibility that HEV from various species can be transmitted to humans via pigs is increasing. We investigated the potential cross-species transmission of HEV by infecting minipigs with swine HEV (swHEV), rabbit HEV (rbHEV), and human HEV (huHEV) and examining their histopathological characteristics and distribution in various organs. Fifteen specific-pathogen-free Yucatan minipigs were infected with swHEV, rbHEV, huHEV, or a mock control. In the present study, we analysed faecal shedding, viremia, and serological parameters over a seven-week period. Our results indicated that swHEV exhibited more robust shedding and viremia than non-swHEVs. Only swHEV affected the serological parameters, suggesting strain-specific differences. Histopathological examination revealed distinct patterns in the liver, pancreas, intestine, and lymphoid tissues after infection with each HEV strain. Notably, all three HEVs induced histopathological changes in the pancreas, supporting the association of HEVs with acute pancreatitis. Our results also identified skeletal muscle as a site of HEV antigen presence, suggesting a potential link to myositis. In conclusion, this study provides valuable insights into the infection dynamics of different HEV strains in minipigs, emphasizing the strain-specific variations in virological, serological, and histological parameters. The observed differences in infection kinetics and tissue tropism will contribute to our understanding of HEV pathogenesis and the potential for cross-species transmission.