Liver engraftment potential of hepatic cells derived from patient-specific induced pluripotent stem cells

Human induced pluripotent stem cells (iPSCs) are potential renewable sources of hepatocytes for drug development and cell therapy. Differentiation of human iPSCs into different developmental stages of hepatic cells has been achieved and improved during the last several years. We have recently demonstrated the liver engraftment and regenerative capabilities of human iPSC-derived multistage hepatic cells in vivo. Here we describe the in vitro and in vivo activities of hepatic cells derived from patientspecific iPSCs, including multiple lines established from either inherited or acquired liver diseases, and discuss basic and clinical applications of these cells for disease modeling, drug screening and discovery, gene therapy and cell replacement therapy.Key words: induced pluripotent stem cells (iPSCs), hepatic differentiation, liver ngraftment, disease modeling, drug testing, alpha-1 antitrypsin, liver cirrhosis, hepatocellular carcinoma, cell therapy     

Identifying differentially expressed genes in meta-analysis via Bayesian model-based clustering

A Bayesian model-based clustering approach is proposed for identifying differentially expressed genes in meta-analysis. A Bayesian hierarchical model is used as a scientific tool for combining information from different studies, and a mixture prior is used to separate differentially expressed genes from non-differentially expressed genes. Posterior estimation of the parameters and missing observations are done by using a simple Markov chain Monte Carlo method. From the estimated mixture model, useful measure of significance of a test such as the Bayesian false discovery rate (FDR), the local FDR (Efron et al., 2001), and the integration-driven discovery rate (IDR; Choi et al., 2003) can be easily computed. The model-based approach is also compared with commonly used permutation methods, and it is shown that the model-based approach is superior to the permutation methods when there are excessive under-expressed genes compared to over-expressed genes or vice versa. The proposed method is applied to four publicly available prostate cancer gene expression data sets and simulated data sets.     

Ss-bCNGa: a unique member of the bacterial cyclic nucleotide gated (bCNG) channel family that gates in response to mechanical tension

Bacterial cyclic nucleotide gated (bCNG) channels are generally a nonmechanosensitive subset of the mechanosensitive channel of small conductance (MscS) superfamily. bCNG channels are composed of an MscS channel domain, a linking domain, and a cyclic nucleotide binding domain. Among bCNG channels, the channel domain of Ss-bCNGa, a bCNG channel from Synechocystis sp. PCC 6803, is most identical to Escherichia coli (Ec) MscS. This channel also exhibits limited mechanosensation in response to osmotic downshock assays, making it the only known full-length bCNG channel to respond to hypoosmotic stress. Here, we compare and contrast the ability of Ss-bCNGa to gate in response to mechanical tension with Se-bCNG, a nonmechanosensitive bCNG channel, and Ec-MscS, a prototypical mechanosensitive channel. Compared with Ec-MscS, Ss-bCNGa only exhibits limited mechanosensation, which is most likely a result of the inability of Ss-bCNGa to form the strong lipid contacts needed for significant function. Unlike Ec-MscS, Ss-bCNGa displays a mechanical response that increases with protein expression level, which may result from channel clustering driven by interchannel cation?C?? interactions.     

Environmental impacts of the rental business model compared to the conventional business model: a Korean case of water purifier for home use

Purpose

This paper compares environmental impacts of the rental business model with the conventional model of manufacturing and selling. The case study examines a home use-water purifier by defining scenarios for operation and maintenance of the conventional and rental business models. Another purpose is to explore the potential improvement for the environmental performance of the rental business model in terms of the resource consumption and climate change.

Methods

The functional unit was supplying hot/cold drinking water for 15 years between 1998 and 2013. Primary data were from a Korean company that manufactures and servicizes water purifier; secondary data were from the Korean national LCI database, literatures, and interviews. Scenarios associated with all life cycle stages of a water purifier including operation and maintenance were based on current sales and rental market. Impact assessments were conducted according to the International Organization for Standardization’s 14044, and impact categories considered were global warming and abiotic resource depletion. The key issues and improvement potential of the rental business model were determined with the impact categories of global warming and abiotic resource depletion.

Results and discussion

This study indicates that the rental business model is more environmentally friendly than the conventional model in the impact on global warming while the conventional model shows lower abiotic resource depletion. Product operation was the most significant contributor to the selected environmental impacts for both conventional and rental models. Product maintenance was the second major contributor for the rental business model in terms of abiotic resource depletion. For the conventional model, however, production was a more significant contributor to the selected environmental impacts. The rental model showed approximately 32~37% improvements in the selected environmental impacts by focusing on the environmental education or information to consumers.

Conclusions

This quantitative life cycle assessment can be a tool for service business providers to understand the life cycle environmental impacts of Korean water purifier and explore potential improvement opportunities for sustainability. The lower life cycle impacts of the water purifier-rental business model can be attributed to the following: the preparation of instruction or environmental education regarding the consumer’s turning off behavior when the product is not in use, thus lower energy consumption during the use stage and shorter distance traveled for maintenance.

     

Survival and differentiation of mammary epithelial cells in mammary gland development require nuclear retention of Id2 due to RANK signaling

RANKL plays an essential role in mammary gland development during pregnancy. However, the molecular mechanism by which RANK signaling leads to mammary gland development is largely unknown. We report here that RANKL stimulation induces phosphorylation of Id2 at serine 5, which leads to nuclear retention of Id2. In lactating Id2Tg; RANKL(-/-) mice, Id2 was not phosphorylated and was localized in the cytoplasm. In addition, in lactating Id2(S5A)Tg mice, Id2(S5A) (with serine 5 mutated to alanine) was exclusively localized in the cytoplasm of mammary epithelial cells (MECs), while endogenous Id2 was localized in the nucleus. Intriguingly, nuclear expression of Id2(S5A) rescued increased apoptosis and defective differentiation of MECs in RANKL(-/-) mice. Our results demonstrate that nuclear retention of Id2 due to RANK signaling plays a decisive role in the survival and differentiation of MECs during mammary gland development.     

Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1

Mutations in Drosophila neuralized (Dneur) result in a variety of developmental defects that closely resemble those of Notch mutants and other Notch pathway mutants. However, mice with disrupted neur1 do not show any aberrant cell fate specifications in neurogenesis and somitogenesis. Thus, we speculated that other vertebrate neur homolog(s) might compensate for loss of the neur gene. Here, we report the paralog of mouse Neur1, named Neuralized-2 (Neur2), which is a ubiquitin-protein isopeptide ligase (E3) that interacts with and ubiquitinates Delta. Both murine Neur1 and Neur2 have similar degrees of homology to DNeur, and neur2 is expressed in patterns similar to those of neur1 in embryos, suggesting potential functional redundancy. Interestingly, two distinct classes of E3 ligases, Mind bomb-1 (Mib1) and Neur2, have cooperative but distinct roles in Delta endocytosis to Hrs-positive vesicles, i.e. Mib1 functions in the initial step of Delta endocytosis, and Neur2 is required for targeting endocytosed Delta to Hrs-positive vesicles. Thus, our study provides a new insight into how distinct E3 ligases work together in the endocytic pathways for Notch signaling.     

Estimation of carbon storage, carbon inputs, and soil CO2 efflux of alder plantations on granite soil in central Korea: comparison with Japanese larch plantation

Alder is a typical species used for forest rehabilitation after disturbances because of its N₂-fixing activities through microbes. To investigate forest dynamics of the carbon budget, we determined the aboveground and soil carbon content, carbon input by litterfall to belowground, and soil CO₂ efflux over 2 years in 38-year-old alder plantations in central Korea. The estimated aboveground carbon storage and increment were 47.39 Mg C ha⁻¹ and 2.17 Mg C ha⁻¹ year⁻¹. Carbon storage in the organic layer and in mineral soil in the topsoil to 30 cm depth were, respectively, 3.21 and 66.85 Mg C ha⁻¹. Annual carbon input by leaves and total litter in the study stand were, respectively, 1.78 and 2.68 Mg C ha⁻¹ year⁻¹. The aboveground carbon increment at this stand was similar to the annual carbon inputs by total litterfall. The diurnal pattern of soil CO₂ efflux was significantly different in May, August, and October, typically varying approximately twofold throughout the course of a day. In the seasonally observed pattern, soil CO₂ efflux varied strongly with soil temperature; increasing trends were evident during the early growing season, with sustained high rates from mid May through late October. Soil CO₂ efflux was related exponentially to soil temperature (R ² = 0.85, P < 0.0001), but not to soil water content. The Q ₁₀ value for this plantation was 3.8, and annual soil respiration was estimated at 10.2 Mg C ha⁻¹ year⁻¹. An erratum to this article can be found at     

Glucose intolerance in young TallyHo mice is induced by leptin-mediated inhibition of insulin secretion

The pathophysiology of TallyHo mouse, a recently established animal model for type 2 diabetes mellitus, was analyzed at prediabetic state to examine the inherent defects which contribute to the development of diabetes. At 4 weeks of age, the TallyHo mice already revealed glucose intolerance while their peripheral tissues exhibited normal insulin sensitivity. On the other hand, decreased plasma insulin concentration was observed with little differences in pancreatic insulin contents, indicating the impaired insulin secretion. Such defect, however, was not found in the isolated islets, which suggests a role of endocrine factor in impaired insulin secretion of TallyHo mice. Treatment of leptin inhibited the glucose-stimulated insulin secretion from the isolated islets of TallyHo mice, while in vivo administration of anti-leptin antibody lowered plasma glucose concentration with increased insulin level in TallyHo mice. Expression of glucokinase mRNA was decreased both in whole pancreas and leptin treated islets of TallyHo mice compared with whole pancreas in C57BL/6 mice and untreated islets of TallyHo mice, respectively. These results suggest that elevated plasma leptin can, through the inhibition of insulin secretion, induce glucose intolerance in TallyHo mice.     

Cardiomyocyte Specific Deletion of Crif1 Causes Mitochondrial Cardiomyopathy in Mice

Mitochondria are key organelles dedicated to energy production. Crif1, which interacts with the large subunit of the mitochondrial ribosome, is indispensable for the mitochondrial translation and membrane insertion of respiratory subunits. To explore the physiological function of Crif1 in the heart, Crif1^f/f mice were crossed with Myh6-cre/Esr1 transgenic mice, which harbor cardiomyocyte-specific Cre activity in a tamoxifen-dependent manner. The tamoxifen injections were given at six weeks postnatal, and the mutant mice survived only five months due to hypertrophic heart failure. In the mutant cardiac muscles, mitochondrial mass dramatically increased, while the inner structure was altered with lack of cristae. Mutant cardiac muscles showed decreased rates of oxygen consumption and ATP production, suggesting that Crif1 plays a critical role in the maintenance of both mitochondrial structure and respiration in cardiac muscles.