Generation, Purification and Transplantation of Photoreceptors Derived from Human Induced Pluripotent Stem Cells

Background: Inherited and acquired retinal degenerations are frequent causes of visual impairment and photoreceptor cell replacement therapy may restore visual function to these individuals. To provide a source of new retinal neurons for cell based therapies, we developed methods to derive retinal progenitors from human ES cells. Methodology/Physical Findings: In this report we have used a similar method to direct induced pluripotent stem cells (iPS) from human fibroblasts to a retinal progenitor fate, competent to generate photoreceptors. We also found we could purify the photoreceptors derived from the iPS cells using fluorescence activated cell sorting (FACS) after labeling photoreceptors with a lentivirus driving GFP from the IRBP cis-regulatory sequences. Moreover, we found that when we transplanted the FACS purified iPSC derived photoreceptors, they were able to integrate into a normal mouse retina and express photoreceptor markers. Conclusions: This report provides evidence that enriched populations of human photoreceptors can be derived from iPS cells

Scientific rationale of a Saturn probe mission

We describe the main scientific goals to be addressed by future in situ exploration of Saturn

A Vision for Ice Giant Exploration

From Voyager to a Vision for 2050: NASA and ESA have just completed a study of candidate missionsto Uranus and Neptune, the so-called ice giant planets. It is a Pre-Decadal Survey Study, meant to inform the next Planetary Science Decadal Survey about opportunities for missions launching in the 2020's and early 2030's. There have been no space flight missions to the ice giants since the Voyager 2 flybys of Uranus in 1986 and Neptune in 1989. This paper presents some conclusions of that study (hereafter referred to as The Study), and how the results feed into a vision for where planetary science can be in 2050. Reaching that vision will require investments in technology andground-based science in the 2020's, flight during the 2030's along with continued technological development of both ground- and space-based capabilities, and data analysis and additional flights in the 2040's. We first discuss why exploring the ice giants is important. We then summarize the science objectives identified by The Study, and our vision of the science goals for 2050. We then review some of the technologies needed to make this vision a reality

Health and human rights in eastern Myanmar prior to political transition: a population-based assessment using multistaged household cluster sampling

Background: Myanmar/Burma has received increased development and humanitarian assistance since the election in November 2010. Monitoring the impact of foreign assistance and economic development on health and human rights requires knowledge of pre-election conditions. Methods: From October 2008-January 2009, community-based organizations conducted household surveys using three-stage cluster sampling in Shan, Kayin, Bago, Kayah, Mon and Tanintharyi areas of Myanmar. Data was collected from 5,592 heads of household on household demographics, reproductive health, diarrhea, births, deaths, malaria, and acute malnutrition of children 6–59 months and women aged 15–49 years. A human rights focused survey module evaluated human rights violations (HRVs) experienced by household members during the previous year. Results: Estimated infant and under-five rates were 77 (95% CI 56 to 98) and 139 (95% CI 107 to 171) deaths per 1,000 live births; and the crude mortality rate was 13 (95% CI 11 to 15) deaths per thousand persons. The leading respondent-reported cause of death was malaria, followed by acute respiratory infection and diarrhea, causing 21.2% (95% CI 16.5 to 25.8), 16.6% (95% CI 11.8 to 21.4), and 12.3% (95% CI 8.7 to 15.8), respectively. Over a third of households suffered at least one human rights violation in the preceding year (36.2%; 30.7 to 41.7). Household exposure to forced labor increased risk of death among infants (rate ratio (RR) = 2.2; 95% CI 1.1 to 4.4) and children under five (RR = 2.1; 95% CI 1.3 to 3.6). The proportion of children suffering from moderate to severe acute malnutrition was higher among households that were displaced (prevalence ratio (PR) = 3.3; 95% CI 1.9 to 5.6). Conclusions: Prior to the 2010 election, populations of eastern Myanmar experienced high rates of disease and death and high rates of HRVs. These population-based data provide a baseline that can be used to monitor national and international efforts to improve the health and human rights situation in the region

Texts as Data I : Document Analysis

Peer reviewe

PDGF Upregulates Mcl-1 Through Activation of β-Catenin and HIF-1α-Dependent Signaling in Human Prostate Cancer Cells

BACKGROUND: Aberrant platelet derived growth factor (PDGF) signaling has been associated with prostate cancer (PCa) progression. However, its role in the regulation of PCa cell growth and survival has not been well characterized. METHODOLOGY/PRINCIPAL FINDINGS: Using experimental models that closely mimic clinical pathophysiology of PCa progression, we demonstrated that PDGF is a survival factor in PCa cells through upregulation of myeloid cell leukemia-1 (Mcl-1). PDGF treatment induced rapid nuclear translocation of β-catenin, presumably mediated by c-Abl and p68 signaling. Intriguingly, PDGF promoted formation of a nuclear transcriptional complex consisting of β-catenin and hypoxia-inducible factor (HIF)-1α, and its binding to Mcl-1 promoter. Deletion of a putative hypoxia response element (HRE) within the Mcl-1 promoter attenuated PDGF effects on Mcl-1 expression. Blockade of PDGF receptor (PDGFR) signaling with a pharmacological inhibitor AG-17 abrogated PDGF induction of Mcl-1, and induced apoptosis in metastatic PCa cells. CONCLUSIONS/SIGNIFICANCE: Our study elucidated a crucial survival mechanism in PCa cells, indicating that interruption of the PDGF-Mcl-1 survival signal may provide a novel strategy for treating PCa metastasis

Live Imaging at the Onset of Cortical Neurogenesis Reveals Differential Appearance of the Neuronal Phenotype in Apical versus Basal Progenitor Progeny

The neurons of the mammalian brain are generated by progenitors dividing either at the apical surface of the ventricular zone (neuroepithelial and radial glial cells, collectively referred to as apical progenitors) or at its basal side (basal progenitors, also called intermediate progenitors). For apical progenitors, the orientation of the cleavage plane relative to their apical-basal axis is thought to be of critical importance for the fate of the daughter cells. For basal progenitors, the relationship between cell polarity, cleavage plane orientation and the fate of daughter cells is unknown. Here, we have investigated these issues at the very onset of cortical neurogenesis. To directly observe the generation of neurons from apical and basal progenitors, we established a novel transgenic mouse line in which membrane GFP is expressed from the beta-III-tubulin promoter, an early pan-neuronal marker, and crossed this line with a previously described knock-in line in which nuclear GFP is expressed from the Tis21 promoter, a pan-neurogenic progenitor marker. Mitotic Tis21-positive basal progenitors nearly always divided symmetrically, generating two neurons, but, in contrast to symmetrically dividing apical progenitors, lacked apical-basal polarity and showed a nearly randomized cleavage plane orientation. Moreover, the appearance of beta-III-tubulin–driven GFP fluorescence in basal progenitor-derived neurons, in contrast to that in apical progenitor-derived neurons, was so rapid that it suggested the initiation of the neuronal phenotype already in the progenitor. Our observations imply that (i) the loss of apical-basal polarity restricts neuronal progenitors to the symmetric mode of cell division, and that (ii) basal progenitors initiate the expression of neuronal phenotype already before mitosis, in contrast to apical progenitors

Does Maternal Underweight Prior to Conception Influence Pregnancy Risks and Outcome?

While obesity in pregnancy and pregnancy outcome in obese women are subjects of diverse research in recent publications, it is remarkable that the data for pregnancy outcome in pre-conceptional underweight mothers is extremely limited. Apart from an increasing prevalence of obesity, however, the prevalence for underweight in distinct sub-groups of mothers is also increasing. In contrary to obesity, less people are affected by underweight in Europe. The World Health Organization (WHO) classifies human weight into different categories (1). A body mass index (BMI) less than 18.5 kg/m 2 is defined as underweight. In Germany, the incidence of underweight in women is low with a nationwide prevalence of 3% (2). Especially in young women in certain social groups, an anorectic model-like weight is the ideal of beauty and a lot of cases of underweight in women of childbearing age are due to eating disorders (3). The lifetime incidence of eating disorders in young women of childbearing age is 5.2-6.5 % (4). While obesity is a frequently encountered problem in pregnant women with multiple complications during pregnancy and delivery (5-16), data on pregnant women with underweight or anorexia are scarce Because of hormonal disorders due to anorexia, underweight women often have menstrual irregularities leading to amenorrhea and infertility. Disorders in hypothalamic-hypophysis functions result in hypogonadotrope anovulatory cycle

Genomic analysis of the function of the transcription factor gata3 during development of the Mammalian inner ear

We have studied the function of the zinc finger transcription factor gata3 in auditory system development by analysing temporal profiles of gene expression during differentiation of conditionally immortal cell lines derived to model specific auditory cell types and developmental stages. We tested and applied a novel probabilistic method called the gamma Model for Oligonucleotide Signals to analyse hybridization signals from Affymetrix oligonucleotide arrays. Expression levels estimated by this method correlated closely (p<0.0001) across a 10-fold range with those measured by quantitative RT-PCR for a sample of 61 different genes. In an unbiased list of 26 genes whose temporal profiles clustered most closely with that of gata3 in all cell lines, 10 were linked to Insulin-like Growth Factor signalling, including the serine/threonine kinase Akt/PKB. Knock-down of gata3 in vitro was associated with a decrease in expression of genes linked to IGF-signalling, including IGF1, IGF2 and several IGF-binding proteins. It also led to a small decrease in protein levels of the serine-threonine kinase Akt2/PKB beta, a dramatic increase in Akt1/PKB alpha protein and relocation of Akt1/PKB alpha from the nucleus to the cytoplasm. The cyclin-dependent kinase inhibitor p27(kip1), a known target of PKB/Akt, simultaneously decreased. In heterozygous gata3 null mice the expression of gata3 correlated with high levels of activated Akt/PKB. This functional relationship could explain the diverse function of gata3 during development, the hearing loss associated with gata3 heterozygous null mice and the broader symptoms of human patients with Hearing-Deafness-Renal anomaly syndrome