The role of maternal-specific H3K9me3 modification in establishing imprinted X-chromosome inactivation and embryogenesis in mice

Maintaining a single active X-chromosome by repressing Xist is crucial for embryonic development in mice. Although the Xist activator RNF12/RLIM is present as a maternal factor, maternal Xist (Xm-Xist) is repressed during preimplantation phases to establish imprinted X-chromosome inactivation (XCI). Here we show, using a highly reproducible chromatin immunoprecipitation method that facilitates chromatin analysis of preimplantation embryos, that H3K9me3 is enriched at the Xist promoter region, preventing Xm-Xist activation by RNF12. The high levels of H3K9me3 at the Xist promoter region are lost in embryonic stem (ES) cells, and ES-cloned embryos show RNF12-dependent Xist expression. Moreover, lack of Xm-XCI in the trophectoderm, rather than loss of paternally expressed imprinted genes, is the primary cause of embryonic lethality in 70–80% of parthenogenotes immediately after implantation. This study reveals that H3K9me3 is involved in the imprinting that silences Xm-Xist. Our findings highlight the role of maternal-specific H3K9me3 modification in embryo development

Estimating Tail-Latency of Latency-Sensitive Workloads

Mange av arbeidsoppgavene som behandles i dagens datasentre er følsomme for forsinkelse, og krever at brukere har en tilfredsstillende opplevelse, noe som gjør energibesparing til en utfordring, som følge av strenge krav til forsinkelse. Oppgaveplanleggere er avgjørende for å redusere energiforbruket samtidig som disse kravene møtes. Denne masteroppgaven introduserer Heimdall, en løsning basert på enkle maskinlæringsmodeller (random forest og support vector machine) for å forstå korrelasjonen mellom kjerner, dynamisk spennings -og frekvensskalering (DVFS), arbeidsbelastning og forsinkelse. Våre eksperiment er gjennomført på et Nvidia Jetson TX1 brett, med resultater som viser at Heimdall reduserer energiforbruket med henholdsvis 2% og 16% i forhold til eksisterende oppgavebehandlere som Hipster og Heracles, og møter kravene for forsinkelse henholdsvis 11.2% og 6.1% oftere

FUS is sequestered in nuclear aggregates in ALS patient fibroblasts

Mutations in the RNA-binding protein FUS have been shown to cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We investigate whether mutant FUS protein in ALS patient–derived fibroblasts affects normal FUS functions in the nucleus. We investigated fibroblasts from two ALS patients possessing different FUS mutations and a normal control. Fibroblasts from these patients have their nuclear FUS protein trapped in SDS-resistant aggregates. Genome-wide analysis reveals an inappropriate accumulation of Ser-2 phosphorylation on RNA polymerase II (RNA Pol II) near the transcription start sites of 625 genes for ALS patient cells and after small interfering RNA (siRNA) knockdown of FUS in normal fibroblasts. Furthermore, both the presence of mutant FUS protein and siRNA knockdown of wild-type FUS correlate with altered distribution of RNA Pol II within fibroblast nuclei. A loss of FUS function in orchestrating Ser-2 phosphorylation of the CTD of RNA Pol II is detectable in ALS patient–derived fibroblasts expressing mutant FUS protein, even when the FUS protein remains largely nuclear. A likely explanation for this loss of function is the aggregation of FUS protein in nuclei. Thus our results suggest a specific mechanism by which mutant FUS can have biological consequences other than by the formation of cytoplasmic aggregates

The Fama-French five-factor asset pricing model: A replication across the globe

Til tross for den kraftige empiriske ytelsen til fem-faktor-modellen til Fama og French (2015), er litteraturen om moderne kapitalverdimodeller (verdsetting av finansielle aktiva) sterkt påvirket av funn i det amerikanske aksjemarkedet. Denne oppgaven utvider dagens litteratur og søker å evaluere om fem-faktor-modellen rettet mot å fange størrelse, verdi, lønnsomhet og investeringsmønster i gjennomsnittlig aksjeavkastning er replikerbar over hele kloden. Denne oppgaven undersøker spesielt den empiriske ytelsen til fem-faktor-modellen og ulike varianter av den i USA, Nord-Amerika, Asia-Stillehavet (utenom Japan), Japan, Europa og fremvoksende markeder. Fem-faktor-modellen overgår konsekvent tre-faktor-modellen i USA, Nord-Amerika, Asia-Stillehavet (utenom Japan), Europa og fremvoksende markeder. I Japan tilføyer ikke fem-faktor-modellen en forbedring over tre-faktor-modellen. Resultatene indikerer at fem-faktor-modellen presterer bra, men at den ikke kan bli replikert over hele verden, og forskjellige markeder må ta hensyn til forskjellige sett med faktorer. Praktiske anvendelser av fem-faktor-modellen, som beregning av avkastningskrav til egenkapitalen og porteføljens ytelse kan være best uført på landsspesifikk basis.Despite the powerful empirical performance of the five-factor model of Fama and French (2015), the literature on modern asset pricing is heavily influenced by findings in the US stock market. This thesis extends the current literature and seeks to evaluate whether the five-factor model directed at capturing the size, value, profitability, and investment patterns in average stock returns is replicable across the globe. In particular, this paper empirically investigates the performance of the five-factor model and subset of its factors in the US, North America, Asia Pacific (excluding Japan), Japan, Europe, and Emerging Markets. The five-factor model consistently outperforms the three-factor model in the US, North America, Asia Pacific (excluding Japan), Europe, and Emerging Markets. In Japan, the five-factor model does not offer an improvement over the three-factor model. Results indicates that the five-factor model performs well, but does not replicate across the world, and different markets need to account for different sets of factors. Practical applications of the five-factor model, such as cost of equity capital calculations and performance evaluations, may be best performed on a country-specific basis

Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development

Reprogramming of postnatal neurons into induced pluripotent stem cells by defined factors

Pluripotent cells can be derived from different types of somatic cells by nuclear reprogramming through the ectopic expression of four transcription factors, Oct3/4, Sox2, Klf4, and c-Myc. However, it is unclear whether postmitotic neurons are susceptible to direct reprogramming. Here, we show that postnatal cortical neurons, the vast majority of which are postmitotic, are amenable to epigenetic reprogramming. However, ectopic expression of the four canonical reprogramming factors is not sufficient to reprogram postnatal neurons. Efficient reprogramming was only achieved after forced cell proliferation by p53 suppression. Additionally, overexpression of repressor element-1 silencing transcription, a suppressor of neuronal gene activity, increased reprogramming efficiencies in combination with the reprogramming factors. Our findings indicate that terminally differentiated postnatal neurons are able to acquire the pluripotent state by direct epigenetic reprogramming, and this process is made more efficient through the suppression of lineage specific gene expression. STEM CELLS 2011;29:992–1000National Institutes of Health (U.S.) (Grant NIH HD045022)National Institutes of Health (U.S.) (Grant 5R37CA084198)Howard Hughes Medical Institut

What\u27s Next?: Eco Materialism & Contemporary Art by Linda Weintraub

Review of Linda Weintraub\u27s What\u27s Next?: Eco Materialism & Contemporary Ar

Developmental Bias in Cleavage-Stage Mouse Blastomeres

BACKGROUND: The cleavage-stage mouse embryo is composed of superficially equivalent blastomeres that will generate both the embryonic inner cell mass (ICM) and the supportive trophectoderm (TE). However, it remains unsettled whether the contribution of each blastomere to these two lineages can be accounted for by chance. Addressing the question of blastomere cell fate may be of practical importance, because preimplantation genetic diagnosis requires removal of blastomeres from the early human embryo. To determine whether blastomere allocation to the two earliest lineages is random, we developed and utilized a recombination-mediated, noninvasive combinatorial fluorescent labeling method for embryonic lineage tracing. RESULTS: When we induced recombination at cleavage stages, we observed a statistically significant bias in the contribution of the resulting labeled clones to the trophectoderm or the inner cell mass in a subset of embryos. Surprisingly, we did not find a correlation between localization of clones in the embryonic and abembryonic hemispheres of the late blastocyst and their allocation to the TE and ICM, suggesting that TE-ICM bias arises separately from embryonic-abembryonic bias. Rainbow lineage tracing also allowed us to demonstrate that the bias observed in the blastocyst persists into postimplantation stages and therefore has relevance for subsequent development. CONCLUSIONS: The Rainbow transgenic mice that we describe here have allowed us to detect lineage-dependent bias in early development. They should also enable assessment of the developmental equivalence of mammalian progenitor cells in a variety of tissues.Molecular and Cellular Biolog

Cannabinoid CB1 Receptor: Role in Primate Prefrontal Circuitry and Schizophrenia

Schizophrenia is a complex and devastating psychiatric disorder that creates a substantial emotional and economic burden on individuals with the illness, their families, and society. Understanding the causes and identifying the molecular alterations in the brain that underlie the pathophysiology of core clinical features of schizophrenia are central to the development of new therapeutic interventions. In particular, schizophrenia is characterized by impairments in working memory, which are thought to result from a deficit in GABA neurotransmission in the dorsolateral prefrontal cortex (DLPFC). Interestingly, exposure to cannabis has been associated with an increased risk for developing schizophrenia and cannabis use is associated with DLPFC-related working memory impairments similar to those observed in schizophrenia. The effects of cannabis are mediated by the brain cannabinoid 1 (CB1) receptor, which in the rodent, is heavily localized to certain inhibitory axon terminals and, when activated, inhibits GABA release. Here, we have investigated the anatomical distribution of the CB1 receptor in the primate brain and characterized the cellular localization and synaptic targets of the CB1 receptor in the primate DLPFC. In addition, we explored the potential relationship between CB1 receptor signaling and altered GABA neurotransmission in schizophrenia by evaluating CB1 receptor mRNA and protein expression in the DLPFC of subjects with schizophrenia. We found that CB1 receptors are highly expressed in the primate DLPFC and that CB1 receptors are localized in the terminals of the subtype of perisomatic-targeting GABA interneurons that contain the neuropeptide cholecystokinin (CCK). We found that CB1 mRNA and protein are reduced in schizophrenia, which may represent a compensatory mechanism to increase GABA transmission from perisomatic-targeting CCK neurons with impaired GABA synthesis. We conclude that reductions in the expression of the CB1 receptor mRNA and protein in CCK neurons represent a novel neuropathological entity in the DLPFC of individuals with schizophrenia. These findings suggest a novel drug target for the treatment of cognitive dysfunction in schizophrenia

Reprogramming within Hours Following Nuclear Transfer into Mouse but not Human Zygotes

Fertilized mouse zygotes can reprogram somatic cells to a pluripotent state. Human zygotes might therefore be useful for producing patient-derived pluripotent stem cells. However, logistical, legal and social considerations have limited the availability of human eggs for research. Here we show that a significant number of normal fertilized eggs (zygotes) can be obtained for reprogramming studies. Using these zygotes, we found that when the zygotic genome was replaced with that of a somatic cell, development progressed normally throughout the cleavage stages, but then arrested before the morula stage. This arrest was associated with a failure to activate transcription in the transferred somatic genome. In contrast to human zygotes, mouse zygotes reprogrammed the somatic cell genome to a pluripotent state within hours after transfer. Our results suggest that there may be a previously unappreciated barrier to successful human nuclear transfer, and that future studies could focus on the requirements for genome activation.Stem Cell and Regenerative Biolog