In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach

<p>Abstract</p> <p>Background</p> <p>The transcription factor OCT4 is highly expressed in pluripotent embryonic stem cells which are derived from the inner cell mass of mammalian blastocysts. Pluripotency and self renewal are controlled by a transcription regulatory network governed by the transcription factors OCT4, SOX2 and NANOG. Recent studies on reprogramming somatic cells to induced pluripotent stem cells highlight OCT4 as a key regulator of pluripotency.</p> <p>Results</p> <p>We have carried out an integrated analysis of high-throughput data (ChIP-on-chip and RNAi experiments along with promoter sequence analysis of putative target genes) and identified a core OCT4 regulatory network in human embryonic stem cells consisting of 33 target genes. Enrichment analysis with these target genes revealed that this integrative analysis increases the functional information content by factors of 1.3 – 4.7 compared to the individual studies. In order to identify potential regulatory co-factors of OCT4, we performed a <it>de novo </it>motif analysis. In addition to known validated OCT4 motifs we obtained binding sites similar to motifs recognized by further regulators of pluripotency and development; e.g. the heterodimer of the transcription factors C-MYC and MAX, a prerequisite for C-MYC transcriptional activity that leads to cell growth and proliferation.</p> <p>Conclusion</p> <p>Our analysis shows how heterogeneous functional information can be integrated in order to reconstruct gene regulatory networks. As a test case we identified a core OCT4-regulated network that is important for the analysis of stem cell characteristics and cellular differentiation. Functional information is largely enriched using different experimental results. The <it>de novo </it>motif discovery identified well-known regulators closely connected to the OCT4 network as well as potential new regulators of pluripotency and differentiation. These results provide the basis for further targeted functional studies.</p

The GALEX View of "Boyajian's Star" (KIC 8462852)

The enigmatic star KIC 8462852, informally known as "Boyajian's Star", has exhibited unexplained variability from both short timescale (days) dimming events, and years-long fading in the Kepler mission. No single physical mechanism has successfully explained these observations to date. Here we investigate the ultraviolet variability of KIC 8462852 on a range of timescales using data from the GALEX mission that occurred contemporaneously with the Kepler mission. The wide wavelength baseline between the Kepler and GALEX data provides a unique constraint on the nature of the variability. Using 1600 seconds of photon-counting data from four GALEX visits spread over 70 days in 2011, we find no coherent NUV variability in the system on 10-100 second or months timescales. Comparing the integrated flux from these 2011 visits to the 2012 NUV flux published in the GALEX-CAUSE Kepler survey, we find a 3% decrease in brightness for KIC 8462852. We find this level of variability is significant, but not necessarily unusual for stars of similar spectral type in the GALEX data. This decrease coincides with the secular optical fading reported by Montet & Simon (2016). We find the multi-wavelength variability is somewhat inconsistent with typical interstellar dust absorption, but instead favors a R$_V$ = 5.0 $\pm$ 0.9 reddening law potentially from circumstellar dust.Comment: 8 pages, 4 figures, ApJ Accepte

Targeted sampling by autonomous underwater vehicles

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Zhang, Y., Ryan, J. P., Kieft, B., Hobson, B. W., McEwen, R. S., Godin, M. A., Harvey, J. B., Barone, B., Bellingham, J. G., Birch, J. M., Scholin, C. A., & Chavez, F. P. Targeted sampling by autonomous underwater vehicles. Frontiers in Marine Science, 6 (2019): 415, doi:10.3389/fmars.2019.00415.In the vast ocean, many ecologically important phenomena are temporally episodic, localized in space, and move according to local currents. To effectively study these complex and evolving phenomena, methods that enable autonomous platforms to detect and respond to targeted phenomena are required. Such capabilities allow for directed sensing and water sample acquisition in the most relevant and informative locations, as compared against static grid surveys. To meet this need, we have designed algorithms for autonomous underwater vehicles that detect oceanic features in real time and direct vehicle and sampling behaviors as dictated by research objectives. These methods have successfully been applied in a series of field programs to study a range of phenomena such as harmful algal blooms, coastal upwelling fronts, and microbial processes in open-ocean eddies. In this review we highlight these applications and discuss future directions.This work was supported by the David and Lucile Packard Foundation. The 2015 experiment in Monterey Bay was partially supported by NOAA Ecology and Oceanography of Harmful Algal Blooms (ECOHAB) Grant NA11NOS4780030. The 2018 SCOPE Hawaiian Eddy Experiment was partially supported by the National Science Foundation (OCE-0962032 and OCE-1337601), Simons Foundation Grant #329108, the Gordon and Betty Moore Foundation (Grant #3777, #3794, and #2728), and the Schmidt Ocean Institute for R/V Falkor Cruise FK180310. Publication of this paper was funded by the Schmidt Ocean Institute

Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors

ABSTRACT Human neuronal nicotinic acetylcholine receptors (nAChRs) h␣2␤2, h␣2␤4, h␣3␤2, h␣3␤4, h␣4␤2, h␣4␤4 and h␣7 were expressed in Xenopus oocytes and tested for their sensitivities to the nicotinic agonists acetylcholine (ACh), nicotine, cytisine (CYT) and 1,1-dimethyl-4-phenylpiperazinium (DMPP) and the nAChR. antagonists mecamylamine (MEC), d-tubocurarine and dihydro-␤-erythroidine. CYT was the least efficacious agonist at hnAChRs containing ␤2 subunits, but it displayed significant activity at h␣2␤4, h␣3␤4, h␣4␤4 and h␣7 nAChRs. ACh was one of the most efficacious agonists at all hnAChRs, except at h␣3␤2, where DMPP was markedly more efficacious than ACh. ACh was among the least potent agonists at all hnAChRs. The rank order of potency displayed by h␣3␤2 and h␣3␤4 nAChRs (DMPPϷCYTϷnicotineϾACh and DMPP Ͼ CYTϷnicotineϾACh, respectively), differs from that reported for their rat homolog

Financing water resource infrastructure, 1987 September 1

The contents of this paper were drafted from a workgroup report to an Engineering Foundation Conference entitled Financing and Amortizing Water Resources Infrastructure held at Palm Coast, Florida, March 29-April 3, 1987. A slightly different version of this paper appeared in the conference proceedings

PU.1 is required to restrain myelopoiesis during chronic inflammatory stress

Chronic inflammation is a common feature of aging and numerous diseases such as diabetes, obesity, and autoimmune syndromes and has been linked to the development of hematological malignancy. Blood-forming hematopoietic stem cells (HSC) can contribute to these diseases via the production of tissue-damaging myeloid cells and/or the acquisition of mutations in epigenetic and transcriptional regulators that initiate evolution toward leukemogenesis. We previously showed that the myeloid “master regulator” transcription factor PU.1 is robustly induced in HSC by pro-inflammatory cytokines such as interleukin (IL)-1β and limits their proliferative activity. Here, we used a PU.1-deficient mouse model to investigate the broader role of PU.1 in regulating hematopoietic activity in response to chronic inflammatory challenges. We found that PU.1 is critical in restraining inflammatory myelopoiesis via suppression of cell cycle and self-renewal gene programs in myeloid-biased multipotent progenitor (MPP) cells. Our data show that while PU.1 functions as a key driver of myeloid differentiation, it plays an equally critical role in tailoring hematopoietic responses to inflammatory stimuli while limiting expansion and self-renewal gene expression in MPPs. These data identify PU.1 as a key regulator of “emergency” myelopoiesis relevant to inflammatory disease and leukemogenesis

Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP

Biogenic Control of Manganese Doping in Zinc Sulfide Nanomaterial Using Shewanella oneidensis MR-1

Bacteria naturally alter the redox state of many compounds and perform atom-by-atom nanomaterial synthesis to create many inorganic materials. Recent advancements in synthetic biology have spurred interest in using biological systems to manufacture nanomaterials, implementing biological strategies to specify the nanomaterial characteristics such as size, shape, and optical properties. Here, we combine the natural synthetic capabilities of microbes with engineered genetic control circuits toward biogenically synthesized semiconductor nanomaterials. Using an engineered strain of Shewanella oneindensis with inducible expression of the cytochrome complex MtrCAB, we control the reduction of manganese (IV) oxide. Cytochrome expression levels were regulated using an inducer molecule, which enabled precise modulation of dopant incorporation into manganese doped zinc sulfide nanoparticles (Mn:ZnS). Thereby, a synthetic gene circuit controlled the optical properties of biogenic quantum dots. These biogenically assembled nanomaterials have similar physical and optoelectronic properties to chemically synthesized particles. Our results demonstrate the promise of implementing synthetic gene circuits for tunable control of nanomaterials made by biological systems