G-CSFR Ubiquitination Critically Regulates Myeloid Cell Survival and Proliferation

The granulocyte colony-stimulating factor receptor (G-CSFR) is a critical regulator of granulopoiesis. Mutations in the G-CSFR in patients with severe congenital neutropenia (SCN) transforming to acute myelogenous leukemia (AML) have been shown to induce hypersensitivity and enhanced growth responses to G-CSF. Recent studies have demonstrated the importance of the ubiquitin/proteasome system in the initiation of negative signaling by the G-CSFR. To further investigate the role of ubiquitination in regulating G-CSFR signaling, we generated a mutant form of the G-CSFR (K762R/G-CSFR) which abrogates the attachment of ubiquitin to the lysine residue at position 762 of the G-CSFR that is deleted in the Δ716 G-CSFR form isolated from patients with SCN/AML. In response to G-CSF, mono-/polyubiquitination of the G-CSFR was impaired in cells expressing the mutant K762R/G-CSFR compared to cells transfected with the WT G-CSFR. Cells stably transfected with the K762R/G-CSFR displayed a higher proliferation rate, increased sensitivity to G-CSF, and enhanced survival following cytokine depletion, similar to previously published data with the Δ716 G-CSFR mutant. Activation of the signaling molecules Stat5 and Akt were also increased in K762R/G-CSFR transfected cells in response to G-CSF, and their activation remained prolonged after G-CSF withdrawal. These results indicate that ubiquitination is required for regulation of G-CSFR-mediated proliferation and cell survival. Mutations that disrupt G-CSFR ubiquitination at lysine 762 induce aberrant receptor signaling and hyperproliferative responses to G-CSF, which may contribute to leukemic transformation

Impact of Space Weather on Climate and Habitability of Terrestrial Type Exoplanets

The current progress in the detection of terrestrial type exoplanets has opened a new avenue in the characterization of exoplanetary atmospheres and in the search for biosignatures of life with the upcoming ground-based and space missions. To specify the conditions favorable for the origin, development and sustainment of life as we know it in other worlds, we need to understand the nature of astrospheric, atmospheric and surface environments of exoplanets in habitable zones around G-K-M dwarfs including our young Sun. Global environment is formed by propagated disturbances from the planet-hosting stars in the form of stellar flares, coronal mass ejections, energetic particles, and winds collectively known as astrospheric space weather. Its characterization will help in understanding how an exoplanetary ecosystem interacts with its host star, as well as in the specification of the physical, chemical and biochemical conditions that can create favorable and/or detrimental conditions for planetary climate and habitability along with evolution of planetary internal dynamics over geological timescales. A key linkage of (astro) physical, chemical, and geological processes can only be understood in the framework of interdisciplinary studies with the incorporation of progress in heliophysics, astrophysics, planetary and Earth sciences. The assessment of the impacts of host stars on the climate and habitability of terrestrial (exo)planets will significantly expand the current definition of the habitable zone to the biogenic zone and provide new observational strategies for searching for signatures of life. The major goal of this paper is to describe and discuss the current status and recent progress in this interdisciplinary field and to provide a new roadmap for the future development of the emerging field of exoplanetary science and astrobiology.Comment: 206 pages, 24 figures, 1 table; Review paper. International Journal of Astrobiology (2019

Proximity of Iron Pnictide Superconductors to a Quantum Tricritical Point

We determine the nature of the magnetic quantum critical point in the doped LaFeAsO using a set of constrained density functional calculations that provide ab initio coefficients for a Landau order parameter analysis. The system turns out to be remarkably close to a quantum tricritical point, where the nature of the phase transition changes from first to second order. We compare with the effective field theory and discuss the experimental consequences.Comment: 4 pages, 4 figure

Reaction rates and transport in neutron stars

Understanding signals from neutron stars requires knowledge about the transport inside the star. We review the transport properties and the underlying reaction rates of dense hadronic and quark matter in the crust and the core of neutron stars and point out open problems and future directions.Comment: 74 pages; commissioned for the book "Physics and Astrophysics of Neutron Stars", NewCompStar COST Action MP1304; version 3: minor changes, references updated, overview graphic added in the introduction, improvements in Sec IV.A.

Frequent Occurrence of Mitochondrial DNA Mutations in Barrett’s Metaplasia without the Presence of Dysplasia

BACKGROUND: Barrett's esophagus (BE) is one of the most common premalignant lesions and can progress to esophageal adenocarcinoma (EA). The numerous molecular events may play a role in the neoplastic transformation of Barrett's mucosa such as the change of DNA ploidy, p53 mutation and alteration of adhesion molecules. However, the molecular mechanism of the progression of BE to EA remains unclear and most studies of mitochondrial DNA (mtDNA) mutations in BE have performed on BE with the presence of dysplasia. METHODS/FINDINGS: Thus, the current study is to investigate new molecular events (Barrett's esophageal tissue-specific-mtDNA alterations/instabilities) in mitochondrial genome and causative factors for their alterations using the corresponding adjacent normal mucosal tissue (NT) and tissue (BT) from 34 patients having Barrett's metaplasia without the presence of dysplasia. Eighteen patients (53%) exhibited mtDNA mutations which were not found in adjacent NT. mtDNA copy number was about 3 times higher in BT than in adjacent NT. The activity of the mitochondrial respiratory chain enzyme complexes in tissues from Barrett's metaplasia without the presence of dysplasia was impaired. Reactive oxygen species (ROS) level in BT was significantly higher than those in corresponding samples. CONCLUSION/SIGNIFICANCE: High ROS level in BT may contribute to the development of mtDNA mutations, which may play a crucial role in disease progression and tumorigenesis in BE

W2S: Microscopy Data with Joint Denoising and Super-Resolution for Widefield to SIM Mapping

In fluorescence microscopy live-cell imaging, there is a critical trade-off between the signal-to-noise ratio and spatial resolution on one side, and the integrity of the biological sample on the other side. To obtain clean high-resolution (HR) images, one can either use microscopy techniques, such as structured-illumination microscopy (SIM), or apply denoising and super-resolution (SR) algorithms. However, the former option requires multiple shots that can damage the samples, and although efficient deep learning based algorithms exist for the latter option, no benchmark exists to evaluate these algorithms on the joint denoising and SR (JDSR) tasks. To study JDSR on microscopy data, we propose such a novel JDSR dataset, Widefield2SIM (W2S), acquired using a conventional fluorescence widefield and SIM imaging. W2S includes 144,000 real fluorescence microscopy images, resulting in a total of 360 sets of images. A set is comprised of noisy low-resolution (LR) widefield images with different noise levels, a noise-free LR image, and a corresponding high-quality HR SIM image. W2S allows us to benchmark the combinations of 6 denoising methods and 6 SR methods. We show that state-of-the-art SR networks perform very poorly on noisy inputs. Our evaluation also reveals that applying the best denoiser in terms of reconstruction error followed by the best SR method does not necessarily yield the best final result. Both quantitative and qualitative results show that SR networks are sensitive to noise and the sequential application of denoising and SR algorithms is sub-optimal. Lastly, we demonstrate that SR networks retrained end-to-end for JDSR outperform any combination of state-of-the-art deep denoising and SR networksComment: ECCVW 2020. Project page: \<https://github.com/ivrl/w2s

Coupling of Glucose Deprivation with Impaired Histone H2B Monoubiquitination in Tumors

Metabolic reprogramming is associated with tumorigenesis. However, glucose metabolism in tumors is poorly understood. Here, we report that glucose levels are significantly lower in bulk tumor specimens than those in normal tissues of the same tissue origins. We show that mono-ubiquitinated histone H2B (uH2B) is a semi-quantitative histone marker for glucose. We further show that loss of uH2B occurs specifically in cancer cells from a wide array of tumor specimens of breast, colon, lung and additional 23 anatomic sites. In contrast, uH2B levels remain high in stromal tissues or non-cancerous cells in the tumor specimens. Taken together, our data suggest that glucose deficiency and loss of uH2B are novel properties of cancer cells in vivo, which may represent important regulatory mechanisms of tumorigenesis