Distinct regulation of c-myb gene expression by HoxA9, Meis1 and Pbx proteins in normal hematopoietic progenitors and transformed myeloid cells

The proto-oncogenic protein c-Myb is an essential regulator of hematopoiesis and is frequently deregulated in hematological diseases such as lymphoma and leukemia. To gain insight into the mechanisms underlying the aberrant expression of c-Myb in myeloid leukemia, we analyzed and compared c-myb gene transcriptional regulation using two cell lines modeling normal hematopoietic progenitor cells (HPCs) and transformed myelomonocytic blasts. We report that the transcription factors HoxA9, Meis1, Pbx1 and Pbx2 bind in vivo to the c-myb locus and maintain its expression through different mechanisms in HPCs and leukemic cells. Our analysis also points to a critical role for Pbx2 in deregulating c-myb expression in murine myeloid cells cotransformed by the cooperative activity of HoxA9 and Meis1. This effect is associated with an intronic positioning of epigenetic marks and RNA polymerase II binding in the orthologous region of a previously described alternative promoter for c-myb. Taken together, our results could provide a first hint to explain the abnormal expression of c-myb in leukemic cells

Functionalized Positive Nanoparticles Reduce Mucin Swelling and Dispersion

Multi-functionalized nanoparticles (NPs) have been extensively investigated for their potential in household and commercial products, and biomedical applications. Previous reports have confirmed the cellular nanotoxicity and adverse inflammatory effects on pulmonary systems induced by NPs. However, possible health hazards resulting from mucus rheological disturbances induced by NPs are underexplored. Accumulation of viscous, poorly dispersed, and less transportable mucus leading to improper mucus rheology and dysfunctional mucociliary clearance are typically found to associate with many respiratory diseases such as asthma, cystic fibrosis (CF), and COPD (Chronic Obstructive Pulmonary Disease). Whether functionalized NPs can alter mucus rheology and its operational mechanisms have not been resolved. Herein, we report that positively charged functionalized NPs can hinder mucin gel hydration and effectively induce mucin aggregation. The positively charged NPs can significantly reduce the rate of mucin matrix swelling by a maximum of 7.5 folds. These NPs significantly increase the size of aggregated mucin by approximately 30 times within 24 hrs. EGTA chelation of indigenous mucin crosslinkers (Ca2+ ions) was unable to effectively disperse NP-induced aggregated mucins. Our results have demonstrated that positively charged functionalized NPs can impede mucin gel swelling by crosslinking the matrix. This report also highlights the unexpected health risk of NP-induced change in mucus rheological properties resulting in possible mucociliary transport impairment on epithelial mucosa and related health problems. In addition, our data can serve as a prospective guideline for designing nanocarriers for airway drug delivery applications

Calpain and PARP Activation during Photoreceptor Cell Death in P23H and S334ter Rhodopsin Mutant Rats

Retinitis pigmentosa (RP) is a heterogeneous group of inherited neurodegenerative diseases affecting photoreceptors and causing blindness. Many human cases are caused by mutations in the rhodopsin gene. An important question regarding RP pathology is whether different genetic defects trigger the same or different cell death mechanisms. To answer this question, we analysed photoreceptor degeneration in P23H and S334ter transgenic rats carrying rhodopsin mutations that affect protein folding and sorting respectively. We found strong activation of calpain and poly(ADP-ribose) polymerase (PARP) in both mutants, concomitant with calpastatin down-regulation, increased oxidative DNA damage and accumulation of PAR polymers. These parameters were strictly correlated with the temporal progression of photoreceptor degeneration, mirroring earlier findings in the phosphodiesterase-6 mutant rd1 mouse, and suggesting execution of non-apoptotic cell death mechanisms. Interestingly, activation of caspases-3 and -9 and cytochrome c leakage—key events in apoptotic cell death—were observed only in the S334ter mutant, which also showed increased expression of PARP-1. The identification of the same metabolic markers triggered by different mutations in two different species suggests the existence of common cell death mechanisms, which is a major consideration for any mutation independent treatment

Glioblastoma—a moving target

The slow development of effective treatment of glioblastoma is contrasted by the rapidly advancing research on the molecular mechanisms underlying the disease. Amplification and overexpression of receptor tyrosine kinases, particularly EGFR and PDGFRA, are complemented by mutations in the PI3K, RB1, and p53 signaling pathways. In addition to finding effective means to target these pathways, we may take advantage of the recent understanding of the hierarchical structure of tumor cell populations, where the progressive expansion of the tumor relies on a minor subpopulation of glioma stem cells, or glioma-initiating cells. Finding ways to reprogram these cells and block their self-renewal is one of the most important topics for future research

Shaping Skeletal Growth by Modular Regulatory Elements in the Bmp5 Gene

Cartilage and bone are formed into a remarkable range of shapes and sizes that underlie many anatomical adaptations to different lifestyles in vertebrates. Although the morphological blueprints for individual cartilage and bony structures must somehow be encoded in the genome, we currently know little about the detailed genomic mechanisms that direct precise growth patterns for particular bones. We have carried out large-scale enhancer surveys to identify the regulatory architecture controlling developmental expression of the mouse Bmp5 gene, which encodes a secreted signaling molecule required for normal morphology of specific skeletal features. Although Bmp5 is expressed in many skeletal precursors, different enhancers control expression in individual bones. Remarkably, we show here that different enhancers also exist for highly restricted spatial subdomains along the surface of individual skeletal structures, including ribs and nasal cartilages. Transgenic, null, and regulatory mutations confirm that these anatomy-specific sequences are sufficient to trigger local changes in skeletal morphology and are required for establishing normal growth rates on separate bone surfaces. Our findings suggest that individual bones are composite structures whose detailed growth patterns are built from many smaller lineage and gene expression domains. Individual enhancers in BMP genes provide a genomic mechanism for controlling precise growth domains in particular cartilages and bones, making it possible to separately regulate skeletal anatomy at highly specific locations in the body

Articular cartilage and changes in Arthritis: Cell biology of osteoarthritis

The reaction patterns of chondrocytes in osteoarthritis can be summarized in five categories: (1) proliferation and cell death (apoptosis); changes in (2) synthetic activity and (3) degradation; (4) phenotypic modulation of the articular chondrocytes; and (5) formation of osteophytes. In osteoarthritis, the primary responses are reinitiation of synthesis of cartilage macromolecules, the initiation of synthesis of types IIA and III procollagens as markers of a more primitive phenotype, and synthesis of active proteolytic enzymes. Reversion to a fibroblast-like phenotype, known as 'dedifferentiation', does not appear to be an important component. Proliferation plays a role in forming characteristic chondrocyte clusters near the surface, while apoptosis probably occurs primarily in the calcified cartilage

Mathematical modeling of microRNA-mediated mechanisms of translation repression

MicroRNAs can affect the protein translation using nine mechanistically different mechanisms, including repression of initiation and degradation of the transcript. There is a hot debate in the current literature about which mechanism and in which situations has a dominant role in living cells. The worst, same experimental systems dealing with the same pairs of mRNA and miRNA can provide ambiguous evidences about which is the actual mechanism of translation repression observed in the experiment. We start with reviewing the current knowledge of various mechanisms of miRNA action and suggest that mathematical modeling can help resolving some of the controversial interpretations. We describe three simple mathematical models of miRNA translation that can be used as tools in interpreting the experimental data on the dynamics of protein synthesis. The most complex model developed by us includes all known mechanisms of miRNA action. It allowed us to study possible dynamical patterns corresponding to different miRNA-mediated mechanisms of translation repression and to suggest concrete recipes on determining the dominant mechanism of miRNA action in the form of kinetic signatures. Using computational experiments and systematizing existing evidences from the literature, we justify a hypothesis about co-existence of distinct miRNA-mediated mechanisms of translation repression. The actually observed mechanism will be that acting on or changing the limiting "place" of the translation process. The limiting place can vary from one experimental setting to another. This model explains the majority of existing controversies reported.Comment: 40 pages, 9 figures, 4 tables, 91 cited reference. The analysis of kinetic signatures is updated according to the new model of coupled transcription, translation and degradation, and of miRNA-based regulation of this process published recently (arXiv:1204.5941). arXiv admin note: text overlap with arXiv:0911.179

In Situ Data and Effect Correlation During September 2017 Solar Particle Event

Solar energetic particles are one of the main sources of particle radiation seen in space. In the first part of September 2017 the most active solar period of cycle 24 produced four large X-class flares and a series of (interplanetary) coronal mass ejections, which gave rise to radiation storms seen over all energies and at the ground by neutron monitors. This paper presents comprehensive cross comparisons of in situ radiation detector data from near-Earth satellites to give an appraisal on the state of present data processing for monitors of such particles. Many of these data sets have been the target of previous cross calibrations, and this event with a hard spectrum provides the opportunity to validate these results. As a result of the excellent agreement found between these data sets and the use of neutron monitor data, this paper also presents an analytical expression for fluence spectrum for the event. Derived ionizing dose values have been computed to show that although there is a significant high-energy component, the event was not particularly concerning as regards dose effects in spacecraft electronics. Several sets of spacecraft data illustrating single event effects are presented showing a more significant impact in this regard. Such a hard event can penetrate thick shielding; human dose quantities measured inside the International Space Station and derived through modeling for aircraft altitudes are also presented. Lastly, simulation results of coronal mass ejection propagation through the heliosphere are presented along with data from Mars-orbiting spacecraft in addition to data from the Mars surface

Regulation of MicroRNA Biogenesis: A miRiad of mechanisms

microRNAs are small, non-coding RNAs that influence diverse biological functions through the repression of target genes during normal development and pathological responses. Widespread use of microRNA arrays to profile microRNA expression has indicated that the levels of many microRNAs are altered during development and disease. These findings have prompted a great deal of investigation into the mechanism and function of microRNA-mediated repression. However, the mechanisms which govern the regulation of microRNA biogenesis and activity are just beginning to be uncovered. Following transcription, mature microRNA are generated through a series of coordinated processing events mediated by large protein complexes. It is increasingly clear that microRNA biogenesis does not proceed in a 'one-size-fits-all' manner. Rather, individual classes of microRNAs are differentially regulated through the association of regulatory factors with the core microRNA biogenesis machinery. Here, we review the regulation of microRNA biogenesis and activity, with particular focus on mechanisms of post-transcriptional control. Further understanding of the regulation of microRNA biogenesis and activity will undoubtedly provide important insights into normal development as well as pathological conditions such as cardiovascular disease and cancer

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta