Exploration of key stakeholders' preferences for pre-hospital physiologic monitoring by emergency rescue services

Peer reviewedPostprintPostprin

Panspecies small-molecule disruptors of heterochromatin-mediated transcriptional gene silencing

Heterochromatin underpins gene repression, genome integrity, and chromosome segregation. In the fission yeast Schizosaccharomyces pombe, conserved protein complexes effect heterochromatin formation via RNA interference-mediated recruitment of a histone H3 lysine 9 methyltransferase to cognate chromatin regions. To identify small molecules that inhibit heterochromatin formation, we performed an in vivo screen for loss of silencing of a dominant selectable kanMX reporter gene embedded within fission yeast centromeric heterochromatin. Two structurally unrelated compounds, HMS-I1 and HMS-I2, alleviated kanMX silencing and decreased repressive H3K9 methylation levels at the transgene. The decrease in methylation caused by HMS-I1 and HMS-I2 was observed at all loci regulated by histone methylation, including centromeric repeats, telomeric regions, and the mating-type locus, consistent with inhibition of the histone deacetylases (HDACs) Clr3 and/or Sir2. Chemical-genetic epistasis and expression profiles revealed that both compounds affect the activity of the Clr3-containing Snf2/HDAC repressor complex (SHREC). In vitro HDAC assays revealed that HMS-I1 and HMS-I2 inhibit Clr3 HDAC activity. HMS-I1 also alleviated transgene reporter silencing by heterochromatin in Arabidopsis and a mouse cell line, suggesting a conserved mechanism of action. HMS-I1 and HMS-I2 bear no resemblance to known inhibitors of chromatin-based activities and thus represent novel chemical probes for heterochromatin formation and function

Near-surface hydraulic conductivity of Northern Hemisphere glaciers

The hydrology of near‐surface glacier ice remains a neglected aspect of glacier hydrology despite its role in modulating meltwater delivery to downstream environments. To elucidate the hydrological characteristics of this near‐surface glacial weathering crust, we describe the design and operation of a capacitance‐based piezometer that enables rapid, economical deployment across multiple sites and provides an accurate, high‐resolution record of near‐surface water‐level fluctuations. Piezometers were employed at 10 northern hemisphere glaciers, and through the application of standard bail–recharge techniques, we derive hydraulic conductivity (K) values from 0.003 to 3.519 m day−1, with a mean of 0.185 ± 0.019 m day−1. These results are comparable to those obtained in other discrete studies of glacier near‐surface ice, and for firn, and indicate that the weathering crust represents a hydrologically inefficient aquifer. Hydraulic conductivity correlated positively with water table height but negatively with altitude and cumulative short‐wave radiation since the last synoptic period of either negative air temperatures or turbulent energy flux dominance. The large range of K observed suggests complex interactions between meteorological influences and differences arising from variability in ice structure and crystallography. Our data demonstrate a greater complexity of near‐surface ice hydrology than hitherto appreciated and support the notion that the weathering crust can regulate the supraglacial discharge response to melt production. The conductivities reported here, coupled with typical supraglacial channel spacing, suggest that meltwater can be retained within the weathering crust for at least several days. Not only does this have implications for the accuracy of predictive meltwater run‐off models, but we also argue for biogeochemical processes and transfers that are strongly conditioned by water residence time and the efficacy of the cascade of sediments, impurities, microbes, and nutrients to downstream ecosystems. Because continued atmospheric warming will incur rising snowline elevations and glacier thinning, the supraglacial hydrological system may assume greater importance in many mountainous regions, and consequently, detailing weathering crust hydraulics represents a research priority because the flow path it represents remains poorly constrained

Serum Metabolome and Lipidome Changes in Adult Patients with Primary Dengue Infection

10.1371/journal.pntd.0002373PLoS Neglected Tropical Diseases78

Purification and Characterization of a Novel Hypersensitive Response-Inducing Elicitor from Magnaporthe oryzae that Triggers Defense Response in Rice

<div><h3>Background</h3><p><em>Magnaporthe oryzae</em>, the rice blast fungus, might secrete certain proteins related to plant-fungal pathogen interactions.</p> <h3>Methodology/Principal Findings</h3><p>In this study, we report the purification, characterization, and gene cloning of a novel hypersensitive response-inducing protein elicitor (MoHrip1) secreted by <em>M. oryzae</em>. The protein fraction was purified and identified by de novo sequencing, and the sequence matched the genomic sequence of a putative protein from <em>M. oryzae</em> strain 70-15 (GenBank accession No. XP_366602.1). The elicitor-encoding gene <em>mohrip1</em> was isolated; it consisted of a 429 bp cDNA, which encodes a polypeptide of 142 amino acids with a molecular weight of 14.322 kDa and a pI of 4.53. The deduced protein, MoHrip1, was expressed in <em>E. coli</em>. And the expression protein collected from bacterium also forms necrotic lesions in tobacco. MoHrip1 could induce the early events of the defense response, including hydrogen peroxide production, callose deposition, and alkalization of the extracellular medium, in tobacco. Moreover, MoHrip1-treated rice seedlings possessed significantly enhanced systemic resistance to <em>M. oryzae</em> compared to the control seedlings. The real-time PCR results indicated that the expression of some pathogenesis-related genes and genes involved in signal transduction could also be induced by MoHrip1.</p> <h3>Conclusion/Significance</h3><p>The results demonstrate that MoHrip1 triggers defense responses in rice and could be used for controlling rice blast disease.</p> </div

The Scaffolding Protein Dlg1 Is a Negative Regulator of Cell-Free Virus Infectivity but Not of Cell-to-Cell HIV-1 Transmission in T Cells

Background: Cell-to-cell virus transmission of Human immunodeficiency virus type-1 (HIV-1) is predominantly mediated by cellular structures such as the virological synapse (VS). The VS formed between an HIV-1-infected T cell and a target T cell shares features with the immunological synapse (IS). We have previously identified the human homologue of the Drosophila Discs Large (Dlg1) protein as a new cellular partner for the HIV-1 Gag protein and a negative regulator of HIV-1 infectivity. Dlg1, a scaffolding protein plays a key role in clustering protein complexes in the plasma membrane at cellular contacts. It is implicated in IS formation and T cell signaling, but its role in HIV-1 cell-to-cell transmission was not studied before. Methodology/Principal Findings: Kinetics of HIV-1 infection in Dlg1-depleted Jurkat T cells show that Dlg1 modulates the replication of HIV-1. Single-cycle infectivity tests show that this modulation does not take place during early steps of the HIV-1 life cycle. Immunofluorescence studies of Dlg1-depleted Jurkat T cells show that while Dlg1 depletion affects IS formation, it does not affect HIV-1-induced VS formation. Co-culture assays and quantitative cell-to-cell HIV-1 transfer analyses show that Dlg1 depletion does not modify transfer of HIV-1 material from infected to target T cells, or HIV-1 transmission leading to productive infection via cell contact. Dlg1 depletion results in increased virus yield and infectivity of the viral particles produced. Particles with increased infectivity present an increase in their cholesterol content and during the first hours of T cell infection these particles induce higher accumulation of total HIV-1 DNA

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

How many myloid post-progenitor cells have to be transplanted to completely abrogate neutropenia after peripheral blood progenitor cell transplantation ? Results of a computer simulation.

Although hematopoietic recovery following high-dose chemotherapy (HD-CT) and peripheral blood progenitor cell (PBPC) transplantation is rapid, there is still a 5- to 7-day period of severe neutropenia which, theoretically, might be abrogated by an additional transplantation of more differentiated myeloid post-progenitor cells (MPPC). However, both the number of MPPC required to abrogate neutropenia as well as the optimum scheduling of MPPC infusions are currently unknown. Therefore, these questions were addressed by applying a computer model of human granulopoiesis. First, model calculations simulating varying levels of chemotherapy dose intensity were performed and compared with typical clinical neutrophil recovery curves. Using this approach, the data for HD-CT without PBPC transplantation could be reproduced by assuming a reduction of stem cells, committed granulopoietic progenitors and proliferating precursors to about 0.001% of normal. PBPC-supported HD-CT was reproduced by increasing the starting values to at least 0.1%, which corresponded to about 1 to 2 x 10(5)/kg transplanted CFU-GM. Interestingly, reproduction of PBPC-supported HD-CT data could be observed for a wide range of starting values (0.1%-10% of normal), thus confirming the clinical observation that hematopoietic recovery after PBPCT cannot be improved by increasing the dose of transplanted cells over a certain threshold. Using the same simulation model, we then studied the effects of an additional MPPC transplantation. The results showed, that at least 5.7 X 10(8) MPPC/kg have to be provided in addition to the normal PBPC graft to avoid neutropenia &lt;100/microL, and that MPPC are best transplanted on days 0 and 6 after HD-CT. Assuming a 100- to 120-fold cellular ex-vivo expansion rate and MPPC representing about 70% of total expanded cells, 5.7 X 10(8) MPPC/kg could be generated starting from 1 to 2 leukapheresis preparations with about 7 to 8 x 10(6) CD34+ PBPC/kg. Considering furthermore, that only a fraction of ex-vivo generated cells will seed and effectively produce neutrophils in-vivo, the required number of MPPC is most likely even higher and, therefore, might be difficult to be achieved clinically. However, the validity of the model results remains to be proven in appropriate clinical studies