Growth and dislocation studies of β-HMX

Background: The defect structure of organic materials is important as it plays a major role in their crystal growth properties. It also can play a subcritical role in “hot-spot” detonation processes of energetics and one such energetic is cyclotetramethylene-tetranitramine, in the commonly used beta form (β-HMX). Results: The as-grown crystals grown by evaporation from acetone show prismatic, tabular and columnar habits, all with {011}, {110}, (010) and (101) faces. Etching on (010) surfaces revealed three different types of etch pits, two of which could be identified with either pure screw or pure edge dislocations, the third is shown to be an artifact of the twinning process that this material undergoes. Examination of the {011} and {110} surfaces show only one type of etch pit on each surface; however their natural asymmetry precludes the easy identification of their Burgers vector or dislocation type. Etching of cleaved {011} surfaces demonstrates that the etch pits can be associated with line dislocations. All dislocations appear randomly on the crystal surfaces and do not form alignments characteristic of mechanical deformation by dislocation slip. Conclusions: Crystals of β-HMX grown from acetone show good morphological agreement with that predicted by modelling, with three distinct crystal habits observed depending upon the supersaturation of the growth solution. Prismatic habit was favoured at low supersaturation, while tabular and columnar crystals were predominant at higher super saturations. The twin plane in β-HMX was identified as a (101) reflection plane. The low plasticity of β-HMX is shown by the lack of etch pit alignments corresponding to mechanically induced dislocation arrays. On untwinned {010} faces, two types of dislocations exist, pure edge dislocations with b = [010] and pure screw dislocations with b = [010]. On twinned (010) faces, a third dislocation type exists and it is proposed that these pits are associated with pure screw dislocations with b = [010]

Gravitational waves from binary supermassive black holes missing in pulsar observations.

This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aab1910Gravitational waves are expected to be radiated by supermassive black hole binaries formed during galaxy mergers. A stochastic superposition of gravitational waves from all such binary systems would modulate the arrival times of pulses from radio pulsars. Using observations of millisecond pulsars obtained with the Parkes radio telescope, we constrained the characteristic amplitude of this background, A(c,yr), to be <1.0 × 10(-15) with 95% confidence. This limit excludes predicted ranges for A(c,yr) from current models with 91 to 99.7% probability. We conclude that binary evolution is either stalled or dramatically accelerated by galactic-center environments and that higher-cadence and shorter-wavelength observations would be more sensitive to gravitational waves.The PPTA project was initiated with support from R.N.M.’s Australian Research Council (ARC) Federation Fellowship (grant FF0348478) and from CSIRO under that fellowship program. The PPTA project has also received support from ARC through Discovery Project grants DP0985272 and DP140102578. N.D.R.B. acknowledges support from a Curtin University research fellowship. G.H. and Y.L. are recipients of ARC Future Fellowships (respectively, grants FT120100595 and FT110100384). S.O. is supported by the Alexander von Humboldt Foundation. R.M.S. acknowledges travel support from CSIRO through a John Philip Award for excellence in early-career research. The authors declare no conflicts of interest. Data used in this analysis can be accessed via the Australian National Data Service (www.ands.org.au)

Tau Interaction with Tubulin and Microtubules: From Purified Proteins to Cells

International audienceMicrotubules (MTs) play an important role in many cellular processes and are dynamic structures regulated by an important network of microtubules-associated proteins, MAPs, such as Tau. Tau has been discovered as an essential factor for MTs formation in vitro, and its region implicated in binding to MTs has been identified. By contrast, the affinity, the stoichiometry, and the topology of Tau-MTs interaction remain controversial. Indeed, depending on the experiment conditions a wide range of values have been obtained. In this chapter, we focus on three biophysical methods, turbidimetry, cosedimentation assay, and Förster Resonance Energy Transfer to study Tau-tubulin interaction both in vitro and in cell. We highlight precautions that must be taken in order to avoid pitfalls and we detail the nature of the conclusions that can be drawn from these methods about Tau-tubulin interaction

Serial Killing of Tumor Cells by Human Natural Killer Cells – Enhancement by Therapeutic Antibodies

BACKGROUND: Natural killer cells are an important component of the innate immune system. Anti-cancer therapies utilizing monoclonal antibodies also rely on the cytotoxicity of NK cells for their effectiveness. Here, we study the dynamics of NK cell cytotoxicity. METHODOLOGY/PRINCIPAL FINDINGS: We observe that IL-2 activated human NK cells can serially hit multiple targets. Using functional assays, we demonstrate that on an average, a single IL-2 activated NK cell can kill four target cells. Data using live video microscopy suggest that an individual NK cell can make serial contacts with multiple targets and majority of contacts lead to lysis of target cells. Serial killing is associated with a loss of Perforin and Granzyme B content. A large majority of NK cells survive serial killing, and IL-2 can replenish their granular stock and restore the diminished cytotoxicity of ‘exhausted’ NK cells. IL-2 and IL-15 are equally effective in enhancing the killing frequency of resting NK cells. Significantly, Rituximab, a therapeutic monoclonal antibody increases the killing frequency of both resting and IL-2 activated NK cells. CONCLUSION/SIGNIFICANCE: Our data suggest that NK cell-based therapies for overcoming tumors rely on their serial killing ability. Therefore, strategies augmenting the killing ability of NK cells can boost the immune system and enhance the effectiveness of monoclonal antibody-based therapies

Potential Sensitivity of Gamma-Ray Burster Observations to Wave Dispersion in Vacuo

The recent confirmation that at least some gamma-ray bursters (GRBs) are indeed at cosmological distances raises the possibility that observations of these could provide interesting constraints on the fundamental laws of physics. Here we demonstrate that the fine-scale time structure and hard spectra of GRB emissions are very sensitive to the possible dispersion of electromagnetic waves in vacuo with velocity differences \delta v \sim E/E_{\QG}, as suggested in some approaches to quantum gravity. A simple estimate shows that GRB measurements might be sensitive to a dispersion scale $E_{QG}$ comparable to the Planck energy scale $E_{P} \sim 10^{19}$ GeV, sufficient to test some of these theories, and we outline aspects of an observational programme that could address this goal.Comment: LaTex. 9 pages. Version accepted for publication in Nature. (A few changes to the reference list. Additional comments on the analyticity properties of the dispersion law.

Sub-threshold depression and antidepressants use in a community sample: searching anxiety and finding bipolar disorder

<p>Abstract</p> <p>Background</p> <p>To determine the use of antidepressants (ADs) in people with sub-threshold depression (SD); the lifetime prevalence of mania and hypomania in SD and the link between ADs use, bipolarity and anxiety disorders in SD.</p> <p>Methods</p> <p>Study design: community survey. Study population: samples randomly drawn, after stratification from the adult population of municipal records. Sample size: 4999 people from seven areas within six Italian regions. Tools: Questionnaire on psychotropic drug consumption, prescription; Structured Clinical Interview NP for DSM-IV modified (ANTAS); Hamilton Depression Rating Scale (HAM-D); Mood Disorder Questionnaire (MDQ); Short Form Health Survey (SF-12). SD definition: HAM-D > 10 without lifetime diagnosis of Depressive Episode (DE).</p> <p>Results</p> <p>SD point prevalence is 5.0%. The lifetime prevalence of mania and hypomania episodes in SD is 7.3%. Benzodiazepines (BDZ) consumption in SD is 24.1%, followed by ADs (19.7%). In SD, positive for MDQ and comorbidity with Panic Disorder (PD) or Generalized Anxiety Disorders (GAD) are associated with ADs use, whereas the association between a positive MDQ and ADs use, without a diagnosis of PD or GAD, is not significant. Only in people with DE the well-being (SF-12) is higher among those using first-line antidepressants compared to those not using any medication. In people with SD no significant differences were found in terms of SF-12 score according to drug use.</p> <p>Conclusions</p> <p>This study suggests caution in prescribing ADs to people with SD. In people with concomitant anxiety disorders and SD, it should be mandatory to perform a well-designed assessment and evaluate the presence of previous manic or hypomanic symptoms prior to prescribing ADs.</p

SLUG/SNAI2 and Tumor Necrosis Factor Generate Breast Cells With CD44+/CD24- Phenotype

<p>Abstract</p> <p>Background</p> <p>Breast cancer cells with CD44+/CD24- cell surface marker expression profile are proposed as cancer stem cells (CSCs). Normal breast epithelial cells that are CD44+/CD24- express higher levels of stem/progenitor cell associated genes. We, amongst others, have shown that cancer cells that have undergone epithelial to mesenchymal transition (EMT) display the CD44+/CD24- phenotype. However, whether all genes that induce EMT confer the CD44+/CD24- phenotype is unknown. We hypothesized that only a subset of genes associated with EMT generates CD44+/CD24- cells.</p> <p>Methods</p> <p>MCF-10A breast epithelial cells, a subpopulation of which spontaneously acquire the CD44+/CD24- phenotype, were used to identify genes that are differentially expressed in CD44+/CD24- and CD44-/CD24+ cells. Ingenuity pathway analysis was performed to identify signaling networks that linked differentially expressed genes. Two EMT-associated genes elevated in CD44+/CD24- cells, SLUG and Gli-2, were overexpressed in the CD44-/CD24+ subpopulation of MCF-10A cells and MCF-7 cells, which are CD44-/CD24+. Flow cytometry and mammosphere assays were used to assess cell surface markers and stem cell-like properties, respectively.</p> <p>Results</p> <p>Two thousand thirty five genes were differentially expressed (p < 0.001, fold change ≥ 2) between the CD44+/CD24- and CD44-/CD24+ subpopulations of MCF-10A. Thirty-two EMT-associated genes including SLUG, Gli-2, ZEB-1, and ZEB-2 were expressed at higher levels in CD44+/CD24- cells. These EMT-associated genes participate in signaling networks comprising TGFβ, NF-κB, and human chorionic gonadotropin. Treatment with tumor necrosis factor (TNF), which induces NF-κB and represses E-cadherin, or overexpression of SLUG in CD44-/CD24+ MCF-10A cells, gave rise to a subpopulation of CD44+/CD24- cells. Overexpression of constitutively active p65 subunit of NF-κB in MCF-10A resulted in a dramatic shift to the CD44+/CD24+ phenotype. SLUG overexpression in MCF-7 cells generated CD44+/CD24+ cells with enhanced mammosphere forming ability. In contrast, Gli-2 failed to alter CD44 and CD24 expression.</p> <p>Conclusions</p> <p>EMT-mediated generation of CD44+/CD24- or CD44+/CD24+ cells depends on the genes that induce or are associated with EMT. Our studies reveal a role for TNF in altering the phenotype of breast CSC. Additionally, the CD44+/CD24+ phenotype, in the context of SLUG overexpression, can be associated with breast CSC "stemness" behavior based on mammosphere forming ability.</p

High risk for occupational exposure to HIV and utilization of post-exposure prophylaxis in a teaching hospital in Pune, India

<p>Abstract</p> <p>Background</p> <p>The risk for occupational exposure to HIV has been well characterized in the developed world, but limited information is available about this transmission risk in resource-constrained settings facing the largest burden of HIV infection. In addition, the feasibility and utilization of post-exposure prophylaxis (PEP) programs in these settings are unclear. Therefore, we examined the rate and characteristics of occupational exposure to HIV and the utilization of PEP among health care workers (HCW) in a large, urban government teaching hospital in Pune, India.</p> <p>Methods</p> <p>Demographic and clinical data on occupational exposures and their management were prospectively collected from January 2003–December 2005. US Centers for Diseases Control guidelines were utilized to define risk exposures, for which PEP was recommended. Incidence rates of reported exposures and trends in PEP utilization were examined using logistic regression.</p> <p>Results</p> <p>Of 1955 HCW, 557 exposures were reported by 484 HCW with an incidence of 9.5 exposures per 100 person-years (PY). Housestaff, particularly interns, reported the greatest number of exposures with an annual incidence of 47.0 per 100 PY. Personal protective equipment (PPE) was used in only 55.1% of these exposures. The incidence of high-risk exposures was 6.8/100 PY (n = 339); 49.1% occurred during a procedure or disposing of equipment and 265 (80.0%) received a stat dose of PEP. After excluding cases in which the source tested HIV negative, 48.4% of high-risk cases began an extended PEP regimen, of whom only 49.5% completed it. There were no HIV or Hepatitis B seroconversions identified. Extended PEP was continued unnecessarily in 7 (35%) of 20 cases who were confirmed to be HIV-negative. Over time, there was a significant reduction in proportion of percutaneous exposures and high-risk exposures (p < 0.01) and an increase in PEP utilization for high risk exposures (44% in 2003 to 100% in 2005, p = 0.002).</p> <p>Conclusion</p> <p>Housestaff are a vulnerable population at high risk for bloodborne exposures in teaching hospital settings in India. With implementation of a hospital-wide PEP program, there was an encouraging decrease of high-risk exposures over time and appropriate use of PEP. However, overall use of PPE was low, suggesting further measures are needed to prevent occupational exposures in India.</p