Testing Cluster Structure of Graphs

We study the problem of recognizing the cluster structure of a graph in the framework of property testing in the bounded degree model. Given a parameter $\varepsilon$, a $d$-bounded degree graph is defined to be $(k, \phi)$-clusterable, if it can be partitioned into no more than $k$ parts, such that the (inner) conductance of the induced subgraph on each part is at least $\phi$ and the (outer) conductance of each part is at most $c_{d,k}\varepsilon^4\phi^2$, where $c_{d,k}$ depends only on $d,k$. Our main result is a sublinear algorithm with the running time $\widetilde{O}(\sqrt{n}\cdot\mathrm{poly}(\phi,k,1/\varepsilon))$ that takes as input a graph with maximum degree bounded by $d$, parameters $k$, $\phi$, $\varepsilon$, and with probability at least $\frac23$, accepts the graph if it is $(k,\phi)$-clusterable and rejects the graph if it is $\varepsilon$-far from $(k, \phi^*)$-clusterable for $\phi^* = c'_{d,k}\frac{\phi^2 \varepsilon^4}{\log n}$, where $c'_{d,k}$ depends only on $d,k$. By the lower bound of $\Omega(\sqrt{n})$ on the number of queries needed for testing graph expansion, which corresponds to $k=1$ in our problem, our algorithm is asymptotically optimal up to polylogarithmic factors.Comment: Full version of STOC 201

Multi-Zone Modeling of The Pulsar Wind Nebula HESS J1825-137

The pulsar wind nebula associated with PSR J1826-1334, HESS J1825-137, is a bright very high energy source with an angular extent of ~1 degree and spatially-resolved spectroscopic TeV measurements. The gamma-ray spectral index is observed to soften with increasing distance from the pulsar, likely the result of cooling losses as electrons traverse the nebula. We describe analysis of X-ray data of the extended nebula, as well as 3-D time-dependent spectral energy distribution modeling, with emphasis on the spatial variations within HESS J1825-137. The multi-wavelength data places significant constraints on electron injection, transport, and cooling within the nebula. The large size and high nebular energy budget imply a relatively rapid initial pulsar spin period of 13 \pm 7 ms and an age of 40 \pm 9 kyr. The relative fluxes of each VHE zone can be explained by advective particle transport with a radially decreasing velocity profile with $v(r) \propto r^{-0.5}$. The evolution of the cooling break requires an evolving magnetic field which also decreases radially from the pulsar, $B(r,t) \propto r^{-0.7} \dot{E}(t)^{1/2}$. Detection of 10 TeV flux ~80 pc from the pulsar requires rapid diffusion of high energy particles with $\tau_{esc} \approx 90 (R / 10 pc)^2 (E_e/100 TeV)^{-1}$ year, contrary to the common assumption of toroidal magnetic fields with strong magnetic confinement. The model predicts a rather uniform Fermi LAT surface brightness out to ~1 degree from the pulsar, in good agreement with the recently discovered LAT source centered 0.5 degree southwest of PSR J1826-1334 with extension 0.6 \pm 0.1 degree.Comment: Updated to published versio

Pulmonary effects of inhalation of spark-generated silver nanoparticles in Brown-Norway and Sprague-Dawley rats

The increasing use of silver nanoparticles (AgNPs) in consumer products is concerning. We examined the potential toxic effects when inhaled in Brown-Norway (BN) rats with a pre-inflammatory state compared to Sprague-Dawley (SD) rats.We determined the effect of AgNPs generated from a spark generator (mass concentration: 600-800 μg/mm(3); mean diameter: 13-16 nm; total lung doses: 8 [Low] and 26-28 [High] μg) inhaled by the nasal route in both rat strains. Rats were sacrificed at day 1 and day 7 after exposure and measurement of lung function.In both strains, there was an increase in neutrophils in bronchoalveolar lavage (BAL) fluid at 24 h at the high dose, with concomitant eosinophilia in BN rats. While BAL inflammatory cells were mostly normalised by Day 7, lung inflammation scores remained increased although not the tissue eosinophil scores. Total protein levels were elevated at both lung doses in both strains. There was an increase in BAL IL-1β, KC, IL-17, CCL2 and CCL3 levels in both strains at Day 1, mostly at high dose. Phospholipid levels were increased at the high dose in SD rats at Day 1 and 7, while in BN rats, this was only seen at Day 1; surfactant protein D levels decreased at day 7 at the high dose in SD rats, but was increased at Day 1 at the low dose in BN rats. There was a transient increase in central airway resistance and in tissue elastance in BN rats at Day 1 but not in SD rats. Positive silver-staining was seen particularly in lung tissue macrophages in a dose and time-dependent response in both strains, maximal by day 7. Lung silver levels were relatively higher in BN rat and present at day 7 in both strains.Presence of cellular inflammation and increasing silver-positive macrophages in lungs at day 7, associated with significant levels of lung silver indicate that lung toxicity is persistent even with the absence of airway luminal inflammation at that time-point. The higher levels and persistence of lung silver in BN rats may be due to the pre-existing inflammatory state of the lungs

Diamond Dicing

In OLAP, analysts often select an interesting sample of the data. For example, an analyst might focus on products bringing revenues of at least 100 000 dollars, or on shops having sales greater than 400 000 dollars. However, current systems do not allow the application of both of these thresholds simultaneously, selecting products and shops satisfying both thresholds. For such purposes, we introduce the diamond cube operator, filling a gap among existing data warehouse operations. Because of the interaction between dimensions the computation of diamond cubes is challenging. We compare and test various algorithms on large data sets of more than 100 million facts. We find that while it is possible to implement diamonds in SQL, it is inefficient. Indeed, our custom implementation can be a hundred times faster than popular database engines (including a row-store and a column-store).Comment: 29 page

Protein/DNA arrays identify nitric oxide-regulated cis-element and trans-factor activities some of which govern neuroblastoma cell viability

Toxic nitric oxide (NO) levels can regulate gene expression. Using a novel protein/DNA array, we show that toxic NO levels regulate the binding of trans-factors to various cis-elements in neuroblastoma cells, including CRE and those recognized by the transcription factors AP1, AP2, Brn-3a, EGR, E2F1 and SP1. Functionality of some of the cis-elements was confirmed by electro mobility shift and reporter assays. Interestingly, CREB, AP-1, Brn-3a, EGR and E2F1 can control mammalian cell viability. NO induced the anti-apoptotic Bcl-2 protein and its mRNA prior to the onset of death of 30–60% of the cells. Promoter analysis of the bcl-2 gene confirmed the involvement of a CRE in NO-dependent bcl-2 transcription. Neuroblastoma cells over-expressing bcl-2 became much more resistant to NO-induced apoptosis; conversely, Bcl-2 knockdown cells were rendered markedly more sensitive to NO. Together these results suggest that Bcl-2 counteracts NO-induced apoptosis in a fraction of the cell population. Thus, NO stimulates the binding of many trans-factors to their cognate cis-elements, some of which can regulate cell viability through transcriptional activation of target genes. Our results emphasize that a DNA/protein array approach can reveal novel, global transcription factor activities stimulated by cell death-regulating molecules

Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations

PURPOSE: Predicting the phenotypic effects of mutations has become an important application in clinical genetic diagnostics. Computational tools evaluate the behavior of the variant over evolutionary time and assume that variations seen during the course of evolution are probably benign in humans. However, current tools do not take into account orthologous/paralogous relationships. Paralogs have dramatically different roles in Mendelian diseases. For example, whereas inactivating mutations in the NPC1 gene cause the neurodegenerative disorder Niemann-Pick C, inactivating mutations in its paralog NPC1L1 are not disease-causing and, moreover, are implicated in protection from coronary heart disease. METHODS: We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism’s fitness. RESULTS: Removing the paralogs and distant homologs improved the overall performance of categorizing disease-causing and benign amino acid substitutions. CONCLUSION: The results show that a thorough evolutionary analysis followed by identification of orthologs improves the accuracy in predicting disease-causing missense mutations. We anticipate that this approach will be used as a reference in the interpretation of variants in other genetic diseases as well. Genet Med 18 10, 1029–1036

Nanomolar potency and selectivity of a Ca2+ release-activated Ca2+ channel inhibitor against store-operated Ca2+ entry and migration of vascular smooth muscle cells

BACKGROUND AND PURPOSE The aim was to advance the understanding of Orai proteins and identify a specific inhibitor of the associated calcium entry mechanism in vascular smooth muscle cells (VSMCs). EXPERIMENTAL APPROACH Proliferating VSMCs were cultured from human saphenous veins. Intracellular calcium was measured using fura‐2, whole‐cell current was recorded using patch‐clamp and cell migration quantified in modified Boyden chambers. Subcellular protein localization was determined by microscopy. Isometric tension was recorded from mouse aortic rings. KEY RESULTS Molecular disruption and rescue experiments indicated the importance of Orai1 in calcium entry caused by store depletion evoked passively or by platelet‐derived growth factor (PDGF), suggesting the presence of Ca2+ release‐activated Ca2+ (CRAC) channels like those of the immune system. The CRAC channel blocker, S66, was a potent inhibitor of the VSMC signals, IC50 26 nM, which was almost two orders of magnitude greater than with leucocytes. S66 had no effect on PDGF‐ and ATP‐evoked calcium release, overexpressed transient receptor potential canonical (TRPC)5 channels, native TRPC1/5‐containing channels, stromal interaction molecule 1 clustering, non‐selective cationic current evoked by store depletion and phenylephrine‐evoked aortic contraction. S66 reduced PDGF‐evoked VSMC migration while having only modest effects on cell proliferation and no effect on cell viability. CONCLUSIONS AND IMPLICATIONS The data suggest that Orai1 has a role in human VSMC migration, and that a CRAC channel inhibitor has high potency and selectivity for the associated calcium entry, suggesting a distinct characteristic of vascular CRAC channels and the potential for selective chemical suppression of vascular remodelling

Empty rituals? A qualitative study of users’ experience of monitoring & evaluation systems in HIV interventions in western India

In global health initiatives, particularly in the context of private philanthropy and its ‘business minded’ approach, detailed programme data plays an increasing role in informing assessments, improvements, evaluations, and ultimately continuation or discontinuation of funds for individual programmes. The HIV/AIDS literature predominantly treats monitoring as unproblematic. However, the social science of audit and indicators emphasises the constitutive power of indicators, noting that their effects at a grassroots level are often at odds with the goals specified in policy. This paper investigates users' experiences of Monitoring and Evaluation (M&E) systems in the context of HIV interventions in western India. Six focus groups (totalling 51 participants) were held with employees of 6 different NGOs working for government or philanthropy-funded HIV interventions for sex workers in western India. Ten donor employees were interviewed. Thematic analysis was conducted. NGO employees described a major gap between what they considered their “real work” and the indicators used to monitor it. They could explain the official purposes of M&E systems in terms of programme improvement and financial accountability. More cynically, they valued M&E experience on their CVs and the rhetorical role of data in demonstrating their achievements. They believed that inappropriate and unethical means were being used to meet targets, including incentives and coercion, and criticised indicators for being misleading and inflexible. Donor employees valued the role of M&E in programme improvement, financial accountability, and professionalising NGO-donor relationships. However, they were suspicious that NGOs might be falsifying data, criticised the insensitivity of indicators, and complained that data were under-used. For its users, M& E appears an ‘empty ritual’, enacted because donors require it, but not put to local use. In this context, monitoring is constituted as an instrument of performance management rather than as a means of rational programme improvement

Study of Four Young TeV Pulsar Wind Nebulae with a Spectral Evolution Model

We study four young Pulsar Wind Nebulae (PWNe) detected in TeV gamma-rays, G21.5-0.9, G54.1+0.3, Kes 75, and G0.9+0.1, using the spectral evolution model developed and applied to the Crab Nebula in our previous work. We model the evolution of magnetic field and particle distribution function inside a uniformly expanding PWN considering a time-dependent injection from the pulsar and radiative and adiabatic losses. Considering uncertainties in the interstellar radiation field (ISRF) and their distance, we study two cases for each PWN. Because TeV PWNe have a large TeV gamma-rays to X-rays flux ratio, the magnetic energy of the PWNe accounts for only a small fraction of the total energy injected (typically a few x 10^{-3}). The gamma-ray emission is dominated by inverse Compton scattering off the infrared photons of the ISRF. A broken power-law distribution function for the injected particles reproduces the observed spectrum well, except for G0.9+0.1. For G0.9+0.1, we do not need a low energy counterpart because adiabatic losses alone are enough to reproduce the radio observations. High energy power-law indices at injection are similar (2.5 -- 2.6), while low energy power-law indices range from 1.0 to 1.6. The lower limit of the particle injection rate indicates that the pair multiplicity is larger than 10^4. The corresponding upper limit of the bulk Lorentz factor of the pulsar winds is close to the break energy of the broken power-law injection, except for Kes 75.Comment: Accepted for publication in ApJ; 56pages, 15figure

Abundances and density structure of the inner circumstellar ring around SN 1987A

We present optical spectroscopic data of the inner circumstellar ring around SN 1987A from the Anglo-Australian Telescope (AAT) and the Very Large Telescope (VLT) between ~1400 and ~5000 days post-explosion. We also assembled the available optical and near-infrared line fluxes from the literature between ~300 and ~2000 days. These line light curves were fitted with a photoionization model to determine the density structure and the elemental abundances for the inner ring. We found densities ranging from 1x10^3 to 3x10^4 atoms cm^-3 and a total mass of the ionized gas of ~0.058 Msun within the inner ring. Abundances inferred from the optical and near-infrared data were also complemented with estimates of Lundqvist & Fransson (1996) based on ultraviolet lines. This way we found an He/H-ratio (by number of atoms) of 0.17+-0.06 which is roughly 30% lower than previously estimated and twice the solar and the Large Magellanic Cloud (LMC) value. We found an N/O-ratio of 1.5+-0.7, and the total (C+N+O)/(H+He) abundance about 1.6 times its LMC value or roughly 0.6 times the most recent solar value. An iron abundance of 0.20+-0.11 times solar was found which is within the range of the estimates for the LMC. We also present late time (~5000 - 7500 days) line light curves of [O III], [Ne III], [Ne IV], [Ar III], [Ar IV], and [Fe VII] from observations with the VLT. We compared these with model fluxes and found that an additional 10^2 atoms cm^-3 component was required to explain the data of the highest ionization lines. Such low density gas is expected in the H II-region interior to the inner ring which likely extends also to larger radii at higher latitudes (out of the ring plane). At epochs later than ~5000 days our models underproduce the emission of most of these lines as expected due to the contribution from the interaction of the supernova ejecta with the ring.Comment: 17 pages, 8 figures, accepted for publication in Ap