Bench-to-bedside review: Future novel diagnostics for sepsis - a systems biology approach

The early, accurate diagnosis and risk stratification of sepsis remains an important challenge in the critically ill. Since traditional biomarker strategies have not yielded a gold standard marker for sepsis, focus is shifting towards novel strategies that improve assessment capabilities. The combination of technological advancements and information generated through the human genome project positions systems biology at the forefront of biomarker discovery. While previously available, developments in the technologies focusing on DNA, gene expression, gene regulatory mechanisms, protein and metabolite discovery have made these tools more feasible to implement and less costly, and they have taken on an enhanced capacity such that they are ripe for utilization as tools to advance our knowledge and clinical research. Medicine is in a genome-level era that can leverage the assessment of thousands of molecular signals beyond simply measuring selected circulating proteins. Genomics is the study of the entire complement of genetic material of an individual. Epigenetics is the regulation of gene activity by reversible modifications of the DNA. Transcriptomics is the quantification of the relative levels of messenger RNA for a large number of genes in specific cells or tissues to measure differences in the expression levels of different genes, and the utilization of patterns of differential gene expression to characterize different biological states of a tissue. Proteomics is the large-scale study of proteins. Metabolomics is the study of the small molecule profiles that are the terminal downstream products of the genome and consists of the total complement of all low-molecular-weight molecules that cellular processes leave behind. Taken together, these individual fields of study may be linked during a systems biology approach. There remains a valuable opportunity to deploy these technologies further in human research. The techniques described in this paper not only have the potential to increase the spectrum of diagnostic and prognostic biomarkers in sepsis, but they may also enable the discovery of new disease pathways. This may in turn lead us to improved therapeutic targets. The objective of this paper is to provide an overview and basic framework for clinicians and clinical researchers to better understand the 'omics technologies' to enhance further use of these valuable tools

The X-ray luminosity function of Active Galactic Nuclei in the redshift interval z=3-5

We combine deep X-ray survey data from the Chandra observatory and the wide-area/shallow XMM-XXL field to estimate the AGN X-ray luminosity function in the redshift range z=3-5. The sample consists of nearly 340 sources with either photometric (212) or spectroscopic (128) redshift in the above range. The combination of deep and shallow survey fields provides a luminosity baseline of three orders of magnitude, Lx(2-10keV)~1e43-1e46erg/s at z>3. We follow a Bayesian approach to determine the binned AGN space density and explore their evolution in a model-independent way. Our methodology accounts for Poisson errors in the determination of X-ray fluxes and uncertainties in photometric redshift estimates. We demonstrate that the latter is essential for unbiased measurement of space densities. We find that the AGN X-ray luminosity function evolves strongly between the redshift intervals z=3-4 and z=4-5. There is also suggestive evidence that the amplitude of this evolution is luminosity dependent. The space density of AGN with Lx<1e45erg/s drops by a factor of 5 between the redshift intervals above, while the evolution of brighter AGN appears to be milder. Comparison of our X-ray luminosity function with that of UV/optical selected QSOs at similar redshifts shows broad agreement at bright luminosities, Lx>1e45erg/s. The faint-end slope of UV/optical luminosity functions however, is steeper than for X-ray selected AGN. This implies that the type-I AGN fraction increases with decreasing luminosity at z>3, opposite to trends established at lower redshift. We also assess the significance of AGN in keeping the hydrogen ionised at high redshift. Our X-ray luminosity function yields ionising photon rate densities that are insufficient to keep the Universe ionised at redshift z>4. A source of uncertainty in this calculation is the escape fraction of UV photons for X-ray selected AGN.Comment: MNRAS accepte

Optically faint X-ray sources in the CDFN: Spitzer constraints

We investigate the properties of the most optically faint sources in the GOODS-N area (R > 26.5 AB). Such extremely optically faint populations present an uncharted territory despite the fact that they represent an appreciable fraction of the X-ray sources in the GOODS-N field. They are believed to contain either red AGN at moderate redshifts or possibly QSO at very high redshift. We compile our sample by first finding the 3.6um IRAC counterparts of the X-ray sources and searching for the optical counterparts of the IRAC sources. 35 sources do not have counterparts in the R-band Subaru optical images. Of these, 18 have HST-ACS counterparts while the remaining have no optical counterparts. The vast majority of our 35 sources are classified as Extremely Red Objects (EROs) on the basis of their V-K lower limits. Their photometric redshifts show that these populate moderate redshifts (median z~2.8), being markedly different from the already spectroscopically identified population which peaks at z~0.7. The Spitzer-IRAC mid-IR colours of the sources which have no HST counterparts tend to lie within the mid-IR colour diagram AGN "wedge", suggesting either QSO, ULIRG (Mrk231), or early-type galaxy templates at z>3. A large fraction of our sources (17/35), regardless of whether they have HST counterparts, can be classified as mid-IR bright/optically faint sources (Dust Obscured Galaxies) a class which is believed to include many heavily absorbed AGN. The co-added X-ray spectrum of the optically faint sources is very flat having a spectral index of Gamma~0.87, significantly flatter than the spectrum of the X-ray background. The optically faint R>26.5 X-ray sources constitute more than 50% of the total X-ray population at redshifts z>2 bearing important implications for the luminosity function and its evolution; considering X-ray sources with 2<z<4 we find good agreement with a modified PLE model.Comment: Accepted for publication in A&

The galaxy’s gas content regulated by the dark matter halo mass results in a superlinear M BH–M ⋆ Relation

Supermassive black holes (SMBHs) are tightly correlated with their hosts, but the origin of such connection remains elusive. To explore the cosmic buildup of this scaling relation, we present an empirically motivated model that tracks galaxy and SMBH growth down to z = 0. Starting from a random mass seed distribution at z = 10, we assume that each galaxy evolves on the star-forming "main sequence" (MS) and each BH follows the recently derived stellar mass (M sstarf) dependent ratio between BH accretion rate and star formation rate, going as $\mathrm{BHAR}/\mathrm{SFR}\propto {M}_{\star }^{0.73[+0.22,-0.29]}$. Our simple recipe naturally describes the BH–galaxy buildup in two stages. At first, the SMBH lags behind the host that evolves along the MS. Later, as the galaxy grows in M sstarf, our M sstarf-dependent BHAR/SFR induces a superlinear BH growth, as ${M}_{\mathrm{BH}}\propto {M}_{\star }^{1.7}$. According to this formalism, smaller BH seeds increase their relative mass faster and earlier than bigger BH seeds, at fixed M sstarf, thus setting along a gradually tighter M BH–M sstarf locus toward higher M sstarf. Assuming reasonable values of the radiative efficiency epsilon ~ 0.1, our empirical trend agrees with both high-redshift model predictions and intrinsic M BH–M sstarf relations of local BHs. We speculate that the observed nonlinear BH–galaxy buildup is reflected in a twofold behavior with dark matter halo mass (M DM), displaying a clear turnover at M DM ~ 2 × 1012 M ⊙. While supernovae-driven feedback suppresses BH growth in smaller halos ($\mathrm{BHAR}/\mathrm{SFR}\propto {M}_{\mathrm{DM}}^{1.6}$), above the M DM threshold cold gas inflows possibly fuel both BH accretion and star formation in a similar fashion ($\mathrm{BHAR}/\mathrm{SFR}\propto {M}_{\mathrm{DM}}^{0.3}$)

A wide search for obscured active galactic nuclei using XMM-Newton and WISE

Heavily obscured and Compton-thick active galactic nuclei (AGNs) are missing even in the deepest X-ray surveys, and indirect methods are required to detect them. Here we use a combination of the XMM–Newton serendipitous X-ray survey with the optical Sloan Digital Sky Survey (SDSS), and the infrared WISE all-sky survey in order to check the efficiency of the low X-ray-to-infrared luminosity selection method in finding heavily obscured AGNs. We select the sources which are detected in the hard X-ray band (2–8 keV), and also have a redshift determination (photometric or spectroscopic) in the SDSS catalogue. We match this sample with the WISE catalogue, and fit the spectral energy distributions of the 2844 sources which have three, or more, photometric data points in the infrared. We then select the heavily obscured AGN candidates by comparing their 12 μm luminosity to the observed 2–10 keV X-ray luminosity and the intrinsic relation between the X-ray and the mid-infrared luminosities. With this approach, we find 20 candidate heavily obscured AGNs and we then examine their X-ray and optical spectra. Of the 20 initial candidates, we find nine (64 per cent; out of the 14, for which X-ray spectra could be fitted) based on the X-ray spectra, and seven (78 per cent; out of the nine detected spectroscopically in the SDSS) based on the [O III] line fluxes. Combining all criteria, we determine the final number of heavily obscured AGNs to be 12–19, and the number of Compton-thick AGNs to be 2–5, showing that the method is reliable in finding obscured AGNs, but not Compton thick. However, those numbers are smaller than what would be expected from X-ray background population synthesis models, which demonstrates how the optical–infrared selection and the scatter of the Lx-LMIR relation limit the efficiency of the method. Finally, we test popular obscured AGN selection methods based on mid-infrared colours, and find that the probability of an AGN to be selected by its mid-infrared colours increases with the X-ray luminosity. The (observed) X-ray luminosities of heavily obscured AGNs are relatively low (L2−10keV<1044ergs−1), even though most of them are located in the ‘quasi stellar object (QSO) locus’. However, a selection scheme based on a relatively low X-ray luminosity and mid-infrared colours characteristic of QSOs would not select ∼25 per cent of the heavily obscured AGNs of our sample

Concentration Dependence of Superconductivity and Order-Disorder Transition in the Hexagonal Rubidium Tungsten Bronze RbxWO3. Interfacial and bulk properties

We revisited the problem of the stability of the superconducting state in RbxWO3 and identified the main causes of the contradictory data previously published. We have shown that the ordering of the Rb vacancies in the nonstoichiometric compounds have a major detrimental effect on the superconducting temperature Tc.The order-disorder transition is first order only near x = 0.25, where it cannot be quenched effectively and Tc is reduced below 1K. We found that the high Tc's which were sometimes deduced from resistivity measurements, and attributed to compounds with .25 < x < .30, are to be ascribed to interfacial superconductivity which generates spectacular non-linear effects. We also clarified the effect of acid etching and set more precisely the low-rubidium-content boundary of the hexagonal phase.This work makes clear that Tc would increase continuously (from 2 K to 5.5 K) as we approach this boundary (x = 0.20), if no ordering would take place - as its is approximately the case in CsxWO3. This behaviour is reminiscent of the tetragonal tungsten bronze NaxWO3 and asks the same question : what mechanism is responsible for this large increase of Tc despite the considerable associated reduction of the electron density of state ? By reviewing the other available data on these bronzes we conclude that the theoretical models which are able to answer this question are probably those where the instability of the lattice plays a major role and, particularly, the model which call upon local structural excitations (LSE), associated with the missing alkali atoms.Comment: To be published in Physical Review

Acupuncture Point Localization Varies Among Acupuncturists

Background: Studies assessing the point-specific effect of acupuncture or the characteristics of acupuncture points (APs) tend to yield inconclusive results. In order to identify a possible confounding factor, we aimed to examine the variability in AP localization by means of a survey. Material and Methods: Attendees of the 14th ICMART (International Council of Medical Acupuncture and Related Techniques) congress as well as DAGfA (German Medical Society of Acupuncture) lecturers and students were asked to locate and mark the APs LI 10 and TH 5 on a research assistant's arm. Identified points were transferred into a coordinate system, and the respective bivariate distribution function was calculated. Additionally, participants filled out a questionnaire about their acupuncture education and experience, the acupuncture style and point localization techniques used most frequently, and their estimation of the size of an AP. Results: The areas of the ellipses, theoretically containing 95% of AP localizations, varied between 44.49 and 5.18 cm(2). The largest distance between 2 identified points was 8.45 cm for LI 10 and 5.3 cm for TH 5. Apart from being trained at the same school, no other factor could be identified that determined the variability in AP localization. Conclusion: Our results indicate that congruity of AP localization among experienced acupuncturists might be low. Although there are some limitations to our results, this possible bias should be taken into account when conducting acupuncture trials and interpreting results of previous acupuncture studies