Dynamic hierarchies in temporal directed networks

The outcome of interactions in many real-world systems can be often explained by a hierarchy between the participants. Discovering hierarchy from a given directed network can be formulated as follows: partition vertices into levels such that, ideally, there are only forward edges, that is, edges from upper levels to lower levels. In practice, the ideal case is impossible, so instead we minimize some penalty function on the backward edges. One practical option for such a penalty is agony, where the penalty depends on the severity of the violation. In this paper we extend the definition of agony to temporal networks. In this setup we are given a directed network with time stamped edges, and we allow the rank assignment to vary over time. We propose 2 strategies for controlling the variation of individual ranks. In our first variant, we penalize the fluctuation of the rankings over time by adding a penalty directly to the optimization function. In our second variant we allow the rank change at most once. We show that the first variant can be solved exactly in polynomial time while the second variant is NP-hard, and in fact inapproximable. However, we develop an iterative method, where we first fix the change point and optimize the ranks, and then fix the ranks and optimize the change points, and reiterate until convergence. We show empirically that the algorithms are reasonably fast in practice, and that the obtained rankings are sensible

Building cooperation through health initiatives: an Arab and Israeli case study

<p>Abstract</p> <p>Background</p> <p>Ongoing conflict in the Middle East poses a major threat to health and security. A project screening Arab and Israeli newborns for hearing loss provided an opportunity to evaluate ways for building cooperation. The aims of this study were to: a) examine what attracted Israeli, Jordanian and Palestinian participants to the project, b) describe challenges they faced, and c) draw lessons learned for guiding cross-border health initiatives.</p> <p>Methods</p> <p>A case study method was used involving 12 key informants stratified by country (3 Israeli, 3 Jordanian, 3 Palestinian, 3 Canadian). In-depth interviews were tape-recorded, transcribed and analyzed using an inductive qualitative approach to derive key themes.</p> <p>Results</p> <p>Major reasons for getting involved included: concern over an important health problem, curiosity about neighbors and opportunities for professional advancement. Participants were attracted to prospects for opening the dialogue, building relationships and facilitating cooperation in the region. The political situation was a major challenge that delayed implementation of the project and placed participants under social pressure. Among lessons learned, fostering personal relationships was viewed as critical for success of this initiative.</p> <p>Conclusion</p> <p>Arab and Israeli health professionals were prepared to get involved for two types of reasons: a) Project Level: opportunity to address a significant health issue (e.g. congenital hearing loss) while enhancing their professional careers, and b) Meta Level: concern about taking positive steps for building cooperation in the region. We invite discussion about roles that health professionals can play in building "cooperation networks" for underpinning health security, conflict resolution and global health promotion.</p

Reasons given by general practitioners for non-treatment decisions in younger and older patients with newly diagnosed type 2 diabetes mellitus in the United Kingdom: a survey study

<p>Abstract</p> <p>Background</p> <p>Older patients with newly diagnosed type 2 diabetes mellitus are less likely to receive antihyperglycaemic therapy compared to their younger counterparts. The purpose of this study was to assess the reasons of general practitioners (GPs) for not treating younger and older patients with newly diagnosed type 2 diabetes mellitus with antihyperglycaemic agents.</p> <p>Methods</p> <p>In a survey conducted between November 2009 and January 2010, 358 GPs from the United Kingdom selected reasons for not initiating antihyperglycaemic therapy in younger (< 65 years) and older (≥65 years) patients with newly diagnosed type 2 diabetes mellitus and untreated with any antihyperglycaemic agent for at least six months following diagnosis. Thirty-six potential reasons were classified into four major categories: <it>Mild hyperglycaemia</it>, <it>Factors related to antihyperglycaemic agents</it>, <it>Comorbidities and polypharmacy</it>, and <it>Patient-related reasons</it>. Reasons for non-treatment were compared between younger (n = 1, 023) and older (n = 1, 005) patients.</p> <p>Results</p> <p>Non-treatment reasons related to <it>Mild hyperglycaemia </it>were selected more often by GPs for both younger (88%) and older (86%) patients than those in other categories. For older patients, <it>Factors related to antihyperglycaemic agents </it>(46% vs. 38%) and <it>Comorbidities and polypharmacy </it>(33% vs. 19%), both including safety-related issues, were selected significantly (p < 0.001) more often by GPs. No between-group difference was observed for the <it>Patient-related reasons </it>category. The GP-reported HbA_1cthreshold for initiating antihyperglycaemic therapy was significantly (p < 0.001) lower for younger patients (mean ± standard deviation: 7.3% ± 0.7) compared to older patients (7.5% ± 0.9).</p> <p>Conclusions</p> <p>GPs selected reasons related to <it>Mild hyperglycaemia </it>for non-treatment of their untreated patients with newly diagnosed type 2 diabetes mellitus, despite nearly one-third of these patients having their most recent HbA_1cvalue ≥7%. The findings further suggest that safety-related issues may influence the non-treatment of older patients with type 2 diabetes mellitus.</p

Impaired Thymic Selection and Abnormal Antigen-Specific T Cell Responses in Foxn1Δ/Δ Mutant Mice

Foxn1(Δ/Δ) mutant mice have a specific defect in thymic development, characterized by a block in TEC differentiation at an intermediate progenitor stage, and blocks in thymocyte development at both the DN1 and DP cell stages, resulting in the production of abnormally functioning T cells that develop from an atypical progenitor population. In the current study, we tested the effects of these defects on thymic selection.We used Foxn1(Δ/Δ); DO11 Tg and Foxn1(Δ/Δ); OT1 Tg mice as positive selection and Foxn1(Δ/Δ); MHCII I-E mice as negative selection models. We also used an in vivo system of antigen-specific reactivity to test the function of peripheral T cells. Our data show that the capacity for positive and negative selection of both CD4 and CD8 SP thymocytes was reduced in Foxn1(Δ/Δ) mutants compared to Foxn1(+/Δ) control mice. These defects were associated with reduction of both MHC Class I and Class II expression, although the resulting peripheral T cells have a broad TCR Vβ repertoire. In this deficient thymic environment, immature CD4 and CD8 SP thymocytes emigrate from the thymus into the periphery. These T cells had an incompletely activated profile under stimulation of the TCR signal in vitro, and were either hypersensitive or hyporesponsive to antigen-specific stimulation in vivo. These cell-autonomous defects were compounded by the hypocellular peripheral environment caused by low thymic output.These data show that a primary defect in the thymic microenvironment can cause both direct defects in selection which can in turn cause indirect effects on the periphery, exacerbating functional defects in T cells

Application of a Mathematical Model to Describe the Effects of Chlorpyrifos on Caenorhabditis elegans Development

The nematode Caenorhabditis elegans is being assessed as an alternative model organism as part of an interagency effort to develop better means to test potentially toxic substances. As part of this effort, assays that use the COPAS Biosort flow sorting technology to record optical measurements (time of flight (TOF) and extinction (EXT)) of individual nematodes under various chemical exposure conditions are being developed. A mathematical model has been created that uses Biosort data to quantitatively and qualitatively describe C. elegans growth, and link changes in growth rates to biological events. Chlorpyrifos, an organophosphate pesticide known to cause developmental delays and malformations in mammals, was used as a model toxicant to test the applicability of the growth model for in vivo toxicological testing.L1 larval nematodes were exposed to a range of sub-lethal chlorpyrifos concentrations (0-75 microM) and measured every 12 h. In the absence of toxicant, C. elegans matured from L1s to gravid adults by 60 h. A mathematical model was used to estimate nematode size distributions at various times. Mathematical modeling of the distributions allowed the number of measured nematodes and log(EXT) and log(TOF) growth rates to be estimated. The model revealed three distinct growth phases. The points at which estimated growth rates changed (change points) were constant across the ten chlorpyrifos concentrations. Concentration response curves with respect to several model-estimated quantities (numbers of measured nematodes, mean log(TOF) and log(EXT), growth rates, and time to reach change points) showed a significant decrease in C. elegans growth with increasing chlorpyrifos concentration.Effects of chlorpyrifos on C. elegans growth and development were mathematically modeled. Statistical tests confirmed a significant concentration effect on several model endpoints. This confirmed that chlorpyrifos affects C. elegans development in a concentration dependent manner. The most noticeable effect on growth occurred during early larval stages: L2 and L3. This study supports the utility of the C. elegans growth assay and mathematical modeling in determining the effects of potentially toxic substances in an alternative model organism using high-throughput technologies

The CCG-domain-containing subunit SdhE of succinate:quinone oxidoreductase from Sulfolobus solfataricus P2 binds a [4Fe–4S] cluster

In type E succinate:quinone reductase (SQR), subunit SdhE (formerly SdhC) is thought to function as monotopic membrane anchor of the enzyme. SdhE contains two copies of a cysteine-rich sequence motif (CXnCCGXmCXXC), designated as the CCG domain in the Pfam database and conserved in many proteins. On the basis of the spectroscopic characterization of heterologously produced SdhE from Sulfolobus tokodaii, the protein was proposed in a previous study to contain a labile [2Fe–2S] cluster ligated by cysteine residues of the CCG domains. Using UV/vis, electron paramagnetic resonance (EPR), 57Fe electron–nuclear double resonance (ENDOR) and Mössbauer spectroscopies, we show that after an in vitro cluster reconstitution, SdhE from S. solfataricus P2 contains a [4Fe–4S] cluster in reduced (2+) and oxidized (3+) states. The reduced form of the [4Fe–4S]2+ cluster is diamagnetic. The individual iron sites of the reduced cluster are noticeably heterogeneous and show partial valence localization, which is particularly strong for one unique ferrous site. In contrast, the paramagnetic form of the cluster exhibits a characteristic rhombic EPR signal with gzyx = 2.015, 2.008, and 1.947. This EPR signal is reminiscent of a signal observed previously in intact SQR from S. tokodaii with gzyx = 2.016, 2.00, and 1.957. In addition, zinc K-edge X-ray absorption spectroscopy indicated the presence of an isolated zinc site with an S3(O/N)1 coordination in reconstituted SdhE. Since cysteine residues in SdhE are restricted to the two CCG domains, we conclude that these domains provide the ligands to both the iron–sulfur cluster and the zinc site

Bank performance and executive pay: tournament or teamwork

We investigate the relationship between the dispersion of executive pay and bank performance/valuation by examining two competing theories, the tournament theory (hierarchical wage structure) and the equity fairness theory (compressed wage structure). The key variable of executive pay dispersion is measured using a hand-collected dataset composed of 63 banks from OECD countries and 29 banks from developing countries. The dataset covers the period 2004 to 2012. By combining and modifying a translog profit function and a pay-dispersion model, we are able to address the potential problems of relying on reduced-form estimation. In our subsample of developed and civil law countries, where bank performance is measured by either Tobin’s Q or by the price-to-book ratio, the overall impact of executive pay dispersion is mostly negative, and we find supporting evidence for the equity fairness theory, except for very high levels of dispersion. There is a non-linear effect, as banks perform best when there is either very low or very high executive pay dispersion. For developing country sample banks, greater executive pay dispersion has a negative impact on bank profit. In our subsample of common law countries, however, we find no evidence of a significant impact of executive pay dispersion on bank performance. We conclude that lower executive pay dispersion, a proxy for teamwork, is mostly effective in enhancing bank performance in a significant section of sample banks, i.e., civil law and developing countries

Vaccination against Human Influenza A/H3N2 Virus Prevents the Induction of Heterosubtypic Immunity against Lethal Infection with Avian Influenza A/H5N1 Virus

Annual vaccination against seasonal influenza viruses is recommended for certain individuals that have a high risk for complications resulting from infection with these viruses. Recently it was recommended in a number of countries including the USA to vaccinate all healthy children between 6 and 59 months of age as well. However, vaccination of immunologically naïve subjects against seasonal influenza may prevent the induction of heterosubtypic immunity against potentially pandemic strains of an alternative subtype, otherwise induced by infection with the seasonal strains. Here we show in a mouse model that the induction of protective heterosubtypic immunity by infection with a human A/H3N2 influenza virus is prevented by effective vaccination against the A/H3N2 strain. Consequently, vaccinated mice were no longer protected against a lethal infection with an avian A/H5N1 influenza virus. As a result H3N2-vaccinated mice continued to loose body weight after A/H5N1 infection, had 100-fold higher lung virus titers on day 7 post infection and more severe histopathological changes than mice that were not protected by vaccination against A/H3N2 influenza. The lack of protection correlated with reduced virus-specific CD8+ T cell responses after A/H5N1 virus challenge infection. These findings may have implications for the general recommendation to vaccinate all healthy children against seasonal influenza in the light of the current pandemic threat caused by highly pathogenic avian A/H5N1 influenza viruses