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

A transient helix in the disordered region of dynein light intermediate chain links the motor to structurally diverse adaptors for cargo transport

All animal cells use the motor cytoplasmic dynein 1 (dynein) to transport diverse cargo toward microtubule minus ends and to organize and position microtubule arrays such as the mitotic spindle. Cargo-specific adaptors engage with dynein to recruit and activate the motor, but the molecular mechanisms remain incompletely understood. Here, we use structural and dynamic nuclear magnetic resonance (NMR) analysis to demonstrate that the C-terminal region of human dynein light intermediate chain 1 (LIC1) is intrinsically disordered and contains two short conserved segments with helical propensity. NMR titration experiments reveal that the first helical segment (helix 1) constitutes the main interaction site for the adaptors Spindly (SPDL1), bicaudal D homolog 2 (BICD2), and Hook homolog 3 (HOOK3). In vitro binding assays show that helix 1, but not helix 2, is essential in both LIC1 and LIC2 for binding to SPDL1, BICD2, HOOK3, RAB-interacting lysosomal protein (RILP), RAB11 family-interacting protein 3 (RAB11FIP3), ninein (NIN), and trafficking kinesin-bind-ing protein 1 (TRAK1). Helix 1 is sufficient to bind RILP, whereas other adaptors require additional segments preceding helix 1 for efficient binding. Point mutations in the C-terminal helix 1 of Caenorhabditis elegans LIC, introduced by genome editing, severely affect development, locomotion, and life span of the animal and disrupt the distribution and transport kinetics of membrane cargo in axons of mechanosensory neurons, identical to what is observed when the entire LIC C-terminal region is deleted. Deletion of the C-terminal helix 2 delays dynein-dependent spindle positioning in the one-cell embryo but overall does not significantly perturb dynein function. We conclude that helix 1 in the intrinsically disordered region of LIC provides a conserved link between dynein and structurally diverse cargo adaptor families that is critical for dynein function in vivo.This work was financed by the Fundo Europeu de Desenvolvimento Regional (FEDER) through the Norte Portugal Regional Operational Programme (NORTE 2020), Portugal 2020 (RG); by the Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project NORTE-01-0145-FEDER-030507 (RG); by FCT fellowships IF/01015/2013/CP1157/CT0006 (RG) and SFRH/ BPD/101898/2014 (DJB); by the European Research Council under the European Union’s Seventh Framework Programme, ERC grant agreement no. ERC-2013-StG-338410-DYNEINOME (RG), and by a start-up package of the University of Colorado (BV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Microarray Method for the Rapid Detection of Glycosaminoglycan–Protein Interactions

Glycosaminoglycans (GAGs) perform numerous vital functions within the body. As major components of the extracellular matrix, these polysaccharides participate in a diverse array of cell-signaling events. We have developed a simple microarray assay for the evaluation of protein binding to various GAG subclasses. In a single experiment, the binding to all members of the GAG family can be rapidly determined, giving insight into the relative specificity of the interactions and the importance of specific sulfation motifs. The arrays are facile to prepare from commercially available materials

Precipitation of Trichoderma reesei commercial cellulase preparations under standard enzymatic hydrolysis conditions for lignocelluloses

Comparative studies between commercial Trichoderma reesei cellulase preparations show that, depending on the preparation and loading, total protein precipitation can be as high as 30 % under standard hydrolysis conditions used for lignocellulosic materials. ATR-IR and SDS-PAGE data verify precipitates are protein-based and contain key cell wall hydrolyzing enzymes. Precipitation increased considerably with incubation temperature; roughly 50–150 % increase from 40 to 50 °C and 800 % greater at 60 °C. All of the reported protein losses translated into significant, and often drastic, losses in activity on related 4-nitrophenyl substrates. In addition, supplementation with the non-ionic surfactant PEG 6,000 decreased precipitation up to 80 % in 24 h precipitation levels. Protein precipitation is potentially substantial during enzymatic hydrolysis of lignocelluloses and should be accounted for during lignocellulose conversion process design, particularly when enzyme recycling is considered.This work was supported by the project "Demonstrating Industrial scale second generation bioethaol production-Kalundborg Cellulosic Ethanol Plant" under the EU FP7 framework program and the project "Development of improved second generation (2G) bioethanol technology to prepare for commercialization under the Danish Energy Technology and Demonstration Programme (EUDP)

Genetic variation in autophagy-related genes influences the risk and phenotype of Buruli ulcer

Introduction Buruli ulcer (BU) is a severe necrotizing human skin disease caused by Mycobacterium ulcerans. Clinically, presentation is a sum of these diverse pathogenic hits subjected to critical immune-regulatory mechanisms. Among them, autophagy has been demonstrated as a cellular process of critical importance. Since microtubules and dynein are affected by mycolactone, the critical pathogenic exotoxin produced by M. ulcerans, cytoskeleton-related changes might potentially impair the autophagic process and impact the risk and progression of infection. Objective Genetic variants in the autophagy-related genes NOD2, PARK2 and ATG16L1 has been associated with susceptibility to mycobacterial diseases. Here, we investigated their association with BU risk, its severe phenotypes and its progression to an ulcerative form. Methods Genetic variants were genotyped using KASPar chemistry in 208 BU patients (70.2% with an ulcerative form and 28% in severe WHO category 3 phenotype) and 300 healthy endemic controls. Results The rs1333955 SNP in PARK2 was significantly associated with increased susceptibility to BU [odds ratio (OR), 1.43; P = 0.05]. In addition, both the rs9302752 and rs2066842 SNPs in NOD2 gee significantly increased the predisposition of patients to develop category 3 (OR, 2.23; P = 0.02; and OR 12.7; P = 0.03, respectively, whereas the rs2241880 SNP in ATG16L1 was found to significantly protect patients from presenting the ulcer phenotype (OR, 0.35; P = 0.02). Conclusion Our findings indicate that specific genetic variants in autophagy-related genes influence susceptibility to the development of BU and its progression to severe phenotypes.The research leading to these results received funding from the Health Services of the Fundação Calouste Gulbenkian under the grant Proc.N°94776 LJ; from the Fundação para a Ciência e Tecnologia (FCT), cofunded by Programa Operacional Regional do Norte (ON.2—O Novo 267 Norte); from the Quadro de Referência Estratégico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and from the Projeto Estratégico – LA 26 – 2013–2014 (PEst-C/SAU/LA0026/2013). JFM received an individual QREN fellowship (UMINHO/BPD/14/2014); CCu and AGF received an individual FCT fellowship (SFRH/BPD/96176/2013 and SFRH/BPD/68547/2010, respectively); and AC received an FCT contract (IF/00735/2014). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Brabykinin B1 Receptor Antagonism Is Beneficial in Renal Ischemia-Reperfusion Injury

Previously we have demonstrated that bradykinin B1 receptor deficient mice (B1KO) were protected against renal ischemia and reperfusion injury (IRI). Here, we aimed to analyze the effect of B1 antagonism on renal IRI and to study whether B1R knockout or antagonism could modulate the renal expression of pro and anti-inflammatory molecules. To this end, mice were subjected to 45 minutes ischemia and reperfused at 4, 24, 48 and 120 hours. Wild-type mice were treated intra-peritoneally with antagonists of either B1 (R-954, 200 µg/kg) or B2 receptor (HOE140, 200 µg/kg) 30 minutes prior to ischemia. Blood samples were collected to ascertain serum creatinine level, and kidneys were harvested for gene transcript analyses by real-time PCR. Herein, B1R antagonism (R-954) was able to decrease serum creatinine levels, whereas B2R antagonism had no effect. The protection seen under B1R deletion or antagonism was associated with an increased expression of GATA-3, IL-4 and IL-10 and a decreased T-bet and IL-1β transcription. Moreover, treatment with R-954 resulted in lower MCP-1, and higher HO-1 expression. Our results demonstrated that bradykinin B1R antagonism is beneficial in renal IRI

Self-assessed health among Thai elderly

<p>Abstract</p> <p>Background</p> <p>The ageing of the population is rapidly progressing in Thailand. Self-assessed health status can provide a holistic view of the health of the elderly. This study aims to identify the determinants of self-assessed health among older Thai people.</p> <p>Methods</p> <p>The data for this study were drawn from a national survey of older persons conducted in 2007. Stratified two-stage random sampling was used for data collection. The analysis was restricted to the population aged 60 and above. The study used univariate, bivariate, and multivariate analysis procedures to analyze the data. Bivariate analysis was used to identify the factors associated with self assessment of health status. After controlling for other variables, the variables were further examined using multivariate analysis (binary logistic regression) in order to identify the significant predictors of the likelihood of reporting poor health.</p> <p>Results</p> <p>Overall, 30,427 elderly people were interviewed in this study. More than half of the sampled respondents (53%) were aged 60-69 years and about one out of seven (13%) were aged 80 years or above. About three in five respondents (56%) reported that their health was either fair or very bad/bad. Logistic regression analysis found that age, education, marital status, working status, income, functional status, number of chronic diseases, and number of psychosocial symptoms are significant predictors in determining health status. Respondents who faced more difficulty in daily life were more likely to rate their health as poor compared to those who faced less such difficulty. For instance, respondents who could not perform 3 or more activities of daily living (ADLs) were 3.3 times more likely to assess their health as poor compared to those who could perform all the ADLs. Similarly, respondents who had 1, 2, or 3 or more chronic diseases were 1.8 times, 2.4 times, and 3.7 times, respectively, more likely to report their health as poor compared to those who had no chronic disease at all. Moreover, respondents who had 1-2, 3-4, or 5 or more psychosocial symptoms in the previous months were 1.6 times, 2.2 times, and 2.7 times, respectively, more likely to report poor health compared to those who did not have any psychosocial symptoms during the same period.</p> <p>Conclusion</p> <p>Self-assessed poor health is not uncommon among older people in Thailand. No single factor accounts for the self-assessed poor health. The study has found that chronic disease, functional status, and psychosocial symptoms are the strongest determinants of self-assessed poor health of elderly people living in Thailand. Therefore, health-related programs should focus on all the factors identified in this paper to improve the overall well-being of the ageing population of Thailand.</p

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente