The PathOlogist: an automated tool for pathway-centric analysis

<p>Abstract</p> <p>Background</p> <p>The PathOlogist is a new tool designed to transform large sets of gene expression data into quantitative descriptors of pathway-level behavior. The tool aims to provide a robust alternative to the search for single-gene-to-phenotype associations by accounting for the complexity of molecular interactions.</p> <p>Results</p> <p>Molecular abundance data is used to calculate two metrics - 'activity' and 'consistency' - for each pathway in a set of more than 500 canonical molecular pathways (source: Pathway Interaction Database, <url>http://pid.nci.nih.gov</url>). The tool then allows a detailed exploration of these metrics through integrated visualization of pathway components and structure, hierarchical clustering of pathways and samples, and statistical analyses designed to detect associations between pathway behavior and clinical features.</p> <p>Conclusions</p> <p>The PathOlogist provides a straightforward means to identify the functional processes, rather than individual molecules, that are altered in disease. The statistical power and biologic significance of this approach are made easily accessible to laboratory researchers and informatics analysts alike. Here we show as an example, how the PathOlogist can be used to establish pathway signatures that robustly differentiate breast cancer cell lines based on response to treatment.</p

Inter-Individual Variability and Conspecific Densities: Consequences for Population Regulation and Range Expansion

The presence of conspecifics can strongly modulate the quality of a breeding site. Both positive and negative effects of conspecifics can act on the same individuals, with the final balance between its costs and benefits depending on individual characteristics. A particular case of inter-individual variation found in many avian species is chromatic variability. Among birds, plumage coloration can co-vary with morphology, physiology and behavior as well as with age. These relationships suggest that cost-benefit balances of conspecific presence may be different for individuals with different colorations. We investigated whether inter-individual variability affects population regulation and expansion processes by analyzing potential differences in density-dependent productivity and settlement patterns in relation to plumage coloration in a population of a long-lived avian species recently undergoing a notable increase in numbers and distribution range. Our results show strong variation in the effect of density on productivity of breeding pairs depending on plumage coloration of their members. Productivity of dark birds decreased along the breeding density gradient while that of lighter breeders remained unchanged with conspecific density. In a similar way, our results showed an uneven occupation of localities by individuals with different plumage coloration in relation to local densities, with the breeding of lighter harriers more aggregated than that of dark-brown ones. At a population scale, darker birds had higher probability of colonization of the most isolated, empty sites. Explanations for species range expansion and population regulation usually make the inferred assumption that species traits are similar among individuals. However, in most species, there could be individual variation in niche requirements or dispersal propensities among individuals with different traits. Our results contribute to the growing appreciation that the individual traits, but not the average trait at the level of species, are important during population regulation and expansion processes

Relationship between Exercise Capacity and Brain Size in Mammals

A great deal of experimental research supports strong associations between exercise, cognition, neurogenesis and neuroprotection in mammals. Much of this work has focused on neurogenesis in individual subjects in a limited number of species. However, no study to date has examined the relationship between exercise and neurobiology across a wide range of mammalian taxa. It is possible that exercise and neurobiology are related across evolutionary time. To test this hypothesis, this study examines the association between exercise and brain size across a wide range of mammals.Controlling for associations with body size, we examined the correlation between brain size and a proxy for exercise frequency and capacity, maximum metabolic rate (MMR; ml O(2) min(-1)). We collected brain sizes and MMRs from the literature and calculated residuals from the least-squares regression line describing the relationship between body mass and each variable of interest. We then analyzed the correlation between residual brain size and residual MMR both before and after controlling for phylogeny using phylogenetic independent contrasts. We found a significant positive correlation between maximum metabolic rate and brain size across a wide range of taxa.These results suggest a novel hypothesis that links brain size to the evolution of locomotor behaviors in a wide variety of mammalian species. In the end, we suggest that some portion of brain size in nonhuman mammals may have evolved in conjunction with increases in exercise capacity rather than solely in response to selection related to cognitive abilities

Proteomic characterization of HIV-modulated membrane receptors, kinases and signaling proteins involved in novel angiogenic pathways

<p>Abstract</p> <p>Background</p> <p>Kaposi's sarcoma (KS), hemangioma, and other angioproliferative diseases are highly prevalent in HIV-infected individuals. While KS is etiologically linked to the human herpesvirus-8 (HHV8) infection, HIV-patients without HHV-8 and those infected with unrelated viruses also develop angiopathies. Further, HIV-Tat can activate protein-tyrosine-kinase (PTK-activity) of the vascular endothelial growth factor receptor involved in stimulating angiogenic processes. However, Tat by itself or HHV8-genes alone cannot induce angiogenesis <it>in vivo </it>unless specific proteins/enzymes are produced synchronously by different cell-types. We therefore tested a hypothesis that <it>chronic </it>HIV-<it>replication in non-endothelial cells </it>may produce novel factors that provoke angiogenic pathways.</p> <p>Methods</p> <p>Genome-wide proteins from HIV-infected and uninfected T-lymphocytes were tested by subtractive proteomics analyses at various stages of virus and cell growth <it>in vitro </it>over a period of two years. Several thousand differentially regulated proteins were identified by mass spectrometry (MS) and >200 proteins were confirmed in multiple gels. Each protein was scrutinized extensively by protein-interaction-pathways, bioinformatics, and statistical analyses.</p> <p>Results</p> <p>By functional categorization, 31 proteins were identified to be associated with various signaling events involved in angiogenesis. 88% proteins were located in the plasma membrane or extracellular matrix and >90% were found to be essential for regeneration, neovascularization and angiogenic processes during embryonic development.</p> <p>Conclusion</p> <p>Chronic HIV-infection of T-cells produces membrane receptor-PTKs, serine-threonine kinases, growth factors, adhesion molecules and many diffusible signaling proteins that have not been previously reported in HIV-infected cells. Each protein has been associated with endothelial cell-growth, morphogenesis, sprouting, microvessel-formation and other biological processes involved in angiogenesis (p = 10^-4to 10^-12). Bioinformatics analyses suggest that overproduction of PTKs and other kinases in HIV-infected cells has <it>suppressed </it>VEGF/VEGFR-PTK expression and promoted <it>VEGFR-independent </it>pathways. This unique mechanism is similar to that observed in neovascularization and angiogenesis during embryogenesis. Validation of clinically relevant proteins by gene-silencing and translational studies <it>in vivo </it>would identify specific targets that can be used for early diagnosis of angiogenic disorders and future development of inhibitors of angiopathies. This is the first comprehensive study to demonstrate that HIV-infection alone, without any co-infection or treatment, can induce numerous "embryonic" proteins and kinases capable of generating novel <it>VEGF-independent </it>angiogenic pathways.</p

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Een literatuuronderzoek naar veiligheidsperformance-indicatoren ter ondersteuning van het toezicht op de beheersing van zware ongevallen

Bedrijven die met grote hoeveelheden gevaarlijke stoffen werken, vallen onder het Besluit risico's zware ongevallen (BRZO). Deze bedrijven moeten aan specifieke regels voldoen om zware ongevallen met grote gevolgen voor mens en milieu te voorkomen. Daarnaast staan deze bedrijven onder toezicht van o.a.de Inspectie SZW (voorheen de Arbeidsinspectie). De Inspectie richt zich op de risico's voor werknemers en beoordeelt onder andere of er binnen de desbetreffende bedrijven een zogeheten veiligheidsbeheerssysteem is. Daarbij is het van belang of dit systeem is toegesneden op de aanwezige risico's en of het goed werkt. Indicatoren: hoe goed beheert een bedrijf gevaren Het RIVM heeft daarom bekeken of het mogelijk is om de veiligheid van een bedrijf te beoordelen op basis van veiligheidsprestatie-indicatoren. Veiligheidsprestatie-indicatoren zijn bedoeld om informatie te leveren over de veiligheidsprestaties van een bedrijf. Ze kunnen managers en werknemers van het bedrijf helpen om te focussen op de belangrijkste risico's. Daarnaast kunnen indicatoren de inspectie helpen vast te stellen hoe goed het bedrijf met risico's omgaat en of dit zonodig verbetert. Indicatoren moeten op maat worden gemaakt als ze worden gebruikt door een bedrijf. Voor de inspectie zijn juist indicatoren nodig die algemeen toepasbaar, communiceerbaar en ondubbelzinnig zijn, zodat bedrijven met elkaar kunnen worden vergeleken. Indicatoren kunnen zich door de tijd heen ontwikkelen op basis van de ervaringen met indicatoren die het meest effectief en efficiënt informatie geven over de mogelijkheid op een zwaar ongeval bij een bedrijf. Criteria voor de ontwikkeling van veiligheidsprestatie-indicatoren Aanbevolen wordt om indicatoren te ontwikkelen op basis van een lijst van 30 criteria. Zo moet een indicator een oorzakelijk verband hebben met het onderdeel dat daadwerkelijk een risico kan vormen. Daarnaast moet er een concrete actie aan de indicator kunnen worden verbonden, zoals een verbeteractie. Om trends te kunnen waarnemen is een set van indicatoren nodig die voldoende frequent worden gemeten. Voor het onderzoek is de wetenschappelijke literatuur onderzocht, evenals richtlijnen van industrie en inspecties.Companies working with large amounts of hazardous substances fall under the Major Accident Risks Decree 1999. These companies must conform to specific requirements to prevent major accidents with serious consequences for man and environment. These companies are regularly visited by regulatory bodies such as the Labour Inspectorate. The inspectorate focuses on the risks to workers and evaluates whether these companies have a safety management system. It is important whether this safety management system is tailored to the risks involved and whether it works well. Indicators: how well a company manages risks The RIVM has explored whether it is possible to evaluate the major accident risks of a company based on safety performance indicators. Safety performance indicators are intended to provide information on the safety performance of a company. A set of indicators helps managers and employees of the company to focus on the important risk factors and helps the regulator determine how well the company is managing its risk controls and whether it is improving. Safety performance indicators should be tailor-made when used by a company but will need to be generally applicable, communicable and unambiguous when used by the regulator. Indicators may develop over time, based on experience as to which provide the most effective and efficient information about the safety performance of a company with respect to the potential for a major accident. Criteria for the development of safety performance indicators It is recommended to develop indicators based on a list of 30 criteria. For example, an indicator should have a causal link with the risk. In addition, a concrete action on the indicator may be attached, such as improvement interventions. The indicator set should also be sufficient in number and frequency to be able to identify trends. For the research, the scientific literature as well as guidelines from industry and regulators were explored

Proposal for alignment of Additional Risk Assessment and Evaluation (ARIE) with the European regulation on Classification, Labelling and Packaging of substances and mixtures (CLP)

Stoffen kunnen eigenschappen hebben die gevaarlijk zijn voor mens en milieu. Om deze gevaren uniform aan te duiden is een mondiaal systeem opgesteld voor de indeling van de stoffen en de bijbehorende etikettering. Dit systeem is onlangs op Europees niveau geïmplementeerd in de verordening Classification, Labelling and Packaging of chemicals (CLP). De Nederlandse ARIE-regeling hanteert echter een andere indeling van gevaarlijke stoffen dan de CLP. Het RIVM doet daarom een voorstel hoe de ARIE-regeling aangepast kan worden aan de CLP-verordening. Aanpassing aan CLP bevordert veilig gebruik gevaarlijke stoffen: ARIE staat voor Aanvullende Risico Inventarisatie en Evaluatie en geldt voor kleinere bedrijven die met veel gevaarlijke stoffen werken. ARIE is bedoeld om de werknemers te beschermen als deze stoffen vrijkomen. Het belangrijkste voordeel van de aanpassing is dat ARIE dezelfde terminologie en criteria zal gebruiken als andere Europese wet- en regelgeving. Er zijn dan geen onduidelijkheden meer of een stof al dan niet gevaarlijk is en of er speciale maatregelen genomen moeten worden om werknemers te beschermen. Dit bevordert het veilig gebruik van gevaarlijke stoffen in Nederland. Resultaat: ARIE onderscheidt brandbare, giftige en ontplofbare stoffen. Het voorstel voor de aanpassing omvat een tabel waarin afgelezen kan worden welke CLPgevarenklassen overeenkomen met de ARIE-categorieën brandbaar, giftig en ontplofbaar.Substances can have properties that are dangerous to humans and the environment. In order to characterize these hazards uniformly, a global system has been established for the classification and labelling of substances. This system was recently implemented at the European level in the regulation Classification, Labelling and Packaging of chemicals (CLP). However, an existing Dutch regulation for hazardous substances, ARIE, uses a different system to classify hazardous substances than the CLP Regulation. The RIVM has made a proposal on how the ARIE regulation can be adapted to the CLP Regulation. Adaptation to CLP promotes safe use of dangerous substances: ARIE stands for Additional Risk Assessment and Evaluation (ARIE). It is a regulation aimed at smaller companies working with hazardous substances. ARIE is intended to protect the workers in case these substances are released. The main advantage of an alignment with the CLP is that ARIE will use the same terminology and criteria as are used in other European legislation. This should increase transparency on the hazards of substances and whether any special measures need to be taken to protect workers. This promotes the safe use of hazardous substances in the Netherlands. Result: ARIE defines the categories flammable, toxic and explosive substances. The proposal includes a table that shows which CLP hazard classifications correspond to the ARIE categories flammable, toxic and explosive.Ministerie van Sociale Zaken en Werkgelegenhei

Safety Performance Indicators for the Safety Management System : Preliminary investigation

Bedrijven die met grote hoeveelheden gevaarlijke stoffen werken vallen onder het Besluit Risico's Zware Ongevallen (BRZO). Zij moeten daardoor aan specifieke regels voldoen om zware ongevallen met grote gevolgen voor mens en milieu te voorkomen. Deze bedrijven staan onder toezicht van onder andere de Inspectie SZW (voorheen de Arbeidsinspectie). De Inspectie SZW beoordeelt of er een zogeheten veiligheidsbeheerssysteem (VBS) aanwezig is, of dit is toegesneden op de aanwezige risico's, en of het goed werkt. Uit een inventarisatie van het RIVM blijkt dat het mogelijk is om bij de beoordeling van een veiligheidsbeheerssysteem gebruik te maken van veiligheidsprestatieindicatoren. Vervolgens is een eerste aanzet gemaakt voor een set van dergelijke indicatoren voor het VBS. Het is nog onduidelijk of deze set bruikbaar is voor de Inspectie SZW. Indicatoren kunnen aangeven hoe goed een bedrijf de gevaren beheerst Het doel van veiligheidsprestatie-indicatoren is om informatie te geven over de veiligheidsprestaties van een bedrijf. Ze kunnen een belangrijke rol spelen in de communicatie en aangeven hoe goed het bedrijf de grote gevaren beheerst. Eerste aanzet voor een set van veiligheidsprestatie-indicatoren De set van veiligheidsprestatie-indicatoren is opgesteld op basis van een verkenning van wetenschappelijke literatuur en informatie van bedrijven, waaronder twaalf BRZO-bedrijven. In een volgende fase wordt onderzocht of de set veiligheidsprestatie-indicatoren voldoet aan de criteria die ervoor zijn gesteld en of ze aansluiten bij de indicatoren die sommige bedrijven zelf al hebben ontwikkeld. Ten slotte wordt de bruikbaarheid voor de Inspectie SZW nader onderzocht.Companies working with large amounts of hazardous substances fall under the Major Accident Risks Decree 1999 (BRZO). They must conform to specific requirements to prevent major accidents with serious consequences for man and environment. These companies are regularly visited by regulatory bodies such as the Labour Inspectorate. The inspectorate evaluates whether these companies have a safety management system, whether it is tailored to the risks involved, and whether it works well. An inventory conducted by RIVM shows that it is possible to assess the safety management system using safety performance indicators. Subsequently, a first step is made for a set of such indicators for the safety management system. At this moment it is unclear whether this set is suitable for inspection purposes. Indicators: how well a company manages risk Safety performance indicators are intended to provide information on the safety performance of a company. They can play an important role in the communication and indicate how well the company is managing it's risk controls. First step for a set of safety performance indicators The presented set of safety performance indicators is formulated based on a survey of scientific literature and information from companies, including twelve BRZO companies. In a next phase, it will be explored whether the set of safety performance indicators meets the formulated criteria and whether they match the indicators that some companies already developed. Finally, it is looked into the usefulness for the Labour Inspectorate.Ministerie van Sociale Zaken en Werkgelegenhei

Exposure to occupational hazards in 2006 and 2011

In opdracht van het ministerie van SZW heeft het RIVM in 2006 en 2011 uitgezocht welke kans werknemers in Nederland tijdens hun werk lopen op een ongeval. Hiervoor is in kaart gebracht hoe lang mensen blootstaan aan risicovolle situaties, zoals werken op hoogte, werken met elektriciteit of machines, vallende voorwerpen en agressieve mensen. Het doel is te identificeren welke werknemers een groter risico lopen op een ongeval. Op die manier kan het ministerie, maar ook de werkgever, beter prioriteiten stellen in zijn beleid en indien nodig de juiste beschermende maatregelen treffen. Ten opzichte van 2006 is het aantal uren per jaar dat een werknemer werd blootgesteld aan risicovolle situaties met 3,7 procent gedaald. Uit het onderzoek blijkt dat een werknemer in een jaar gemiddeld aan 4,6 risicovolle situaties tegelijk blootstaat. Deze aantallen verschillen sterk per beroepsgroep. Bovenaan, met een blootstelling aan gemiddeld 10,5 risicovolle situaties, staan de machinebankwerkers, monteurs, instrumentmakers en reparateurs. Onderaan staan de beroepsgroepen van verzekeringsagenten, boekhouders, makelaars en dergelijke, met 2,5 risicovolle situaties. Effectief arbeidsveiligheid verbeteren Er lijkt een extra risico te schuilen in de combinatie van risicovolle situaties. Werknemers die aan een groot aantal van deze situaties blootstaan, blijken er het meest bij gebaat te zijn als dat aantal afneemt. Dit heeft meer effect dan het totaal aantal uren waarin zij aan risicovolle situaties blootstaan te verminderen. Veel variatie in blootstelling op het werk Per risicovolle situatie varieert bovendien de mate waarin werknemers eraan blootstaan. Zo is voor 90 procent van hen struikelen en uitglijden een van die risicovolle situaties; in totaal stond de Nederlandse beroepsbevolking daaraan in 2011 4,3 miljard uur blootgesteld. Vallen van een vaste trap of helling staat op de tweede plaats, met een aandeel van 62 procent van de werknemers en een totale blootstelling van 353 miljoen uur. Dat is per traploper gemiddeld 80 uur per jaar. Slechts 2 procent van de werkzame beroepsbevolking staat bloot aan het risico op stofexplosies, maar dat betreft per persoon wel een groot aantal uren (gemiddeld 910 uur per jaar). Grote verschillen tussen werknemers Voor het onderzoek is aan 25.000 mensen, representatief voor de werkzame beroepsbevolking, gevraagd of zij in de week voorafgaand aan het onderzoek met risicovolle situaties te maken hebben gehad. Door de informatie over blootstelling en letsel en verzuim als gevolg van ongevallen te combineren, was het bovendien mogelijk te duiden binnen welke groep werknemers bijna alle ongevallen met verzuim plaatsvinden. Deze groep beslaat circa 20 procent van de werkzame beroepsbevolking. Dit betreft vooral personen onder de 25, vrouwen, deeltijders en lager opgeleiden. Als sector is de horeca hierin oververtegenwoordigd, als beroepsgroep zijn dat verpleegkundigen.Commissioned by the Ministry of Social Affairs, RIVM investigated the probability for employees in the Netherlands to have an occupational accident in 2006 and 2011. This required analysing how long people are exposed to hazards, such as working on heights, working with electricity or machinery, falling objects, and aggressive people. The aim is to identify which workers are more at risk of having an accident. That way, the ministry, but also the employer can set priorities better in its policy and take the correct protective measures, if necessary. Compared to 2006, the number of hours per year that a worker was exposed to hazards is reduced by 3.7 percent. The study shows that an employee is exposed to an average 4.6 hazards simultaneously in a year. These numbers vary widely by profession. The top ranking jobs, with a 10.5 average exposure to hazards, are the machinists, mechanics, instrument makers and repairers. At the bottom are the professional groups of insurance agents, accountants, brokers and similar people with 2.5 hazards. Effectively improving occupational safety There seems to be an additional risk when employees are exposed to a large number of hazards. They appear to be best served when that number decreases. This is more effective than reducing the total number of hours in which they are exposed to hazards. Much variation in exposure at work The extent to which employees are exposed varies per hazard. Thus, for 90 percent of the employees, tripping and slipping is one of those hazards; in total the Dutch working population was 4.3 billion hours exposed in 2011. Fall from a staircase or slope comes second with a share of 62 percent of the employees and a total exposure of 353 million hours. That is an average of 80 hours per year for a person walking on stairs. Only 2 percent of the active population is exposed to the risk of dust explosions, but that concerns a large number of hours per person (on average 910 hours per year). Large differences between employees For the study, 25,000 people representative of the working population, were asked whether they had to deal with occupational hazards in the week preceding the survey. Combining information on exposure and injury and absence due to accidents also made it possible to identify which group of employees has almost all occurring accidents with absence. This group covers about 20 percent of the working population. This mainly concerns persons under 25, women, part-timers and less educated. As a sector the catering industry is overrepresented, as a group of professionals health care workers.Ministerie van Sociale Zaken en Werkgelegenhei