High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: structure-activity relationship of daunosamine-modified derivatives of doxorubicin.

A convenient, high yield conversion of doxorubicin to 3'-deamino-3'-(2''-pyrroline-1''-yl)doxorubicin is described. This daunosamine-modified analog of doxorubicin is 500-1000 times more active in vitro than doxorubicin. The conversion is effected by using a 30-fold excess of 4-iodobutyraldehyde in anhydrous dimethylformamide. The yield is higher than 85%. A homolog of this compound, 3'-deamino-3'-(1'',3''-tetrahydropyridine-1''-yl)doxorubicin, was also synthesized by using 5-iodovaleraldehyde. In this homolog, the daunosamine nitrogen is incorporated into a six- instead of a five-membered ring. This analog was 30-50 times less active than its counterpart with a five-membered ring. A similar structure-activity relationship was found when 3'-deamino-3'-(3''-pyrrolidone-1''-yl)doxorubicin (containing a five-membered ring) and 3'-deamino-3'-(3''-piperidone-1''-yl)doxorubicin (with a six-membered ring) were tested in vitro, the former being 5 times more potent than the latter. To further elucidate structure-activity relationships, 3'-deamino-3'-(pyrrolidine-1''-yl)doxorubicin, 3'-deamino-3'-(isoindoline-2''-yl)doxorubicin, 3'-deamino-3'-(2''-methyl-2''-pyrroline-1''-yl)doxorubicin, and 3'-deamino-3'-(3''-pyrroline-1''-yl)doxorubicin were also synthesized and tested. All the analogs were prepared by using reactive halogen compounds for incorporating the daunosamine nitrogen of doxorubicin into a five- or six-membered ring. These highly active antineoplastic agents can be used for incorporation into targeted cytotoxic analogs of luteinizing hormone-releasing hormone intended for cancer therapy.

The Mice at play in the CALIFA survey. A case study of a gas-rich major merger between first passage and coalescence

We present optical integral field spectroscopy (IFS) observations of the Mice, a major merger between two massive (≳10^11 M_⊙) gas-rich spirals NGC 4676A and B, observed between first passage and final coalescence. The spectra provide stellar and gas kinematics, ionised gas properties, and stellar population diagnostics, over the full optical extent of both galaxies with ~1.6 kpc spatial resolution. The Mice galaxies provide a perfect case study that highlights the importance of IFS data for improving our understanding of local galaxies. The impact of first passage on the kinematics of the stars and gas has been significant, with strong bars most likely induced in both galaxies. The barred spiral NGC 4676B exhibits a strong twist in both its stellar and ionised gas disk. The edge-on disk galaxy NGC 4676A appears to be bulge free, with a strong bar causing its “boxy” light profile. On the other hand, the impact of the merger on the stellar populations has been minimal thus far. By combining the IFS data with archival multiwavelength observations we show that star formation induced by the recent close passage has not contributed significantly to the total star formation rate or stellar mass of the galaxies. Both galaxies show bicones of high ionisation gas extending along their minor axes. In NGC 4676A the high gas velocity dispersion and Seyfert-like line ratios at large scaleheight indicate a powerful outflow. Fast shocks (vs ~ 350 km s^-1) extend to ~6.6 kpc above the disk plane. The measured ram pressure (P/k = 4.8 × 10^6 K cm^-3) and mass outflow rate (~8−20 M_⊙ yr^-1) are similar to superwinds from local ultra-luminous infrared galaxies, although NGC 4676A only has a moderate infrared luminosity of 3 × 10^10 L_⊙. Energy beyond what is provided by the mechanical energy of the starburst appears to be required to drive the outflow. Finally, we compare the observations to mock kinematic and stellar population maps extracted from a hydrodynamical merger simulation. The models show little enhancement in star formation during and following first passage, in agreement with the observations. We highlight areas where IFS data could help further constrain the models.

Determining departure times in dynamic and stochastic maritime routing and scheduling problem

In maritime transportation, decisions are made in a dynamic setting where many aspects of the future are uncertain. However, most academic literature on maritime transportation considers static and deterministic routing and scheduling problems. This work addresses a gap in the literature on dynamic and stochastic maritime routing and scheduling problems, by focusing on the scheduling of departure times. Five simple strategies for setting departure times are considered, as well as a more advanced strategy which involves solving a mixed integer mathematical programming problem. The latter strategy is significantly better than the other methods, while adding only a small computational effort.

Structures, Systems and Organizational Communication Processes in Franchises in times of crisis: the Spanish case

Current economic crisis together with the Internet revolution has had direct impacts on the franchise sector of Spain: in particular on its unique communication network. The aim of this research is to analyse how Spanish franchise companies have adapted to these changes through its corporate communications management. We want to determine whether the management of communications is ideal to the growth and consolidation of companies in the market. Corporate communications plans and organizational structures were analyzed to verify whether or not information technology (i.e. the use of the Internet) is maximized: the communications aspect being a critical area of company growth. We found that most franchise companies surveyed had adapted well to the changes in information technology, despite economic challenges. The Internet as a communications tool has been limited to its utility as a “bulletin board” for information. The marketing advantage of Internet communication, or its use as an avenue for customer exchange and exchange of goods and services has yet to be maximized. Future research may look into the details of how companies are able to maximize the communications-marketing advantage that Online/Internet can contribute to the franchise sector.

Health inequality between immigrants and natives in Spain: the loss of the healthy immigrant effect in times of economic crisis

Background: The immigrant population living in Spain grew exponentially in the early 2000s but has been particularly affected by the economic crisis. This study aims to analyse health inequalities between immigrants born in middle- or low-income countries and natives in Spain, in 2006 and 2012, taking into account gender, year of arrival and socioeconomic exposures. Methods: Study of trends using two cross-sections, the 2006 and 2012 editions of the Spanish National Health Survey, including residents in Spain aged 15–64 years (20 810 natives and 2950 immigrants in 2006, 14 291 natives and 2448 immigrants in 2012). Fair/poor self-rated health, poor mental health (GHQ-12 > 2), chronic activity limitation and use of psychotropic drugs were compared between natives and immigrants who arrived in Spain before 2006, adjusting robust Poisson regression models for age and socioeconomic variables to obtain prevalence ratios (PR) and 95% confidence interval (CI). Results: Inequalities in poor self-rated health between immigrants and natives tend to increase among women (age-adjusted PR2006 = 1.39; 95% CI: 1.24–1.56, PR2012 = 1.56; 95% CI: 1.33–1.82). Among men, there is a new onset of inequalities in poor mental health (PR2006 = 1.10; 95% CI: 0.86–1.40, PR2012 = 1.34; 95% CI: 1.06–1.69) and an equalization of the previously lower use of psychotropic drugs (PR2006 = 0.22; 95% CI: 0.11–0.43, PR2012 = 1.20; 95% CI: 0.73–2.01). Conclusions: Between 2006 and 2012, immigrants who arrived in Spain before 2006 appeared to worsen their health status when compared with natives. The loss of the healthy immigrant effect in the context of a worse impact of the economic crisis on immigrants appears as potential explanation. Employment, social protection and re-universalization of healthcare would prevent further deterioration of immigrants’ health status.

The life and times of Anne Royall

by Sarah Harvey Porter.

The climatic changes of later geological times : a discussion based on observations made in the Cordilleras of North America / by J. D. Whitney.

v.7:no.2 (1882)

Talking with the “pouvoir constituant” in times of constitutional reform: The European Court of Justice on Private Applicants’ Access to Justice. Research Paper in Law 3/2003

[From the Introduction]. European lawyers, at least those dealing predominantly with institutional matters, are living particularly interesting times since the setting-up of the “European Convention on the Future of Europe” in December 2001.1 As the Convention’s mandate, spelled out in rather broad terms in the European Council’s declaration of Laeken,2 is potentially unlimited, and as the future constitution of the European Union (EU) will be ultimately adopted by the subsequent Intergovernmental Conference (IGC), there appears to be a great possibility to clarify, to simplify and also to reform many of the more controversial elements in the European legal construction. The present debate on the future of the European constitution also highlights the relationship between the pouvoir constituant3 and the European Courts, the Court of Justice (ECJ) and its Court of First Instance (CFI), who have to interpret the basic rules and principles of the EU.4 In that light, the present article will focus on a classic theme of the Court’s case law: the relationship between judges and pouvoir constituant. In the EU, this relationship has traditionally been marked by the ECJ’s role as driving force in the “constitutionalisation” of the EC Treaties – which has, to a large extent, been accepted and even codified by the Member States in subsequent treaty revisions. However, since 1994, the ECJ appears to be more reluctant to act as a “law-maker.”5 The recent judgment in Unión de Pequeños Agricultores (UPA)6 – an important decision by which the ECJ refused to liberalize individuals’ access to the Community Courts – is also interesting in this context. UPA may be seen as another proof of judicial restraint - or even as indicator of the beginning of a new phase in the “constitutional dialogue” between the ECJ and the “Masters of the Treaties.”

National Parliaments and their Role in European Integration: The EU’s Democratic Deficit in Times of Economic Hardship and Political Insecurity. Bruges Political Research Paper 28/2013

The article describes and assesses the role of national parliaments in EU legislation considering the reforms introduced by the Lisbon Treaty. This is closely connected with the understanding and (political) application of the principle of subsidiarity. After an analysis of the possibilities and limitations of the relevant legal regulations in the post-Lisbon age, alternative ways for participation of national legislators on the European level are being scrutinized and proposed. The issue of democratic legitimization is also interconnected with the current political reforms being discussed in order to overcome the Euro Crisis. Finally, the authors argue that it does not make sense to include national parliaments in the existing legislative triangle of the EU, but instead to promote the creation of a new kind of supervisory body.

La disoccupazione giovanile in tempo di crisi: un monito all’Europa (continentale) per rifondare il diritto del lavoro? = Youth Unemployment in Recessionary Times: a Caveat to (Continental) Europe to Reconstruct its Labour Law. WP C.S.D.L.E. "Massimo D'Antona" .INT - 91/2012

The current debate taking place in continental Europe on the need to reform labour law to reduce the duality between labour market insiders and outsiders, thus giving new employment opportunities to young people seems to be, at its best, a consequence of the crisis, or at its worst, an excuse. The considerable emphasis placed on the power of legislation to reduce youth unemployment prevents real labour market problems from being clearly identified, thus reducing the scope to adopt more effective measures. Action is certainly required to help young people during the current crisis, yet interventions should not be exclusively directed towards increased flexibility and deregulation. This paper questions the “thaumaturgic power” wrongly attributed to legislative interventions and put forward a more holistic approach to solve the problem of youth employment, by focusing on the education systems, school-to-work transition and industrial relations. As a comparative analysis demonstrates, in order to effectively tackle the issue of youth employment, it is not enough to reform labour law. High quality education systems, apprenticeship schemes, efficient placement and employment services, cooperative industrial relations and flexible wage determination mechanisms are the key to success when it comes to youth employment, not only in times of recession.