Synthesis and late-stage functionalization of complex molecules through C-H fluorination and nucleophilic aromatic substitution.

We report the late-stage functionalization of multisubstituted pyridines and diazines at the position α to nitrogen. By this process, a series of functional groups and substituents bound to the ring through nitrogen, oxygen, sulfur, or carbon are installed. This functionalization is accomplished by a combination of fluorination and nucleophilic aromatic substitution of the installed fluoride. A diverse array of functionalities can be installed because of the mild reaction conditions revealed for nucleophilic aromatic substitutions (S(N)Ar) of the 2-fluoroheteroarenes. An evaluation of the rates for substitution versus the rates for competitive processes provides a framework for planning this functionalization sequence. This process is illustrated by the modification of a series of medicinally important compounds, as well as the increase in efficiency of synthesis of several existing pharmaceuticals

Influência do sítio no desenvolvimento do Pinus taeda L.aos 22 anos: estado nutricional das plantas.

A análise de solo, freqüentemente usada na agricultura, tem provado ser pouco útil em prever o crescimento de espécies florestais pela dificuldade em determinar com precisão a camada do solo de maior absorção dos nutrientes para a amostragem. Para avaliar a influência do sítio no crescimento do Pinus taeda, foram selecionados, em área de plantio comercial da Klabin S.A., no município de Telêmaco Borba (PR), oito sítios com essa espécie aos 22 anos de idade, diferenciados pelo tipo de solo (latossolo e cambissolo), textura (argilosa e média) e vegetação original. Foram realizadas avaliações dendrométricas de 50 árvores por sítio, e selecionadas 3 árvores médias por sítio, nas quais foram medidas alturas totais, altura para serraria e para celulose e DAP. Também foram coletados discos em seis posições e acículas no terço superior da copa dessas árvores, para análise do estado nutricional. A concentração de K foi maior nas acículas, na casca e no alburno das árvores dos sítios mais produtivos. Os sítios mais produtivos apresentaram os menores teores de Ca nas acículas das árvores, e estes mostraram uma correlação linear positiva muito forte (r = 0,80) com a porosidade total do solo, evidenciando uma dependência da aeração do solo para absorção de Ca. O teor de Zn nas acículas dos sítios mais produtivos foi muito maior e mostrou as maiores correlações lineares positivas com as variáveis de crescimento. A relação P/Zn nas acículas das plantas apresenta correlação linear negativa forte com o crescimento das árvores

Influência do sítio no desenvolvimento do Pinus taeda aos 22 anos: 1. características físico-hídricas e químicas do solo.

Para avaliar a influência do sítio no crescimento de Pinus taeda, foram selecionados, em área de plantio comercial, no município de Telêmaco Borba (PR), oito sítios com essa espécie aos 22 anos de idade, diferenciados pelo tipo de solo (Latossolo e Cambissolo), textura (argilosa e média) e vegetação original (campo e floresta). Para a caracterização dos sítios, foram realizadas avaliações dendrométricas de 50 árvores por sítio e coleta de solo em 3 profundidades para análises. Selecionaram-se 3 árvores médias por sítio, nas quais foram medidas altura total, altura para serraria e para celulose e DAP. O principal fator que influenciou o volume de madeira para serraria foi a fase de vegetação original, sendo os maiores DAPs encontrados em áreas provenientes de floresta. Na área de Cambissolo textura média fase floresta foi encontrado o maior volume de madeira para serraria, e o menor na área de Cambissolo textura média fase campo. Os sítios mais produtivos apresentaram maiores teores de K e P, pH mais elevado, maior saturação por bases e menor saturação por Al. Esses mesmos sítios apresentaram menor porosidade total e macroporosidade, maior densidade do solo e maior teor de água disponível, que melhor se correlacionou com as variáveis de crescimento

Government policy failure in public support for research and development

peer-reviewedPromoting Research and Development (R&D) and innovative activity is a key element of the EU Lisbon Agenda and is seen as playing a central part in stimulating economic development. In this paper we argue that, even allowing for benevolent policy-makers, informational asymmetries can lead to a misallocation of public support for R&D, hence government policy failure, with the potential to exacerbate preexisting market failures. Initially, we explore alternative allocation mechanisms for public support, which can help to minimize the scale of these government policy failures. Of these mechanisms (grants, tax credits, or allocation rules based on past performance), our results suggest that none is universally most efficient. Rather, the effectiveness of each allocation rule depends on the severity of financial constraints and on the level of innovative capabilities of the firms themselves.ACCEPTEDpeer-reviewe

Combining C-H functionalisation and flow photochemical heterocyclic metamorphosis (FP-HM) for the synthesis of benzo[1,3]oxazepines

C-H Activation/functionalisation and Flow Photochemical Heterocyclic Metamorphosis (FP-HM) have been combined to synthesize a library of benzo[1,3]oxazepines, a rarely described heterocyclic family. This combined protocol allows a range of arylated products to be made from simple starting materials, and the cheap flow photochemical system has proven effective for rapid synthesis of gram-quantities of benzo[1,3]oxazepines

The Effects of Heparins on the Liver: Application of Mechanistic Serum Biomarkers in a Randomized Study in Healthy Volunteers

Heparins have been reported to cause elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but have not been associated with clinically significant liver injury. The mechanisms underlying these benign laboratory abnormalities are unknown. Forty-eight healthy men were randomized to receive subcutaneous injections of unfractionated heparin (UFH; 150 U/kg), enoxaparin sodium (1 mg/kg), dalteparin sodium (120 IU/kg), or adomiparin sodium (125 IU/kg; a novel heparin) every 12 h for 4.5 days. Asymptomatic elevations in serum ALT or AST were observed in >90% of the subjects. Elevations were also observed in the levels of serum sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GLDH), miR-122, high-mobility group box-1 protein (including the acetylated form), full-length keratin 18, and DNA. Keratin 18 fragments, which are apoptosis biomarkers, were not detected. Biomarker profiles did not differ significantly across heparin treatments. We conclude that heparins as a class cause self-limited and mild hepatocyte necrosis with secondary activation of an innate immune response

R&D policy instruments – a critical review of what we do and don’t know

In recent years, the term ‘policy instrument’ has been used more frequently with regard to R&D policy and innovation policy. What does this term mean? Where did it come from? What do we know about it, both with regard to the general field of policy studies but also in the specific context of R&D policy? This article examines the development of the notion of policy instruments as part of a body of research known as ‘policy design’. Over the last 50 years, there has been substantial progress in setting policy design on a more systematic basis, with the development of established concepts and analytical frameworks, including various taxonomies of policy instruments. However, with just a few exceptions, this body of research seems to have had little impact in the world of R&D policy. The paper reviews the literature on R&D policy instruments. It identifies a number of challenges for R&D policy instruments in the light of four transitions – the shift from linear to systemic thinking about R&D and innovation, the shift from national governments to multi-level governance, the shift from individual actors to collaborations and networks, and the shift from individual policies to policy mixes. It sets out a research agenda for the study of R&D policy instruments, before ending with a number of conclusions

Seeking and sharing: why the pulmonaryn fibrosis community engages the web 2.0 environment

Background Pulmonary fibrosis (PF) is a rare, progressive disease that affects patients and their loved ones on many levels. We sought to better understand the needs and interests of PF patients and their loved ones (collectively “reader-participants”) by systematically analyzing their engagement with the World Wide Web (the current version referred to as Web 2.0). Methods Data were collected from three PF-focused, interactive websites hosted by physician-investigators with expertise in PF. All data generated by reader-participants for approximately 10 months were downloaded and then analyzed using qualitative content analysis methods. Results PF experts posted 38 blog entries and reader-participants posted 40 forum entries. Blogs received 363 responses, and forum entries received 108 responses from reader-participants. Reader-participants primarily used the three websites to seek information from or offer a contribution to the PF community. Information was sought about PF symptoms, diagnosis, prognosis, treatments, research, pathophysiology, and disease origin; reader-participants also made requests for new posts and pleas for research and sought clarification on existing content. Contributions included personal narratives about experiences with PF, descriptions of activities or behaviors found to be helpful with PF symptoms, resources or information about PF, and supportive comments to other PF sufferers. Conclusions PF patients and their loved ones engage the Web 2.0 environment at these PF-focused sites to satisfy their needs to better understand PF and its impacts and to support others facing similar challenges. Clinicians may find it beneficial to encourage PF patients’ involvement in internet forums that foster dynamic, bi-directional information sharing