Enzymatic Macrocyclization of 1,2,3-Triazole Peptide Mimetics

Funded by European Research Council. Grant Number: 339367 UK Biotechnology and Biological Sciences Research Council. Grant Number: K015508/1 The Wellcome Trust. Grant Number: 094476 EPSRC Acknowledgements This work was supported by the European Research Council (339367), UK Biotechnology and Biological Sciences Research Council (K015508/1), The Wellcome Trust (TripleTOF 5600 mass spectrometer (094476), the MALDI TOF-TOF Analyser (079272AIA), 700 NMR) and the EPSRC UK National Mass Spectrometry Facility at Swansea University. J.H.N. is a Royal Society Wolfson Merit Award Holder and 1000 talent scholar at Sichuan University.

The Contribution of Agriculture, Forestry and other Land Use activities to Global Warming, 1990-2012

Date of Acceptance: 16/12/2014 Acknowledgements: This work was carried out with generous funding by the Governments of Germany (GCP/GLO/286/GER) and Norway (GCP/GLO/325/NOR) to the ‘Monitoring and Assessment of GHG Emissions and Mitigation Potential from Agriculture’ Project of the FAO Climate, Energy and Tenure Division. P. Smith is a Royal Society Wolfson Merit Award holder, and his input contributes to the University of Aberdeen Environment and Food Security Theme and to Scotland's ClimateXChange. J. House was funded by a Leverhulme Research Fellowship. The FAO Statistics Division maintains the FAOSTAT Emissions database with regular program funds allocated through Strategic Objective 6. © 2015 John Wiley & Sons Ltd.

A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees

Bipolar mood disorder (BP) is a debilitating syndrome characterized by episodes of mania and depression. We designed a multistage study to detect all major loci predisposing to severe BP (termed BP-I) in two pedigrees drawn from the Central Valley of Costa Rica, where the population is largely descended from a few founders in the 16th–18th centuries. We considered only individuals with BP-I as affected and screened the genome for linkage with 473 microsatellite markers. We used a model for linkage analysis that incorporated a high phenocopy rate and a conservative estimate of penetrance. Our goal in this study was not to establish definitive linkage but rather to detect all regions possibly harboring major genes for BP-I in these pedigrees. To facilitate this aim, we evaluated the degree to which markers that were informative in our data set provided coverage of each genome region; we estimate that at least 94% of the genome has been covered, at a predesignated threshold determined through prior linkage simulation analyses. We report here the results of our genome screen for BP-I loci and indicate several regions that merit further study, including segments in 18q, 18p, and 11p, in which suggestive lod scores were observed for two or more contiguous markers. Isolated lod scores that exceeded our thresholds in one or both families also occurred on chromosomes 1, 2, 3, 4, 5, 7, 13, 15, 16, and 17. Interesting regions highlighted in this genome screen will be followed up using linkage disequilibrium (LD) methods.

The future of coral reefs

Coral reefs, with their millions of species, have changed profoundly because of the effects of people, and will continue to do so for the foreseeable future. Reefs are subject to many of the same processes that affect other human-dominated ecosystems, but some special features merit emphasis: (i) Many dominant reef builders spawn eggs and sperm into the water column, where fertilization occurs. They are thus particularly vulnerable to Allee effects, including potential extinction associated with chronic reproductive failure. (ii) The corals likely to be most resistant to the effects of habitat degradation are small, short-lived “weedy” corals that have limited dispersal capabilities at the larval stage. Habitat degradation, together with habitat fragmentation, will therefore lead to the establishment of genetically isolated clusters of inbreeding corals. (iii) Increases in average sea temperatures by as little as 1°C, a likely result of global climate change, can cause coral “bleaching” (the breakdown of coral–algal symbiosis), changes in symbiont communities, and coral death. (iv) The activities of people near reefs increase both fishing pressure and nutrient inputs. In general, these processes favor more rapidly growing competitors, often fleshy seaweeds, and may also result in explosions of predator populations. (v) Combinations of stress appear to be associated with threshold responses and ecological surprises, including devastating pathogen outbreaks. (vi) The fossil record suggests that corals as a group are more likely to suffer extinctions than some of the groups that associate with them, whose habitat requirements may be less stringent.

Genome projects and gene pools: New germplasm for plant breeding?

Crop gene pools have adapted to and sustained the demands of agricultural systems for thousands of years. Yet, very little is known about their content, distribution, architecture, or circuitry. The presumably shallow elite gene pools often continue to yield genetic gains while the exotic pools remain mostly untapped, uncharacterized, and underutilized. The concept and content of a crop’s gene pools are being changed by advancements in plant science and technology. In the first generation of plant genomics, DNA markers have refined some perceptions of genetic variation by providing a glimpse of a primary source, DNA polymorphism. The markers have provided new and more powerful ways of assessing genetic relationships, diversity, and merit by infusing genetic information for the first time in many scenarios or in a more comprehensive manner for others. As a result, crop gene pools may be supplemented through more rapid and directed methods from a greater variety of sources. Previously limited by the barriers of sexual reproduction, the native gene pools will soon be complemented by another gene pool (transgenes) and perhaps by other native exotic gene pools through comparative analyses of plants’ biological repertoire. Plant genomics will be an important force of change for crop improvement. The plant science community and crop gene pools may be united and enriched as never before. Also, the genomes and gene pools, the products of evolution and crop domestication, will be reduced and subjected to the vagaries and potential divisiveness of intellectual property considerations. Let the gains begin.

Programmed cell death: a way of life for plants.

Cell death in higher plants has been widely observed in predictable patterns throughout development and in response to pathogenic infection. Genetic, biochemical, and morphological evidence suggests that these cell deaths occur as active processes and can be defined formally as examples of programmed cell death (PCD). Intriguingly, plants have at least two types of PCD, an observation that is also true of PCD in animals [Schwartz, L. M., Smith, W.W., Jones, M. E. E. & Osborne, B. A. (1993) Proc. Natl. Acad. Sci. USA 90, 980-984]. Thus, in plants, PCD resembles either a common form of PCD seen in animals called apoptosis or it resembles a morphologically distinct form of cell death. The ubiquitous occurrence and necessity of PCD for plant development and defense suggest that the underlying mechanisms of regulation and execution of these processes merit further examination.

Perspectives on archaeal diversity, thermophily and monophyly from environmental rRNA sequences.

Phylogenetic analysis of ribosomal RNA sequences obtained from uncultivated organisms of a hot spring in Yellowstone National Park reveals several novel groups of Archaea, many of which diverged from the crenarchaeal line of descent prior to previously characterized members of that kingdom. Universal phylogenetic trees constructed with the addition of these sequences indicate monophyly of Archaea, with modest bootstrap support. The data also show a specific relationship between low-temperature marine Archaea and some hot spring Archaea. Two of the environmental sequences are enigmatic: depending upon the data set and analytical method used, these sequences branch deeply within the Crenarchaeota, below the bifurcation between Crenarchaeota and Euryarchaeota, or even as the sister group to Eukaryotes. If additional data confirm either of the latter two placements, then the organisms represented by these ribosomal RNA sequences would merit recognition as a new kingdom, provisionally named "Korarchaeota."

The best thermoelectric.

What electronic structure provides the largest figure of merit for thermoelectric materials? To answer that question, we write the electrical conductivity, thermopower, and thermal conductivity as integrals of a single function, the transport distribution. Then we derive the mathematical function for the transport distribution, which gives the largest figure of merit. A delta-shaped transport distribution is found to maximize the thermoelectric properties. This result indicates that a narrow distribution of the energy of the electrons participating in the transport process is needed for maximum thermoelectric efficiency. Some possible realizations of this idea are discussed.

Improved biodistribution, tumor targeting, and reduced immunogenicity in mice with a gamma 4 variant of Campath-1H.

Radiolabeled antibodies have shown promise for the treatment of lymphoma and for solid tumor targeting. Campath-1H is a humanized monoclonal antibody that reacts with the CD52 antigen present on human lymphoid and myeloid cells. Campath-1H is a gamma1 (G1) isotype that induces lymphopenia via an Fc-mediated mechanism(s). Isotype switches were engineered, and the resulting antibodies were expressed in NS0 mouse myeloma cells and biosynthetically radiolabeled with [35S]methionine. The forms included G1, G4, and a G4 variant that contained alanine substitutions at (EU numbering) Leu-235, Gly-237, and Glu-318. All isotypes bound antigen equivalently as assessed by target cell binding in vitro. The G4 variant had a greatly reduced capacity to interact with Fc receptor by virtue of reduced binding to THP-1 human myeloid cells and by a 1000-fold increase in EC50 to intermediate antibody-dependent cellular cytotoxicity. The pharmacokinetics of the isotypes were compared in CD-1 (nu/nu) mice bearing an experimental antigen-expressing tumor. The plasma half-life and tumor uptake were increased for the G4 variant. The G4 variant showed significantly less spleen, liver, and bone uptake but similar uptake in the lung, kidney, and stomach and lower tissue-to-blood ratios. Immunogenicity was assessed after repeated monthly administrations of unlabeled antibody in BALB/c mice. A 50% reduction in the incidence of anti-globulin response was observed for the G4 variant. These properties suggest that antibodies with reduced Fc receptor interaction merit additional study as potential targeting vehicles relative to other isotypes for radioimmunotherapy or situations where diminished normal tissue binding contributes to efficacy.

Liquid-phase combinatorial synthesis.

A concept termed liquid-phase combinatorial synthesis (LPCS) is described. The central feature of this methodology is that it combines the advantages that classic organic synthesis in solution offers with those that solid-phase synthesis can provide, through the application of a linear homogeneous polymer. To validate this concept two libraries were prepared, one of peptide and the second of nonpeptide origin. The peptide-based library was synthesized by a recursive deconvolution strategy [Erb, E., Janda, K. D. & Brenner, S. (1994) Proc. Natl. Acad. Sci. USA 91, 11422-11426] and several ligands were found within this library to bind a monoclonal antibody elicited against beta-endorphin. The non-peptide molecules synthesized were arylsulfonamides, a class of compounds of known clinical bactericidal efficacy. The results indicate that the reaction scope of LPCS should be general, and its value to multiple, high-throughput screening assays could be of particular merit, since multimilligram quantities of each library member can readily be attained.

Estrutura espacial urbana e mobilidade: o caso da Região Metropolitana de São Paulo

A metrópole de São Paulo é a maior e mais importante aglomeração urbana do Brasil e está entre as dez maiores áreas urbanas do mundo. No entanto, a forma como acessibilidade espacial ocorre gera um fardo para a população e para a atividade econômica. Este trabalho pretende contribuir para a discussão de como melhorar a acessibilidade na Região Metropolitana de São Paulo estudando as características e impactos de estruturas espaciais urbana, analisando criticamente a estrutura espacial da metrópole e proporcionando sugestões de melhorias a fim de proporcionar uma mobilidade mais sustentável. Os procedimentos metodológicos incluem uma revisão bibliográfica sobre o tema e uma caracterização da estrutura espacial da Região Metropolitana de São Paulo, considerando a alocação de população, alocação de empregos e os padrões de deslocamento para os modais individual, coletivo e não motorizado. Apresentamos um relato da evolução recente, com dados das pesquisas de origem e destino realizadas pelo Metrô em 1997 e 2007 e da pesquisa de mobilidade de 2012. Também realizamos uma caracterização mais aprofundada com os dados da pesquisa de 2007. As cidades se desenvolvem com base no trade-off entre proximidade e mobilidade: a fim de maximizar as possibilidades de interação, as pessoas e as empresas tendem a se localizar onde o deslocamento necessário para executar essas interações requer menos custos financeiros, perda de tempo e desconforto. Esse processo molda a alocação espacial de atividades, que define parcialmente os hábitos de transporte. A estrutura espacial urbana pode ser caracterizada por sua escala (padrões compacto ou disperso), arranjo de densidades (padrão disperso ou clusterizado) e arranjo de atividade (padrão monocêntrico ou policêntrico). Estruturas espaciais com padrão mais compacto apresentam menores distâncias de viagem, reduzindo o impacto ambiental das viagens e viabilizando o transporte não motorizado e coletivo, e levam a um uso mais eficiente da terra, menor custo de infraestrutura e maior equidade no acesso ao transporte. Já estruturas clusterizadas policêntricas são associadas com maior facilidade de acesso à terra. Existe um debate sobre a capacidade de estruturas policêntricas resultarem em uma aproximação generalizada de empregos e residências. A Região Metropolitana de São Paulo apresenta um padrão monocêntrico na escala metropolitana, com fortes movimentos pendulares da periferia para o centro expandido da iii capital. Durante o período de análise, foi observada uma realocação da população para áreas mais centrais da cidade e uma centralização dos empregos ainda mais forte, resultando no agravamento dos movimentos pendulares. Existe uma clara divisão modal por renda: as classes mais altas utilizam majoritariamente automóveis, enquanto as classes mais baixas utilizam majoritariamente transporte coletivo e não motorizado. Para o futuro, o novo plano diretor tem o mérito de caminhar na direção do desenvolvimento urbano orientado pelo transporte sustentável, porém os níveis de densidade máxima permitidos ainda são parecidos com o do plano anterior e a largura dos eixos de adensamento é restrita. Acreditamos ser vantajoso um aumento do adensamento em áreas próximas dos empregos; geração de polos de adensamento em áreas mais afastadas dos empregos, mas próximas das infraestruturas de transporte coletivo de alta velocidade, e desencorajamento do adensamento em áreas com baixa acessibilidade. Também é necessária uma gestão integrada dos transportes, provendo infraestrutura para viagens não motorizadas e viagens intermodais, e uma gestão dos impactos negativos do adensamento.

Recuperação judicial de empresas: atuação do juiz

Esta dissertação tem como objeto a análise da atuação judicial no âmbito dos processos de recuperação judicial de empresas, regulados pela Lei nº 11.101 de 9 de fevereiro de 2002 (\"LRE\"). No primeiro capítulo, são introduzidas as limitações do trabalho e as principais questões a serem respondidas ao longo do texto. No segundo capítulo, são expostos os panoramas histórico e jurídico da LRE, para que se extraiam os verdadeiros objetivos tutelados pela lei e o diálogo destes objetivos com a atuação do Poder Judiciário. No terceiro capítulo, são propostos três níveis de intervenção judicial no bojo do processo de recuperação, sendo eles: (a) o controle de legalidade estrita, por meio do qual o juiz verificará a observância aos requisitos e vedações impostos pela LRE ao conteúdo do plano de recuperação e à sua votação; (b) o controle de legalidade material ou controle de juridicidade, por meio do qual o juiz avaliará se o conteúdo do plano e sua votação atendem aos princípios gerais orientadores do ordenamento brasileiro; e (c) o juízo de viabilidade, por meio do qual o juiz, usando de critérios objetivos sugeridos pela doutrina, avaliaria o mérito do plano de recuperação judicial para averiguar se, além de atenderem aos critérios de legalidade, as disposições do plano de recuperação atingem os objetivos traçados pela LRE, no sentido de tutela da empresa viável e tutela institucional do crédito. No quarto capítulo, são retomadas as conclusões alcançadas ao final de cada um dos subcapítulos.

Difference Blindness vs. Bias Awareness: Why Law Firms with the Best of Intentions Have Failed to Create Diverse Partnerships

This Article uses the example of BigLaw firms to explore the challenges that many elite organizations face in providing equal opportunity to their workers. Despite good intentions and the investment of significant resources, large law firms have been consistently unable to deliver diverse partnership structures - especially in more senior positions of power. Building on implicit and institutional bias scholarship and on successful approaches described in the organizational behavior literature, we argue that a significant barrier to systemic diversity at the law firm partnership level has been, paradoxically, the insistence on difference blindness standards that seek to evaluate each person on their individual merit. While powerful in dismantling intentional discrimination, these standards rely on an assumption that lawyers are, and have the power to act as, atomistic individuals - a dangerous assumption that has been disproven consistently by the literature establishing the continuing and powerful influence of implicit and institutional bias. Accordingly, difference blindness, which holds all lawyers accountable to seemingly neutral standards, disproportionately disadvantages diverse populations and normalizes the dominance of certain actors - here, white men - by creating the illusion that success or failure depends upon individual rather than structural constraints. In contrast, we argue that a bias awareness approach that encourages identity awareness and a relational framework is a more promising way to promote equality, equity, and inclusion.

“Let the American potter be a professional amateur" Laura Anne Fry and the American art pottery movement

"Artist Laura Anne Fry blended the concepts of professional and amateur, and helped raise the merit of ceramics in the United States. Fry influenced American art pottery with her contributions to Rookwood Pottery of Cincinnati—changing the course of the company. Her successful experiments with decorating techniques helped Rookwood become a national leader in art pottery, and eventually led to over a decade of controversy between Fry and Rookwood"

When Spanish owns English words

The English language and the Internet, both separately and taken together, are nowadays well-acknowledged as powerful forces which influence and affect the lexico-grammatical characteristics of other languages world-wide. In fact, many authors like Crystal (2004) have pointed out the emergence of the so-called Netspeak, that is, the language used in the Net or World Wide Web; as Crystal himself (2004: 19) puts it, ‘a type of language displaying features that are unique to the Internet […] arising out of its character as a medium which is electronic, global and interactive’. This ‘language’, however, may be differently understood: either as an adaptation of the English language proper to internet requirements and purposes, or as a new and rapidly-changing and developing language as a result of a rapid evolution or adaptation to Internet requirements of almost all world languages, for whom English is a trendsetter. If the second and probably most plausible interpretation is adopted, there are three salient features of ‘Netspeak’: (a) the rapid expansion of all its new linguistic developments thanks to the Internet itself, which may lead to the generalization and widespread acceptance of new words, coinages, or meanings, hundreds of times faster than was the case with the printed media. As said above, (b) the visible influence of English, the most prevalent language on the Internet. Consequently, (c) this new language tends to reduce the ‘distance’ between English and other languages as well as the ignorance of the former by speakers of other languages, since the ‘Netspeak’ version of the latter adopts grammatical, syntactic and lexical features of English. Thus, linguistic differences may even disappear when code-switching and/or borrowing occurs, as whole fragments of English appear in other language contexts. As a consequence of the new situation, an ideal context appears for interlanguage or multilingual word formation to thrive: puns, blends, compounds and word creativity in general find in the web the ideal place to gain rapid acceptance world-wide, as a result of fashion, coincidence, or sheer merit of the new linguistic proposals.