Strategies for the Diversity-Oriented Synthesis of Macrocycles.

Macrocycles have long been recognized as useful chemical entities for medicine, with naturally occurring and synthetic macrocycles clinically approved for use as prescription drugs. Despite this promise, the synthesis of collections of macrocycles has been historically challenging due to difficulties in the formation of large rings. Diversity-Oriented Synthesis (DOS) emerged in the early 2000s as a powerful strategic solution to the construction of diverse molecular libraries. This review details the various strategies developed within the field of DOS for the synthesis of macrocycle libraries, utilizing modern synthetic methodology to deliver structurally diverse collections of macrocyclic molecules, and the exploration of their therapeutic potential. Section 1 of this work details the use of algorithmic strategies and is divided into Build/Couple/Pair, Advanced Build/Couple/Pair, Initiate/Propagate/Terminate, Fragment-Based Domain Shuffling, Two-Directional Synthesis, and Successive Ring Expansion. Section 2 covers strategies based on ring distortion reactions, including Sequential Cycloaddition/Fragmentation, Ring Expansions, and Miscellaneous

Clinical and functional outcomes after 2 years in the early detection and intervention for the prevention of psychosis multisite effectiveness trial

OBJECTIVE: To test effectiveness of the Early Detection, Intervention, and Prevention of Psychosis Program in preventing the onset of severe psychosis and improving functioning in a national sample of at-risk youth. METHODS: In a risk-based allocation study design, 337 youth (age 12-25) at risk of psychosis were assigned to treatment groups based on severity of positive symptoms. Those at clinically higher risk (CHR) or having an early first episode of psychosis (EFEP) were assigned to receive Family-aided Assertive Community Treatment (FACT); those at clinically lower risk (CLR) were assigned to receive community care. Between-groups differences on outcome variables were adjusted statistically according to regression-discontinuity procedures and evaluated using the Global Test Procedure that combined all symptom and functional measures. RESULTS: A total of 337 young people (mean age: 16.6) were assigned to the treatment group (CHR + EFEP, n = 250) or comparison group (CLR, n = 87). On the primary variable, positive symptoms, after 2 years FACT, were superior to community care (2 df, p \u3c .0001) for both CHR (p = .0034) and EFEP (p \u3c .0001) subgroups. Rates of conversion (6.3% CHR vs 2.3% CLR) and first negative event (25% CHR vs 22% CLR) were low but did not differ. FACT was superior in the Global Test (p = .0007; p = .024 for CHR and p = .0002 for EFEP, vs CLR) and in improvement in participation in work and school (p = .025). CONCLUSION: FACT is effective in improving positive, negative, disorganized and general symptoms, Global Assessment of Functioning, work and school participation and global outcome in youth at risk for, or experiencing very early, psychosis

Multidimensional cut-off technique, odd-dimensional Epstein zeta functions and Casimir energy of massless scalar fields

Quantum fluctuations of massless scalar fields represented by quantum fluctuations of the quasiparticle vacuum in a zero-temperature dilute Bose-Einstein condensate may well provide the first experimental arena for measuring the Casimir force of a field other than the electromagnetic field. This would constitute a real Casimir force measurement - due to quantum fluctuations - in contrast to thermal fluctuation effects. We develop a multidimensional cut-off technique for calculating the Casimir energy of massless scalar fields in $d$-dimensional rectangular spaces with $q$ large dimensions and $d-q$ dimensions of length $L$ and generalize the technique to arbitrary lengths. We explicitly evaluate the multidimensional remainder and express it in a form that converges exponentially fast. Together with the compact analytical formulas we derive, the numerical results are exact and easy to obtain. Most importantly, we show that the division between analytical and remainder is not arbitrary but has a natural physical interpretation. The analytical part can be viewed as the sum of individual parallel plate energies and the remainder as an interaction energy. In a separate procedure, via results from number theory, we express some odd-dimensional homogeneous Epstein zeta functions as products of one-dimensional sums plus a tiny remainder and calculate from them the Casimir energy via zeta function regularization.Comment: 42 pages, 3 figures. v.2: typos corrected to match published versio

Public International Law: Environmental Law

Noteworthy international activity relating to the environment occurred in a wide variety of fora in 2000. This chapter provides brief updates on some of the most significant developments. Though by no means a comprehensive review, the chapter reflects the wide sweep of issues and large number of entities now involved in the development of international environmental law, at the start of this new century. It also reflects how critical and complex this international work is, and how much remains to be done

The institutional shaping of management: in the tracks of English individualism

Globalisation raises important questions about the shaping of economic action by cultural factors. This article explores the formation of what is seen by some as a prime influence on the formation of British management: individualism. Drawing on a range of historical sources, it argues for a comparative approach. In this case, the primary comparison drawn is between England and Scotland. The contention is that there is a systemic approach to authority in Scotland that can be contrasted to a personal approach in England. An examination of the careers of a number of Scottish pioneers of management suggests the roots of this systemic approach in practices of church governance. Ultimately this systemic approach was to take a secondary role to the personal approach engendered by institutions like the universities of Oxford and Cambridge, but it found more success in the different institutional context of the USA. The complexities of dealing with historical evidence are stressed, as is the value of taking a comparative approach. In this case this indicates a need to take religious practice as seriously as religious belief as a source of transferable practice. The article suggests that management should not be seen as a simple response to economic imperatives, but as shaped by the social and cultural context from which it emerges

Cold adapted variants of influenza A

The genetic and biological properties of 13 recombinant influenza A clones derived at 25°C from the A/AA/6/60-cold variant (by crosses with 4 different wild type strains) were compared with a set of 5-FU induced ts -mutants. The 5-FU mutants had previously been placed into 7 complementation-recombination groups; the A/AA/6/60-cold parent (PI-7) and the 12 cold recombinant clones which were ts were shown to share a lesion with only one of these groups. The parental strain and 5 recombinant clones were evaluated for replication in the lungs and nasal turbinates of hamsters. Each virus appeared to be attenuated; genetic stability correlated with the level of viral replication in the hamster lung, i.e., viruses which grew best showed a tendency to revert to the ts + phenotype. Characterization of the ts + revertants for the presence of the cold adaptation property revealed that these viruses exhibited a spectrum of cold adaptation properties. Two viruses, PI-7 (the parental cold variant) and the CR6 recombinant (A/Queensland/6/72) did not revert in either the lungs or nasal turbinates of hamsters.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41685/1/705_2005_Article_BF01319909.pd

Keeping Steady as She Goes: A Negotiated Order Perspective on Technological Evolution

A central idea in the theory of technology cycles is that social and political mechanisms are most important during the selection of a dominant design, and that eras of incremental change are socially uninteresting periods in which innovation is driven by technological momentum and elaboration of the dominant design. In this essay, we overturn the ontological assumption that social order is inherently stable, drawing on Anselm Strauss's concept of negotiated order to analyze the persistence of a dominant design as a social accomplishment: an outcome of ongoing processes that reinforce or challenge a socially negotiated order. Thus, we shift focus from battles over standards to periods of normal innovation. We extend the technology cycles model to explain social dynamics in periods of incremental change, and to make predictions specifying how contextual conditions in standards-setting organizations affect social interaction, leading to reinforcement or challenge to a socio-technical order

Crystal chemistry and electronic properties of the n=2 Ruddlesden-Popper manganates: unconventional CMR materials

The crystallography and electronic properties of the Ln[sub 2- x]Sr[sub 1+x]Mn[sub 2]O[sub 7] manganese oxides adopting the n=2 Ruddlesden-Popper (RP) structure are discussed, focusing on the structural phase diagrams and electronic properties in the vicinity of the Mn +3.5 oxidation state and in particular the ease of synthesis of single phases of these materials

Description of the Vitis vinifera L. phenotypic variability in eno-carpological traits by a Euro-Asiatic collaborative network among ampelographic collections

The grapevine intra-specific variability captured an increasing interest during the last decades, as demonstrated by the number of recently funded European projects focused on the grapevine biodiversity preservation. However, nowadays, crop plants are mainly characterized by genotyping methods. The present work summarizes the phenotype data collected among 20 ampelographic collections spread in 15 countries, covering mostly of the viticultural areas in the Euro-Asiatic range: from Portugal to Armenia and from Cyprus to Luxembourg. Together with agro-climatic characterization of the experimental site, in two years, about 2400 accessions were described, following a common experimental protocol mainly focused on the carpological and oenological traits, obtaining a general overview of the distribution of the considered phenotypic traits in the cultivated Vitis vinifera species. The most replicated cultivars were selected and, for the subset of these reference cultivars, their behavior in the different environmental conditions over sites and years was described by ANOVA methods