We report the strain-induced 2 + 2 cycloadditions of cyclic allenes for the assembly of highly substituted cyclobutanes. By judicious choice of trapping agent, complex scaffolds bearing heteroatoms, ...fused rings, contiguous stereocenters, spirocycles, and quaternary centers are ultimately accessible. Moreover, we show that the resulting cycloadducts can undergo thermal isomerization. This study provides an alternative strategy to photochemical 2 + 2 cycloadditions for accessing highly functionalized cyclobutanes, while validating the use of underexplored strained intermediates for the assembly of complex architectures.
Identifying the chemical regulators of biological pathways is a time-consuming bottleneck in developing therapeutics and research compounds. Typically, thousands to millions of candidate small ...molecules are tested in target-based biochemical screens or phenotypic cell-based screens, both expensive experiments customized to each disease. Here, our uncustomized, virtual, profile-based screening approach instead identifies compounds that match to pathways based on the phenotypic information in public cell image data, created using the Cell Painting assay. Our straightforward correlation-based computational strategy retrospectively uncovered the expected, known small-molecule regulators for 32% of positive-control gene queries. In prospective, discovery mode, we efficiently identified new compounds related to three query genes and validated them in subsequent gene-relevant assays, including compounds that phenocopy or pheno-oppose YAP1 overexpression and kill a Yap1-dependent sarcoma cell line. This image-profile-based approach could replace many customized labor- and resource-intensive screens and accelerate the discovery of biologically and therapeutically useful compounds.
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•Compounds impacting particular genes’ function are highly sought•Most chemicals and overexpressed genes impact cell morphology in the Cell Painting assay•Matching these image profiles can find chemicals that impact a particular gene’s function•This virtual screen using public data found new chemical regulators of several pathways
If a chemical compound and a gene overexpression yield the same cell morphology in the microscopy-based assay Cell Painting, then they are likely to impact the same functions. This principle is exploited to retrieve useful compounds for particular query genes in public Cell Painting datasets.
The Oxford Handbook of U.S. Health Law covers the breadth and depth of health law, with contributions from the most eminent scholars in the field. The Handbook paints with broad thematic strokes the ...major features of American healthcare law and policy, its recent reforms including the Affordable Care Act, its relationship to medical ethics and constitutional principles, how it compares to the experience of other countries, and the legal framework for the patient experience. This Handbook provides valuable content, accessible to readers new to the subject, as well as to those who write, teach, practice, or make policy in health law.
Two Ways to Be Complex and Why They Matter Conway, Lucian Gideon; Thoemmes, Felix; Allison, Amy M ...
Journal of personality and social psychology,
11/2008, Letnik:
95, Številka:
5
Journal Article
Recenzirano
Integrative complexity broadly measures the structural complexity of statements. This breadth, although beneficial in multiple ways, can potentially hamper the development of specific theories. In ...response, the authors developed a model of complex thinking, focusing on 2 different ways that people can be complex within the
integrative complexity
system and subsequently developed measurements of each of these 2 routes:
Dialectical complexity
focuses on a dialectical tension between 2 or more competing perspectives, whereas
elaborative complexity
focuses on complexly elaborating on 1 singular perspective. The authors posit that many variables have different effects on these 2 forms of complexity and subsequently test this idea in 2 different theoretical domains. In Studies 1a, 1b, and 2, the authors demonstrate that variables related to
attitude strength
(e.g., domain importance, extremism, domain accessibility) decrease dialectical complexity but increase elaborative complexity. In Study 3, the authors show that counterattitudinal lying decreases dialectical complexity but increases elaborative complexity, implicating a strategic (as opposed to a cognitive strain) view of the lying-complexity relationship. The authors argue that this dual demonstration across 2 different theoretical domains helps establish the utility of the new model and measurements as well as offer the potential to reconcile apparent conflicts in the area of cognitive complexity.
OBJECTIVE To explore the frequency of hand hygiene opportunities (HHOs) in multiple units of an acute-care hospital. DESIGN Prospective observational study. SETTING The adult intensive care unit ...(ICU), medical and surgical step-down units, medical and surgical units, and the postpartum mother-baby unit (MBU) of an academic acute-care hospital during May-August 2013, May-July 2014, and June-August 2015. PARTICIPANTS Healthcare workers (HCWs). METHODS HHOs were recorded using direct observation in 1-hour intervals following Public Health Ontario guidelines. The frequency and distribution of HHOs per patient hour were determined for each unit according to time of day, indication, and profession. RESULTS In total, 3,422 HHOs were identified during 586 hours of observation. The mean numbers of HHOs per patient hour in the ICU were similar to those in the medical and surgical step-down units during the day and night, which were higher than the rates observed in medical and surgical units and the MBU. The rate of HHOs during the night significantly decreased compared with day (P92% of HHOs on medical and surgical units, compared to 67% of HHOs on the MBU. CONCLUSIONS Assessment of hand hygiene compliance using product utilization data requires knowledge of the appropriate opportunities for hand hygiene. We have provided a detailed characterization of these estimates across a wide range of inpatient settings as well as an examination of temporal variations in HHOs. Infect Control Hosp Epidemiol 2017;38:411-416.
Small-molecule discovery typically involves large-scale screening campaigns, spanning multiple compound collections. However, such activities can be cost- or time-prohibitive, especially when using ...complex assay systems, limiting the number of compounds tested. Further, low hit rates can make the process inefficient. Sparse coverage of chemical structure or biological activity space can lead to limited success in a primary screen and represents a missed opportunity by virtue of selecting the “wrong” compounds to test. Thus, the choice of screening collections becomes of paramount importance. In this perspective, we discuss the utility of generating “informer sets” for small-molecule discovery, and how this strategy can be leveraged to prioritize probe candidates. While many researchers may assume that informer sets are focused on particular targets (e.g., kinases) or processes (e.g., autophagy), efforts to assemble informer sets based on historical bioactivity or successful human exposure (e.g., repurposing collections) have shown promise as well. Another method for generating informer sets is based on chemical structure, particularly when the compounds have unknown activities and targets. We describe our efforts to screen an informer set representing a collection of 100,000 small molecules synthesized through diversity-oriented synthesis (DOS). This process enables researchers to identify activity early and more extensively screen only a few chemical scaffolds, rather than the entire collection. This elegant and economic outcome is a goal of the informer set approach. Here, we aim not only to shed light on this process, but also to promote the use of informer sets more widely in small-molecule discovery projects.
Structural analyses of the compounds di-μ-acetato-κ
:
'-bis-{2-meth-oxy-
,
-bis-(quinolin-2-ylmeth-yl)ethanamine-κ
,
',
'',
manganese(II)} bis-(tetra-phen-yl-borate) di-chloro-methane 1.45-solvate, ...Mn
(C
O
)
(C
H
N
O)
(C
H
B)·1.45CH
Cl
or Mn(DQMEA)(μ-OAc)
Mn(DQMEA)(BPh
)
·1.45CH
Cl
or
(BPh
)
·1.45CH
Cl
, and (acetato-κ
)2-hy-droxy-
,
-bis(quinolin-2-ylmeth-yl)ethanamine-κ
,
',
'',
(methanol-κ
)manganese(II) tetra-phenyl-borate methanol monosolvate, Mn(CH
COO)(C
H
N
O)(CH
OH)(C
H
B)·CH
OH or Mn(DQEA)(OAc)(CH
OH)BPh
·CH
OH or
BPh
·CH
OH, by single-crystal X-ray diffraction reveal distinct differences in the geometry of coordination of the tripodal DQEA and DQMEA ligands to Mn
ions. In the asymmetric unit, compound
(BPh
)
·(CH
Cl
)
crystallizes as a dimer in which each manganese(II) center is coordinated by the central amine nitro-gen, the nitro-gen atom of each quinoline group, and the meth-oxy-oxygen of the tetra-dentate DQMEA ligand, and two bridging-acetate oxygen atoms. The symmetric Mn
centers have a distorted, octa-hedral geometry in which the quinoline nitro-gen atoms are
to each other resulting in co-planarity of the quinoline rings. For each Mn
center, a coordinated acetate oxygen participates in C-H⋯O hydrogen-bonding inter-actions with the two quinolyl moieties, further stabilizing the
structure. Within the crystal, weak
-
stacking inter-actions and inter-molecular cation-anion inter-actions stabilize the crystal packing. In the asymmetric unit, compound
BPh
·CH
OH crystallizes as a monomer in which the manganese(II) ion is coordinated to the central nitro-gen, the nitro-gen atom of each quinoline group, and the alcohol oxygen of the tetra-dentate DQEA ligand, an oxygen atom of OAc, and the oxygen atom of a methanol ligand. The geometry of the Mn
center in
BPh
·CH
OH is also a distorted octa-hedron, but the quinoline nitro-gen atoms are
to each other in this structure. Hydrogen bonding between the acetate oxygen atoms and hydroxyl (O-H⋯O) and quinolyl (C-H⋯O and N-H⋯O) moieties of the DQEA ligand stabilize the complex in this
configuration. Within the crystal, dimerization of complexes occurs by the formation of a pair of inter-molecular O3-H3⋯O2 hydrogen bonds between the coordinated hydroxyl oxygen of the DQEA ligand of one complex and an acetate oxygen of another. Additional hydrogen-bonding and inter-molecular cation-anion inter-actions contribute to the crystal packing.
The cross-disciplinary Oxford Handbook on the Science of Science Communication contains 47 essays by 57 leading scholars organized into six sections: The first section establishes the need for a ...science of science communication, provides an overview of the area, examines sources of science knowledge and the ways in which changing media structures affect it, reveals what the public thinks about science, and situates current scientific controversies in their historical contexts. The book’s second part examines challenges to science including difficulties in peer review, rising numbers of retractions, publication and statistical biases, and hype. Successes and failures in communicating about four controversies are the subject of Part III: “mad cow,” nanotechnology, biotechnology, and the HPV and HBV vaccines. The fourth section focuses on the ways in which elite intermediaries communicate science. These include the national academies, scholarly presses, government organizations, museums, foundations, and social networks. It examines as well scientific deliberation among citizens and science-based policymaking. In Part V, the handbook treats science media interactions, knowledge-based journalism, polarized media environments, popular images of science, and the portrayal of science in entertainment, narratives, and comedy. The final section identifies the ways in which human biases that can affect communicated science can be overcome. Biases include resistant misinformation, inadequate frames, biases in moral reasoning, confirmation and selective exposure biases, innumeracy, recency effects, fear of the unnatural, normalization, false causal attribution, and public difficulty in processing uncertainty. Each section of the book includes a thematic synthesis.
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