Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation.

There is evidence to suggest that increasing the level of saturation (that is, the number of sp3-hybridized carbon atoms) of small molecules can increase their likelihood of success in the drug discovery pipeline1. Owing to their favourable physical properties, alkylamines have become ubiquitous among pharmaceutical agents, small-molecule biological probes and pre-clinical candidates2. Despite their importance, the synthesis of amines is still dominated by two methods: N-alkylation and carbonyl reductive amination3. Therefore, the increasing demand for saturated polar molecules in drug discovery has continued to drive the development of practical catalytic methods for the synthesis of complex alkylamines4-7. In particular, processes that transform accessible feedstocks into sp3-rich architectures provide a strategic advantage in the synthesis of complex alkylamines. Here we report a multicomponent, reductive photocatalytic technology that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involves a visible-light-mediated reduction of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted α-amino radicals, which subsequently react with alkenes to form C(sp3)-C(sp3) bonds. The operationally straightforward reaction exhibits broad functional-group tolerance, facilitates the synthesis of drug-like amines that are not readily accessible by other methods and is amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochemical research

Great Bay Nitrogen Non-Point Source Study

The Great Bay Estuary is 21 square miles of tidal waters located in southeastern New Hampshire. It is one of 28 “estuaries of national significance” established under the Environmental Protection Agency’s National Estuary Program. The estuary is experiencing the signs of eutrophication, specifically, low dissolved oxygen, macroalgae blooms, and declining eelgrass habitat (DES, 2012). Sixty-eight percent of the nitrogen that ends up in the Great Bay Estuary originates from sources spread across the watershed; the remainder derives from direct discharges of municipal wastewater treatment facilities (DES, 2010; PREP, 2013). In this report, these sources of nitrogen are called non-point sources and consist of atmospheric deposition, fertilizers, human waste disposed into septic systems, and animal waste. The purpose of this study is to determine how much nitrogen each non-point source type contributes to the estuary. The nitrogen loads from municipal wastewater treatment facilities have been reported elsewhere (DES, 2010; PREP, 2012; PREP, 2013) and, therefore, are not included in this study except to provide context. The intended use of this study is for planning purposes, and is not meant for regulatory allocations or specific reduction requirements. The results of the model may be useful for towns or watershed groups for prioritizing nitrogen reduction efforts or as a starting point for more detailed studies of non-point sources. However, more detailed inventories of non-point sources will be needed to track the effects of nitrogen reduction efforts in smaller areas. In addition, the model makes no conclusions about the benefits of nitrogen reductions to receiving waters or overall estuarine health

TITAN Wireless Camera Control System

The Titan Camera Control System is an eletromechanical device that allows the user to wirelessly control a camera’s digital operations as well as physical orientation through the use of a mobile device application. The Titan system accepts input in the form of virtual user commands on the mobile app and performs system output in the form of sending photos/video from the camera back to the app as well as changing the orientation of the camera in accordance with the user’s commands

Cell origin-dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy.

In adult acute myeloid leukemia (AML), the acquisition of driver somatic mutations may be preceded by a benign state termed clonal hematopoiesis (CH). To develop therapeutic strategies to prevent leukemia development from CH, it is important to understand the mechanisms by which CH-driving and AML-driving mutations cooperate. Here, we use mice with inducible mutant alleles common in human CH (DNMT3AR882; mouse Dnmt3aR878H) and AML (NPM1c; mouse Npm1cA). We find that Dnmt3aR878H/+ hematopoietic stem cells (HSCs), but not multipotent progenitor cell (MPP) subsets, have reduced cytokine expression and proinflammatory transcriptional signatures and a functional competitive advantage over their wild-type counterparts. Dnmt3aR878H/+ HSCs are the most potent cell type transformed by Npm1cA, generating myeloid malignancies in which few additional cooperating somatic mutation events were detected. At a molecular level, Npm1cA, in cooperation with Dnmt3aR878H, acutely increased the accessibility of a distinct set of promoters in HSCs compared with MPP cells. These promoters were enriched for cell cycling, PI3K/AKT/mTOR signaling, stem cell signatures, and targets of transcription factors, including NFAT and the chromatin binding factor HMGB1, which have been implicated in human AML. These results demonstrate cooperativity between preexisting Dnmt3aR878H and Npm1cA at the chromatin level, where specific loci altered in accessibility by Npm1cA are dependent on cell context as well as Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention in the transformation from CH to AML

Impacts of active school design on schooltime sedentary behavior and physical activity: A pilot natural experiment

Background Children spend a significant portion of their days in sedentary behavior (SB) and on average fail to engage in adequate physical activity (PA). The school built environment may influence SB and PA, but research is limited. This natural experiment evaluated whether an elementary school designed to promote movement impacted students\u27 school-time SB and PA. Methods Accelerometers measured SB and PA at pre and post time-points in an intervention group who moved to the new school (n = 21) and in a comparison group experiencing no school environmental change (n = 20). Difference-in-difference (DD) analysis examined SB and PA outcomes in these groups. Measures were also collected post-intervention from an independent, grade-matched group of students in the new school (n = 21). Results As expected, maturational increases in SB were observed. However, DD analysis estimated that the intervention attenuated increase in SB by 81.2 ± 11.4 minutes/day (p\u3c0.001), controlling for time in moderate to vigorous physical activity (MVPA). The intervention was also estimated to increase daily number of breaks from SB by 23.4 ± 2.6 (p \u3c .001) and to increase light physical activity (LPA) by 67.7 ± 10.7 minutes/day (p\u3c0.001). However, the intervention decreased MVPA by 10.3 ± 2.3 minutes/day (p\u3c0.001). Results of gradematched independent samples analysis were similar, with students in the new vs. old school spending 90.5 ± 16.1 fewer minutes/day in SB, taking 21.1 ± 2.7 more breaks from SB (p\u3c0.001), and spending 64.5 ± 14.8 more minutes in LPA (p\u3c0.001), controlling for time in MVPA. Students in the new school spent 13.1 ± 2.7 fewer minutes in MVPA (p\u3c0.001) than their counterparts in the old school. Conclusions This pilot study found that active school design had beneficial effects on SB and LPA, but not on MVPA. Mixed results point to a need for active classroom design strategies to mitigate SB, and quick access from classrooms to areas permissive of high-intensity activities to promote MVPA. Integrating active design with programs/policies to promote PA may yield greatest impact on PA of all intensities

Distinct tumor necrosis factor alpha receptors dictate stem cell fitness versus lineage output in Dnmt3a-mutant clonal hematopoiesis

UNLABELLED: Clonal hematopoiesis resulting from the enhanced fitness of mutant hematopoietic stem cells (HSC) associates with both favorable and unfavorable health outcomes related to the types of mature mutant blood cells produced, but how this lineage output is regulated is unclear. Using a mouse model of a clonal hematopoiesis-associated mutation, DNMT3AR882/+ (Dnmt3aR878H/+), we found that aging-induced TNFα signaling promoted the selective advantage of mutant HSCs and stimulated the production of mutant B lymphoid cells. The genetic loss of the TNFα receptor TNFR1 ablated the selective advantage of mutant HSCs without altering their lineage output, whereas the loss of TNFR2 resulted in the overproduction of mutant myeloid cells without altering HSC fitness. These results nominate TNFR1 as a target to reduce clonal hematopoiesis and the risk of associated diseases and support a model in which clone size and mature blood lineage production can be independently controlled to modulate favorable and unfavorable clonal hematopoiesis outcomes. SIGNIFICANCE: Through the identification and dissection of TNFα signaling as a key driver of murine Dnmt3a-mutant hematopoiesis, we report the discovery that clone size and production of specific mature blood cell types can be independently regulated. See related commentary by Niño and Pietras, p. 2724. This article is highlighted in the In This Issue feature, p. 2711

Variation in histone configurations correlates with gene expression across nine inbred strains of mice.

The diversity outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression, and as such are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), and DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represented a distinct combination of the four histone modifications. We found that the epigenetic landscape was highly variable across the DO founders and was associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice

Comparison of Teen Driver Fatality Rates by Vehicle Type in the United States

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74622/1/j.aem.2007.06.038.pd

Catalytic C(sp3)-H bond activation in tertiary alkylamines.

The development of robust catalytic methods to assemble tertiary alkylamines provides a continual challenge to chemical synthesis. In this regard, transformation of a traditionally unreactive C-H bond, proximal to the nitrogen atom, into a versatile chemical entity would be a powerful strategy for introducing functional complexity to tertiary alkylamines. A practical and selective metal-catalysed C(sp3)-H activation facilitated by the tertiary alkylamine functionality, however, remains an unsolved problem. Here, we report a Pd(II)-catalysed protocol that appends arene feedstocks to tertiary alkylamines via C(sp3)-H functionalization. A simple ligand for Pd(II) orchestrates the C-H activation step in favour of deleterious pathways. The reaction can use both simple and complex starting materials to produce a range of multifaceted γ-aryl tertiary alkylamines and can be rendered enantioselective. The enabling features of this transformation should be attractive to practitioners of synthetic and medicinal chemistry as well as in other areas that use biologically active alkylamines

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas