Nature

The synthesis of complex organic compounds usually relies on controlling the reactions of the functional groups. In recent years, it has become possible to carry out reactions directly on the C–H bonds, previously considered to be unreactive. One of the major challenges is to control the site-selectivity because most organic compounds have many similar C–H bonds. The most well developed procedures so far rely on the use of substrate control, in which the substrate has one inherently more reactive C–H bond or contains a directing group or the reaction is conducted intramolecularly so that a specific C–H bond is favoured. A more versatile but more challenging approach is to use catalysts to control which site in the substrate is functionalized. p450 enzymes exhibit C–H oxidation site-selectivity, in which the enzyme scaffold causes a specific C–H bond to be functionalized by placing it close to the iron–oxo haem complex. Several studies have aimed to emulate this enzymatic site-selectivity with designed transition-metal catalysts but it is difficult to achieve exceptionally high levels of site-selectivity. Recently, we reported a dirhodium catalyst for the site-selective functionalization of the most accessible non-activated (that is, not next to a functional group) secondary C–H bonds by means of rhodium-carbene-induced C–H insertion. Here we describe another dirhodium catalyst that has a very different reactivity profile. Instead of the secondary C–H bond, the new catalyst is capable of precise site-selectivity at the most accessible tertiary C–H bonds. Using this catalyst, we modify several natural products, including steroids and a vitamin E derivative, indicating the applicability of this method of synthesis to the late-stage functionalization of complex molecules. These studies show it is possible to achieve site-selectivity at different positions within a substrate simply by selecting the appropriate catalyst. We hope that this work will inspire the design of even more sophisticated catalysts, such that catalyst-controlled C–H functionalization becomes a broadly applied strategy for the synthesis of complex molecules.

Categories: Literature

Exoplanet hunters rethink search for alien life

Mon, 11/20/2017 - 01:00

Exoplanet hunters rethink search for alien life

Nature 551, 7681 (2017). http://www.nature.com/doifinder/10.1038/nature.2017.23023

Author: Alexandra Witze

Astronomers expand ideas of how chemistry and geology could affect chances for life on other worlds.

Categories: Literature

Online software spots genetic errors in cancer papers

Mon, 11/20/2017 - 01:00

Online software spots genetic errors in cancer papers

Nature 551, 7681 (2017). http://www.nature.com/doifinder/10.1038/nature.2017.23003

Author: Nicky Phillips

Tool to scrutinize research papers identifies mistakes in gene sequences.

Categories: Literature

Giant telescope’s mobile-phone ‘dead zones’ rile South African residents

Fri, 11/17/2017 - 01:00

Giant telescope’s mobile-phone ‘dead zones’ rile South African residents

Nature 551, 7681 (2017). http://www.nature.com/doifinder/10.1038/nature.2017.22998

Author: Sarah Wild

Sensitive radio dishes of the Square Kilometre Array will affect phone reception — and could harm local economies, say farmers.

Categories: Literature

Improved diagnostics fail to halt the rise of tuberculosis

Thu, 11/16/2017 - 01:00

Improved diagnostics fail to halt the rise of tuberculosis

Nature 551, 7681 (2017). http://www.nature.com/doifinder/10.1038/nature.2017.23000

Author: Ewen Callaway

TB remains a big killer despite the development of a better test for detecting the disease.

Categories: Literature

Cancer immunotherapy: The dark side of PD-1 receptor inhibition

Wed, 11/15/2017 - 01:00

Cancer immunotherapy: The dark side of PD-1 receptor inhibition

Nature 552, 7683 (2017). doi:10.1038/nature24759

Authors: Aya Ludin & Leonard I. Zon

Inhibiting the protein PD-1 can activate T cells that trigger immune responses against tumour cells. But it emerges that, in mice, this immunotherapy exacerbates a cancer that involves the T cells themselves. See Letter p.121

Categories: Literature

PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis

Wed, 11/15/2017 - 01:00

PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis

Nature 552, 7683 (2017). doi:10.1038/nature24649

Authors: Tim Wartewig, Zsuzsanna Kurgyis, Selina Keppler, Konstanze Pechloff, Erik Hameister, Rupert Öllinger, Roman Maresch, Thorsten Buch, Katja Steiger, Christof Winter, Roland Rad & Jürgen Ruland

T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events. Here we show that the acute enforcement of oncogenic TCR signalling in lymphocytes in a mouse model of human T cell lymphoma drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor programmed death-1 (PD-1), as a master gene that suppresses oncogenic T cell signalling. Mono- and bi-allelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD-1 enhances levels of the tumour suppressor PTEN and attenuates signalling by the kinases AKT and PKC in pre-malignant cells. By contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation, and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology.

Categories: Literature

Microbiota: A high-pressure situation for bacteria

Wed, 11/15/2017 - 01:00

Microbiota: A high-pressure situation for bacteria

Nature 551, 7682 (2017). doi:10.1038/nature24760

Author: David A. Relman

Analyses in mice suggest that dietary salt increases blood pressure partly by affecting some of the microbes that inhabit the gut. The implications of this work for hypertension warrant further study in humans. See Article p.585

Categories: Literature

Archaeology: Inequality has deep roots in Eurasia

Wed, 11/15/2017 - 01:00

Archaeology: Inequality has deep roots in Eurasia

Nature 551, 7682 (2017). doi:10.1038/nature24758

Author: Michelle Elliott

A study of 64 archaeological sites across four continents shows that the growth of agricultural and political systems provoked economic disparities, more so in Eurasia than in North America. See Letter p.619

Categories: Literature

Salt-responsive gut commensal modulates TH17 axis and disease

Wed, 11/15/2017 - 01:00

Salt-responsive gut commensal modulates TH17 axis and disease

Nature 551, 7682 (2017). doi:10.1038/nature24628

Authors: Nicola Wilck, Mariana G. Matus, Sean M. Kearney, Scott W. Olesen, Kristoffer Forslund, Hendrik Bartolomaeus, Stefanie Haase, Anja Mähler, András Balogh, Lajos Markó, Olga Vvedenskaya, Friedrich H. Kleiner, Dmitry Tsvetkov, Lars Klug, Paul I. Costea, Shinichi Sunagawa, Lisa Maier, Natalia Rakova, Valentin Schatz, Patrick Neubert, Christian Frätzer, Alexander Krannich, Maik Gollasch, Diana A. Grohme, Beatriz F. Côrte-Real, Roman G. Gerlach, Marijana Basic, Athanasios Typas, Chuan Wu, Jens M. Titze, Jonathan Jantsch, Michael Boschmann, Ralf Dechend, Markus Kleinewietfeld, Stefan Kempa, Peer Bork, Ralf A. Linker, Eric J. Alm & Dominik N. Müller

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota;

Categories: Literature

Greater post-Neolithic wealth disparities in Eurasia than in North America and Mesoamerica

Wed, 11/15/2017 - 01:00

Greater post-Neolithic wealth disparities in Eurasia than in North America and Mesoamerica

Nature 551, 7682 (2017). doi:10.1038/nature24646

Authors: Timothy A. Kohler, Michael E. Smith, Amy Bogaard, Gary M. Feinman, Christian E. Peterson, Alleen Betzenhauser, Matthew Pailes, Elizabeth C. Stone, Anna Marie Prentiss, Timothy J. Dennehy, Laura J. Ellyson, Linda M. Nicholas, Ronald K. Faulseit, Amy Styring, Jade Whitlam, Mattia Fochesato, Thomas A. Foor & Samuel Bowles

How wealth is distributed among households provides insight into the fundamental characters of societies and the opportunities they afford for social mobility. However, economic inequality has been hard to study in ancient societies for which we do not have written records, which adds to the challenge of placing current wealth disparities into a long-term perspective. Although various archaeological proxies for wealth, such as burial goods or exotic or expensive-to-manufacture goods in household assemblages, have been proposed, the first is not clearly connected with households, and the second is confounded by abandonment mode and other factors. As a result, numerous questions remain concerning the growth of wealth disparities, including their connection to the development of domesticated plants and animals and to increases in sociopolitical scale. Here we show that wealth disparities generally increased with the domestication of plants and animals and with increased sociopolitical scale, using Gini coefficients computed over the single consistent proxy of house-size distributions. However, unexpected differences in the responses of societies to these factors in North America and Mesoamerica, and in Eurasia, became evident after the end of the Neolithic period. We argue that the generally higher wealth disparities identified in post-Neolithic Eurasia were initially due to the greater availability of large mammals that could be domesticated, because they allowed more profitable agricultural extensification, and also eventually led to the development of a mounted warrior elite able to expand polities (political units that cohere via identity, ability to mobilize resources, or governance) to sizes that were not possible in North America and Mesoamerica before the arrival of Europeans. We anticipate that this analysis will stimulate other work to enlarge this sample to include societies in South America, Africa, South Asia and Oceania that were under-sampled or not included in this study.

Categories: Literature

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