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Nearest neighbours reveal fast and slow components of motor learning 期刊论文
NATURE, 2020, 577 (7791) : 526-+
作者:  Kollmorgen, Sepp;  Hahnloser, Richard H. R.;  Mante, Valerio
收藏  |  浏览/下载:28/0  |  提交时间:2020/07/03

A new method for analysing change in high-dimensional data is based on nearest-neighbour statistics and is applied here to song dynamics during vocal learning in zebra finches, but could potentially be applied to other biological and artificial behaviours.


Changes in behaviour resulting from environmental influences, development and learning(1-5) are commonly quantified on the basis of a few hand-picked features(2-4,6,7) (for example, the average pitch of acoustic vocalizations(3)), assuming discrete classes of behaviours (such as distinct vocal syllables)(2,3,8-10). However, such methods generalize poorly across different behaviours and model systems and may miss important components of change. Here we present a more-general account of behavioural change that is based on nearest-neighbour statistics(11-13), and apply it to song development in a songbird, the zebra finch(3). First, we introduce the concept of '  repertoire dating'  , whereby each rendition of a behaviour (for example, each vocalization) is assigned a repertoire time, reflecting when similar renditions were typical in the behavioural repertoire. Repertoire time isolates the components of vocal variability that are congruent with long-term changes due to vocal learning and development, and stratifies the behavioural repertoire into '  regressions'  , '  anticipations'  and '  typical renditions'  . Second, we obtain a holistic, yet low-dimensional, description of vocal change in terms of a stratified '  behavioural trajectory'  , revealing numerous previously unrecognized components of behavioural change on fast and slow timescales, as well as distinct patterns of overnight consolidation(1,2,4,14,15) across the behavioral repertoire. We find that diurnal changes in regressions undergo only weak consolidation, whereas anticipations and typical renditions consolidate fully. Because of its generality, our nonparametric description of how behaviour evolves relative to itself-rather than to a potentially arbitrary, experimenter-defined goal(2,3,14,16)-appears well suited for comparing learning and change across behaviours and species(17,18), as well as biological and artificial systems(5).


  
Late-stage oxidative C(sp(3))-H methylation 期刊论文
NATURE, 2020, 580 (7805) : 621-+
作者:  Fessler, Evelyn;  Eckl, Eva-Maria;  Schmitt, Sabine;  Mancilla, Igor Alves;  Meyer-Bender, Matthias F.;  Hanf, Monika;  Philippou-Massier, Julia;  Krebs, Stefan;  Zischka, Hans;  Jae, Lucas T.
收藏  |  浏览/下载:85/0  |  提交时间:2020/07/03

Frequently referred to as the '  magic methyl effect'  , the installation of methyl groups-especially adjacent (alpha) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules(1-3). However, existing methylation methods show limited scope and have not been demonstrated in complex settings(1). Here we report a regioselective and chemoselective oxidative C(sp(3))-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp(3))-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.


A manganese-catalysed oxidative C(sp(3))-H methylation method allows a methyl group to be selectively installed into medicinally important heterocycles, providing a way to improve pharmaceuticals and better understand the '  magic methyl effect'  .


  
Integrating Bayesian Groundwater Mixing Modeling With On-Site Helium Analysis to Identify Unknown Water Sources 期刊论文
WATER RESOURCES RESEARCH, 2019, 55 (12) : 10602-10615
作者:  Popp, Andrea L.;  Scheidegger, Andreas;  Moeck, Christian;  Brennwald, Matthias S.;  Kipfer, Rolf
收藏  |  浏览/下载:19/0  |  提交时间:2020/02/16
groundwater mixing  Baysian mixing modeling  new tracer methods  end-member mixing  helium  conceptual model  
A quality control approach to better characterize the spatial distribution of snow depth over New Brunswick, Canada 期刊论文
INTERNATIONAL JOURNAL OF CLIMATOLOGY, 2019, 39 (14) : 5470-5485
作者:  Baronetti, Alice;  Fratianni, Simona;  Acquaotta, Fiorella;  Fortin, Guillaume
收藏  |  浏览/下载:31/0  |  提交时间:2020/02/17
climate  geostatistical methods  New Brunswick  quality control  snow depth  
Changing character of rainfall in eastern China, 1951-2007 期刊论文
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115 (9) : 2016-2021
作者:  Day, Jesse A.;  Fung, Inez;  Liu, Weihan
收藏  |  浏览/下载:27/0  |  提交时间:2019/11/27
East Asian monsoon  monsoons  rainfall  Meiyu front  new methods