2,952 research outputs found
Mass rigidity for hyperbolic manifolds
We prove the rigidity of positive mass theorem for asymptotically hyperbolic
manifolds. Namely, if the mass equality holds, then the manifold is isometric
to hyperbolic space. The result was previously proven for spin manifolds or
under special asymptotics.Comment: Appeared in Comm. Math. Phy
Improved contact prediction in proteins: Using pseudolikelihoods to infer Potts models
Spatially proximate amino acids in a protein tend to coevolve. A protein's
three-dimensional (3D) structure hence leaves an echo of correlations in the
evolutionary record. Reverse engineering 3D structures from such correlations
is an open problem in structural biology, pursued with increasing vigor as more
and more protein sequences continue to fill the data banks. Within this task
lies a statistical inference problem, rooted in the following: correlation
between two sites in a protein sequence can arise from firsthand interaction
but can also be network-propagated via intermediate sites; observed correlation
is not enough to guarantee proximity. To separate direct from indirect
interactions is an instance of the general problem of inverse statistical
mechanics, where the task is to learn model parameters (fields, couplings) from
observables (magnetizations, correlations, samples) in large systems. In the
context of protein sequences, the approach has been referred to as
direct-coupling analysis. Here we show that the pseudolikelihood method,
applied to 21-state Potts models describing the statistical properties of
families of evolutionarily related proteins, significantly outperforms existing
approaches to the direct-coupling analysis, the latter being based on standard
mean-field techniques. This improved performance also relies on a modified
score for the coupling strength. The results are verified using known crystal
structures of specific sequence instances of various protein families. Code
implementing the new method can be found at http://plmdca.csc.kth.se/.Comment: 19 pages, 16 figures, published versio
Identification and characterization of an irreversible inhibitor of CDK2
Irreversible inhibitors that modify cysteine or lysine
residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)-
9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal
structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds
An in vitro alveolar macrophage assay for predicting the short-term inhalation toxicity of nanomaterials
Additional file 1: Table S1. Comparison of significant in vitro LOAECs (significant as compared to the negative benchmark material corundum) to NOAECs and LOAECs recorded in rat STISs. Table S2. Bioactivity of four types of CeO2 NMs in rat STISs as compared to cellular effects recorded in the in vitro NR8383 AM assay
Total Synthesis of (±)-Crinane from 6,6-Dibromobicyclo[3.1.0]hexane Using a 5- exo- trig Radical Cyclization Reaction to Assemble the C3a-Arylated Perhydroindole Substructure
Crinane embodies the tetracyclic framework associated with some of the most common Amaryllidaceae alkaloids. It has now been prepared in 10 steps from 6,6-dibromobicyclo[3.1.0]hexane (2). The initial step involves the thermally induced electrocyclic ring opening of cyclopropane 3 and capture of the resulting π-allyl cation with benzylamine to give an allylic amine that is readily elaborated to the 3°-amine 10. This last compound was engaged in a 5-exo-trig free radical cyclization reaction to give the C3a-arylated perhydroindole 11. Compound 11 was then converted, over two steps, into (±)-crinane, the hydrochloride salt of which has been subjected to single-crystal X-ray analysis.The authors thank the Australian Research Council, the
Institute of Advanced Studies at the Australian National
University, Jinan University, the Pearl River Scholar Program
of Guangdong Province, and the Famous Foreign Supervisor
Program (grant 2018-HWMS001) of the Ministry of
Education, People’s Republic of China, for financial support
Application of Electrocyclic Ring-Opening and Desymmetrizing Nucleophilic Trappings of meso-6,6-Dibromobicyclo[3.1.0]hexanes to Total Syntheses of Crinine and Haemanthamine Alkaloids
The thermally induced electrocyclic ring-opening of C2-symmetric (meso) 6,6-dibromobicyclo[3.1.0]hexanes such as 10 in the presence of the chiral, nonracemic 1°-amine 28 afforded a ca. 1:1 mixture of the diastereoisomeric and chromatographically separable 1-amino-2-bromo-2-cyclohexenes 37 (42%) and 38 (45%). Each of these was elaborated over 13 steps, including Suzuki–Miyaura cross-coupling, radical cyclization, and Pictet–Spengler reactions, into (−)- or (+)-crinane (1 or ent-1, respectively). Variations on these protocols were applied to the total syntheses of (+)- and (−)-11-hydroxyvattitine [(+)- and (−)-3], (+)- and (−)-bulbispermine [(+)- and (−)-4], (+)- and (−)-haemanthamine [(+)- and (−)-5], (+)- and (−)-pretazettine [(+)- and (−)-6], and (+)- and (−)-tazettine [(+)- and (−)-7] as well as (±)-hamayne [(±)-8] and (±)-apohaemanthamine [(±)-9]. A number of these alkaloids were synthesized for the first time.We are grateful to the Chinese National Natural Science Foundation (Grant 21801094), the Pearl River Scholar Program of Guangdong Province, The Institute of Advanced Studies, The Australian Research Council, and the Famous Foreign Supervisor Program (Grant 2018-HWMS001) of the Ministry of Education, People’s Republic of China, for financial support
Cortical gray and subcortical white matter associations in Parkinson's disease
Cortical atrophy has been documented in both Parkinson’s disease (PD) and healthy aging, but its relationship to changes in subcortical white matter is unknown. This was investigated by obtaining T1- and diffusion-weighted images from 76 PD and 70 controls at baseline, 18-, and 36-months, from which cortical volumes and underlying subcortical white matter axial (AD), radial (RD) diffusivities, and fractional anisotropy (FA) were determined. Twelve of 69 cortical subregions had significant group differences, and for these underlying subcortical white matter was explored. At baseline, higher cortical volumes were significantly correlated with lower underlying subcortical white matter AD, RD, and higher FA (Ps ≤0.017) in PD. Longitudinally, higher rates of cortical atrophy in PD were associated with increased rates of change in AD RD, and FA values (Ps ≤ 0.0013) in two subregions explored. The significant gray-white matter associations were not found in controls. Thus, unlike healthy aging, cortical atrophy and subcortical white matter changes may not be independent events in PD
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