Electromagnetically induced transparency with resonant nuclei in a cavity

The manipulation of light-matter interactions by quantum control of atomic levels has had a profound impact on optical sciences. Such manipulation has many applications, including nonlinear optics at the few-photon level, slow light, lasing without inversion and optical quantum information processing. The critical underlying technique is electromagnetically induced transparency, in which quantum interference between transitions in multilevel atoms renders an opaque medium transparent near an atomic resonance. With the advent of high-brilliance, accelerator-driven light sources such as storage rings or X-ray lasers, it has become attractive to extend the techniques of optical quantum control to the X-ray regime. Here we demonstrate electromagnetically induced transparency in the regime of hard X-rays, using the 14.4-kiloelectronvolt nuclear resonance of the M?ssbauer isotope iron-57 (a two-level system). We exploit cooperative emission from ensembles of the nuclei, which are embedded in a low-finesse cavity and excited by synchrotron radiation. The spatial modulation of the photonic density of states in a cavity mode leads to the coexistence of superradiant and subradiant states of nuclei, respectively located at an antinode and a node of the cavity field. This scheme causes the nuclei to behave as effective three-level systems, with two degenerate levels in the excited state (one of which can be considered metastable). The radiative coupling of the nuclear ensembles by the cavity field establishes the atomic coherence necessary for the cancellation of resonant absorption. Because this technique does not require atomic systems with a metastable level, electromagnetically induced transparency and its applications can be transferred to the regime of nuclear resonances, establishing the field of nuclear quantum optics.     

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis

Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.     

Pluripotency of spermatogonial stem cells from adult mouse testis

Embryonic germ cells as well as germline stem cells from neonatal mouse testis are pluripotent and have differentiation potential similar to embryonic stem cells, suggesting that the germline lineage may retain the ability to generate pluripotent cells. However, until now there has been no evidence for the pluripotency and plasticity of adult spermatogonial stem cells (SSCs), which are responsible for maintaining spermatogenesis throughout life in the male. Here we show the isolation of SSCs from adult mouse testis using genetic selection, with a success rate of 27%. These isolated SSCs respond to culture conditions and acquire embryonic stem cell properties. We name these cells multipotent adult germline stem cells (maGSCs). They are able to spontaneously differentiate into derivatives of the three embryonic germ layers in vitro and generate teratomas in immunodeficient mice. When injected into an early blastocyst, SSCs contribute to the development of various organs and show germline transmission. Thus, the capacity to form multipotent cells persists in adult mouse testis. Establishment of human maGSCs from testicular biopsies may allow individual cell-based therapy without the ethical and immunological problems associated with human embryonic stem cells. Furthermore, these cells may provide new opportunities to study genetic diseases in various cell lineages.     

A gene expression map of human chromosome 21 orthologues in the mouse

The DNA sequence of human chromosome 21 (HSA21) has opened the route for a systematic molecular characterization of all of its genes. Trisomy 21 is associated with Down's syndrome, the most common genetic cause of mental retardation in humans. The phenotype includes various organ dysmorphies, stereotypic craniofacial anomalies and brain malformations. Molecular analysis of congenital aneuploidies poses a particular challenge because the aneuploid region contains many protein-coding genes whose function is unknown. One essential step towards understanding their function is to analyse mRNA expression patterns at key stages of organism development. Seminal works in flies, frogs and mice showed that genes whose expression is restricted spatially and/or temporally are often linked with specific ontogenic processes. Here we describe expression profiles of mouse orthologues to HSA21 genes by a combination of large-scale mRNA in situ hybridization at critical stages of embryonic and brain development and in silico (computed) mining of expressed sequence tags. This chromosome-scale expression annotation associates many of the genes tested with a potential biological role and suggests candidates for the pathogenesis of Down's syndrome.     

Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors

The citric acid cycle is central to the regulation of energy homeostasis and cell metabolism. Mutations in enzymes that catalyse steps in the citric acid cycle result in human diseases with various clinical presentations. The intermediates of the citric acid cycle are present at micromolar concentration in blood and are regulated by respiration, metabolism and renal reabsorption/extrusion. Here we show that GPR91 (ref. 3), a previously orphan G-protein-coupled receptor (GPCR), functions as a receptor for the citric acid cycle intermediate succinate. We also report that GPR99 (ref. 4), a close relative of GPR91, responds to alpha-ketoglutarate, another intermediate in the citric acid cycle. Thus by acting as ligands for GPCRs, succinate and alpha-ketoglutarate are found to have unexpected signalling functions beyond their traditional roles. Furthermore, we show that succinate increases blood pressure in animals. The succinate-induced hypertensive effect involves the renin-angiotensin system and is abolished in GPR91-deficient mice. Our results indicate a possible role for GPR91 in renovascular hypertension, a disease closely linked to atherosclerosis, diabetes and renal failure.     

Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase

In higher organisms the formation of the steroid scaffold is catalysed exclusively by the membrane-bound oxidosqualene cyclase (OSC; lanosterol synthase). In a highly selective cyclization reaction OSC forms lanosterol with seven chiral centres starting from the linear substrate 2,3-oxidosqualene. Valuable data on the mechanism of the complex cyclization cascade have been collected during the past 50 years using suicide inhibitors, mutagenesis studies and homology modelling. Nevertheless it is still not fully understood how the enzyme catalyses the reaction. Because of the decisive role of OSC in cholesterol biosynthesis it represents a target for the discovery of novel anticholesteraemic drugs that could complement the widely used statins. Here we present two crystal structures of the human membrane protein OSC: the target protein with an inhibitor that showed cholesterol lowering in vivo opens the way for the structure-based design of new OSC inhibitors. The complex with the reaction product lanosterol gives a clear picture of the way in which the enzyme achieves product specificity in this highly exothermic cyclization reaction.     

基于电阻器耦合的电动汽车感应充电定位

目前,市场上出现越来越多的以电池为动力的电动汽车,其中大多数电动汽车必须通过有线充电装置进行充电。与之相对应的感应式无线充电系统,可以让充电过程更加舒适。无线充电系统一般由初级线圈和次级线圈组成,其中初级线圈可以建立在停车场,将电能转化为场能;次级线圈安装在车辆中,接收初级线圈能量并转化为电能,为车辆电池充电。为保证充电过程安全有效,初级线圈和次级线圈必须充分耦合,这可通过将车辆准确定位在初级线圈上方来实现。本文提出了一种简单而经济的方法来验证线圈之间的耦合是否足以满足充电条件。通过安装在次级线圈侧的电阻,来模拟在确定工作条件下无线充电系统的电池负载;电阻两端电压可以用来估计线圈之间的耦合度,以反映车辆与初级线圈的相对位置。本文在数学和物理原理的基础上解释了这个概念,并在一个真实的无线电传输线路上进行了试验评估。     

KIF5C, a kinesin motor involved in apical trafficking of MDCK cells

Polarized traffic in epithelial cells depends on well-organized pathways that direct secretory cargo to the apical or basolateral plasma membrane. In MDCK cells, apical trafficking can be further divided into a lipid raft-dependent and a raft-independent route, which separate biosynthetic cargo in a post-Golgi endosomal compartment. We have now identified KIF5C as a kinesin motor for apical trafficking of both raft-associated sucrase isomaltase and raft-independent neurotrophin receptor. KIF5C was identified by mass spectrometry in vesicle enriched fractions and on immunoisolated post-Golgi vesicles carrying apical cargo. The amount of vesicle-associated KIF5C was highest on material isolated directly after trans-Golgi network release and declined thereafter. Altogether, our data suggest that KIF5C is involved in the passage of apical cargo molecules to a post-Golgi endosomal compartment, where further segregation into distinct vesicle populations proceeds.