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181.
IRS-2 pathways integrate female reproduction and energy homeostasis 总被引:22,自引:0,他引:22
Burks DJ Font de Mora J Schubert M Withers DJ Myers MG Towery HH Altamuro SL Flint CL White MF 《Nature》2000,407(6802):377-382
Severe dietary restriction, catabolic states and even short-term caloric deprivation impair fertility in mammals. Likewise, obesity is associated with infertile conditions such as polycystic ovary syndrome. The reproductive status of lower organisms such as Caenorhabditis elegans is also modulated by availability of nutrients. Thus, fertility requires the integration of reproductive and metabolic signals. Here we show that deletion of insulin receptor substrate-2 (IRS-2), a component of the insulin/insulin-like growth factor-1 signalling cascade, causes female infertility. Mice lacking IRS-2 have small, anovulatory ovaries with reduced numbers of follicles. Plasma concentrations of luteinizing hormone, prolactin and sex steroids are low in these animals. Pituitaries are decreased in size and contain reduced numbers of gonadotrophs. Females lacking IRS-2 have increased food intake and obesity, despite elevated levels of leptin. Our findings indicate that insulin, together with leptin and other neuropeptides, may modulate hypothalamic control of appetite and reproductive endocrinology. Coupled with findings on the role of insulin-signalling pathways in the regulation of fertility, metabolism and longevity in C. elegans and Drosophila, we have identified an evolutionarily conserved mechanism in mammals that regulates both reproduction and energy homeostasis. 相似文献
182.
Barton ES White DW Cathelyn JS Brett-McClellan KA Engle M Diamond MS Miller VL Virgin HW 《Nature》2007,447(7142):326-329
All humans become infected with multiple herpesviruses during childhood. After clearance of acute infection, herpesviruses enter a dormant state known as latency. Latency persists for the life of the host and is presumed to be parasitic, as it leaves the individual at risk for subsequent viral reactivation and disease. Here we show that herpesvirus latency also confers a surprising benefit to the host. Mice latently infected with either murine gammaherpesvirus 68 or murine cytomegalovirus, which are genetically highly similar to the human pathogens Epstein-Barr virus and human cytomegalovirus, respectively, are resistant to infection with the bacterial pathogens Listeria monocytogenes and Yersinia pestis. Latency-induced protection is not antigen specific but involves prolonged production of the antiviral cytokine interferon-gamma and systemic activation of macrophages. Latency thereby upregulates the basal activation state of innate immunity against subsequent infections. We speculate that herpesvirus latency may also sculpt the immune response to self and environmental antigens through establishment of a polarized cytokine environment. Thus, whereas the immune evasion capabilities and lifelong persistence of herpesviruses are commonly viewed as solely pathogenic, our data suggest that latency is a symbiotic relationship with immune benefits for the host. 相似文献
183.
The realization of an entangled photon source will be of great importance in quantum information--for example, for quantum key distribution and quantum computation--and Stevenson et al. have described such a source. However, we show here that first, their source is not entangled; second, they use inappropriate entanglement indicators that rely on assumptions invalidated by their data; and third, their source has insignificant entanglement even after simulating subtraction of the significant quantity of background noise. We therefore find that the standard of proof required for a semiconductor source of triggered entangled photon pairs has not been met by Stevenson et al.. 相似文献
184.
遗传标准化的近交系啮齿类动物体系已有较好的描述.由于生物医学研究的国际化,各国的实验动物供应商应对一般常用的非近交系毒理学动物模型如Sprague Dawley及Hanover Wistar大鼠种系等进行全球标准化.本文描述该类繁育体系,即国际生物医学研究机构采用的Crl:CD(R)(SD)IGSBR和Crl:WI(GLX/BRL/Han/IGS)BR大鼠的国际遗传学标准体系(IGS). 相似文献
185.
Kamel Khalili Martyn K. White Jeffrey M. Jacobson 《Cellular and molecular life sciences : CMLS》2017,74(13):2439-2450
HIV/AIDS remains a major public health issue. In 2014, it was estimated that 36.9 million people are living with HIV worldwide, including 2.6 million children. Since the advent of combination antiretroviral therapy (cART), in the 1990s, treatment has been so successful that in many parts of the world, HIV has become a chronic condition in which progression to AIDS has become increasingly rare. However, while people with HIV can expect to live a normal life span with cART, lifelong medication is required and cardiovascular, renal, liver, and neurologic diseases are still possible, which continues to prompt research for a cure for HIV. Infected reservoir cells, such as CD4+?T cells and myeloid cells, allow persistence of HIV as an integrated DNA provirus and serve as a potential source for the re-emergence of virus. Attempts to eradicate HIV from these cells have focused mainly on the so-called “shock and kill” approach, where cellular reactivation is induced so as to trigger the purging of virus-producing cells by cytolysis or immune attack. This approach has several limitations and its usefulness in clinical applications remains to be assessed. Recent advances in gene-editing technology have allowed the use of this approach for inactivating integrated proviral DNA in the genome of latently infected cells or knocking out HIV receptors. Here, we review this strategy and its potential to eliminate the latent HIV reservoir resulting in a sterile cure of AIDS. 相似文献
186.
Feng JQ Ward LM Liu S Lu Y Xie Y Yuan B Yu X Rauch F Davis SI Zhang S Rios H Drezner MK Quarles LD Bonewald LF White KE 《Nature genetics》2006,38(11):1310-1315
The osteocyte, a terminally differentiated cell comprising 90%-95% of all bone cells, may have multiple functions, including acting as a mechanosensor in bone (re)modeling. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (P(i)) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism. 相似文献
187.
Parallel domestication of the Shattering1 genes in cereals 总被引:3,自引:0,他引:3
Lin Z Li X Shannon LM Yeh CT Wang ML Bai G Peng Z Li J Trick HN Clemente TE Doebley J Schnable PS Tuinstra MR Tesso TT White F Yu J 《Nature genetics》2012,44(6):720-724
188.
189.
Heid IM Jackson AU Randall JC Winkler TW Qi L Steinthorsdottir V Thorleifsson G Zillikens MC Speliotes EK Mägi R Workalemahu T White CC Bouatia-Naji N Harris TB Berndt SI Ingelsson E Willer CJ Weedon MN Luan J Vedantam S Esko T Kilpeläinen TO Kutalik Z Li S Monda KL Dixon AL Holmes CC Kaplan LM Liang L Min JL Moffatt MF Molony C Nicholson G Schadt EE Zondervan KT Feitosa MF Ferreira T Lango Allen H Weyant RJ Wheeler E Wood AR;MAGIC Estrada K Goddard ME Lettre G Mangino M Nyholt DR Purcell S 《Nature genetics》2010,42(11):949-960
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10?? to P = 1.8 × 10???) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10?3 to P = 1.2 × 10?13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions. 相似文献
190.
Loh ND Hampton CY Martin AV Starodub D Sierra RG Barty A Aquila A Schulz J Lomb L Steinbrener J Shoeman RL Kassemeyer S Bostedt C Bozek J Epp SW Erk B Hartmann R Rolles D Rudenko A Rudek B Foucar L Kimmel N Weidenspointner G Hauser G Holl P Pedersoli E Liang M Hunter MS Hunter MM Gumprecht L Coppola N Wunderer C Graafsma H Maia FR Ekeberg T Hantke M Fleckenstein H Hirsemann H Nass K White TA Tobias HJ Farquar GR Benner WH Hau-Riege SP Reich C Hartmann A Soltau H Marchesini S Bajt S 《Nature》2012,486(7404):513-517
The morphology of micrometre-size particulate matter is of critical importance in fields ranging from toxicology to climate science, yet these properties are surprisingly difficult to measure in the particles' native environment. Electron microscopy requires collection of particles on a substrate; visible light scattering provides insufficient resolution; and X-ray synchrotron studies have been limited to ensembles of particles. Here we demonstrate an in situ method for imaging individual sub-micrometre particles to nanometre resolution in their native environment, using intense, coherent X-ray pulses from the Linac Coherent Light Source free-electron laser. We introduced individual aerosol particles into the pulsed X-ray beam, which is sufficiently intense that diffraction from individual particles can be measured for morphological analysis. At the same time, ion fragments ejected from the beam were analysed using mass spectrometry, to determine the composition of single aerosol particles. Our results show the extent of internal dilation symmetry of individual soot particles subject to non-equilibrium aggregation, and the surprisingly large variability in their fractal dimensions. More broadly, our methods can be extended to resolve both static and dynamic morphology of general ensembles of disordered particles. Such general morphology has implications in topics such as solvent accessibilities in proteins, vibrational energy transfer by the hydrodynamic interaction of amino acids, and large-scale production of nanoscale structures by flame synthesis. 相似文献