FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair

Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD.     

地幔柱存在的依据

从一些成熟的观察我们可推测地幔中至少有几个地幔柱, 这并不需要什么假设. 的确, 如果我们对地球早期热状态的假设合理的话, 那么用成熟的定量流体动力学模型不难预测地幔柱的存在. 一些其他重要的观察, 特别是溢流玄武岩和裂谷有关的岩浆活动, 也被证实与物理推论基本一致. 最近有人宣称用地震层析成像方法探测到地幔柱, 这应该说是地幔柱存在的最直接证据, 但地幔柱尾部很难被检测到, 因此该探测结果尚须进一步检验. 尽管地幔柱假说的可行性仍存在重要问题, 但地幔柱假说似乎很值得继续研究. 尽管如此, 许多与板块无关的岩浆活动与地幔柱的关系并不清楚或可能无关. 最近的研究表明化学组成造成的浮力变化会使得地幔柱动力学变得更复杂. 这可用以解释比纯热地幔柱更宽泛的现象, 包括“无柱头”的热点轨迹.     

Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase

Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders. Although the complex molecular pathophysiology of neurodegeneration is largely unknown, major advances have been achieved by elucidating the genetic defects underlying mendelian forms of these diseases. This has led to the discovery of common pathophysiological pathways such as enhanced oxidative stress, protein misfolding and aggregation and dysfunction of the ubiquitin-proteasome system. Here, we describe loss-of-function mutations in a previously uncharacterized, predominantly neuronal P-type ATPase gene, ATP13A2, underlying an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia (PARK9, Kufor-Rakeb syndrome). Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. Our findings link a class of proteins with unknown function and substrate specificity to the protein networks implicated in neurodegeneration and parkinsonism.     

PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron

Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.     

Supernova SN 2011fe from an exploding carbon-oxygen white dwarf star

Type Ia supernovae have been used empirically as 'standard candles' to demonstrate the acceleration of the expansion of the Universe even though fundamental details, such as the nature of their progenitor systems and how the stars explode, remain a mystery. There is consensus that a white dwarf star explodes after accreting matter in a binary system, but the secondary body could be anything from a main-sequence star to a red giant, or even another white dwarf. This uncertainty stems from the fact that no recent type Ia supernova has been discovered close enough to Earth to detect the stars before explosion. Here we report early observations of supernova SN 2011fe in the galaxy M101 at a distance from Earth of 6.4 megaparsecs. We find that the exploding star was probably a carbon-oxygen white dwarf, and from the lack of an early shock we conclude that the companion was probably a main-sequence star. Early spectroscopy shows high-velocity oxygen that slows rapidly, on a timescale of hours, and extensive mixing of newly synthesized intermediate-mass elements in the outermost layers of the supernova. A companion paper uses pre-explosion images to rule out luminous red giants and most helium stars as companions to the progenitor.     

Loss-of-function mutations in sodium channel Nav1.7 cause anosmia

Loss of function of the gene SCN9A, encoding the voltage-gated sodium channel Na(v)1.7, causes a congenital inability to experience pain in humans. Here we show that Na(v)1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with loss-of-function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Na(v)1.7 in odour perception, we generated conditional null mice in which Na(v)1.7 was removed from all olfactory sensory neurons. In the absence of Na(v)1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell.     

What are universities for?

Governments worldwide rightly regard universities as fundamental to the achievement of many national priorities. But it is the paper’s contention that many misunderstand their true benefit to society. Investments in universities are increasingly based on the belief that the science labs in particular of research-intensive universities can be the source of a continuous stream of people and ideas that will spawn innovative and fast growing companies to form the nexus of the knowledge-based economy. This belief is a source of misconceived policies that offer only ultimate disillusion. It is the totality of the university enterprise that is important, as the only place where that totality of ourselves and our world is brought together, and which makes it the strongest provider of the rational explanation and meaning that societies need. In research, universities create new possibilities; in teaching, they shape new people. Its graduates learn to seek the true meaning of things: to distinguish between the true and the merely seemingly true, to verify for themselves what is stable in that very unstable compound that often passes for knowledge. It is the complex, interacting whole of the university that is the source of the separate economic, social, cultural and utilitarian benefits valued by society. It needs to be understood, valued and managed as a whole. These perceptions are a direct challenge to not only to governments but to university administrators who have been either cowed or seduced into the slipshod thinking that is leading to demands that universities cannot satisfy, whilst obscuring their most important contributions. The challenge to both is to permit autonomy without oppressive accountability, and to give staff and students the freedom to think, speculate and research. These are the very conditions of the personal and collective creativity that are the sources of a university’s deepest benefits to its society.