Linkage of Mls genes to endogenous mammary tumour viruses of inbred mice.

T cells that recognize self antigen are clonally deleted in the thymus--a maturation process that occurs in the context of histocompatibility molecules and the T-cell receptor. The minor lymphocyte stimulation antigens (Mls) effect these deletions through interactions with the V beta portion of the T-cell receptor, thus mimicking bacterial 'superantigens'. Intrigued by the fact that each known Mls gene maps to the same chromosomal region as an endogenous mouse mammary tumour virus (Mtv), we reevaluated the linkage relationships between the two gene families. Here we report perfect concordance in inbred and recombinant inbred mice between the presence of four Mtv proviruses with the expression of Mls gene products. These data suggest a general model in which mammary tumour virus gene products themselves are the ligands that shape a considerable portion of the immunological repertoire of common laboratory mice.     

Organelle identity and the signposts for membrane traffic

Eukaryotic cells have systems of internal organelles to synthesize lipids and membrane proteins, to release secreted proteins, to take up nutrients and to degrade membrane-bound and internalized molecules. Proteins and lipids move from organelle to organelle using transport vesicles. The accuracy of this traffic depends upon organelles being correctly recognized. In general, organelles are identified by the activated GTPases and specific lipid species that they display. These short-lived determinants provide organelles with an identity that is both unique and flexible. Recent studies have helped to establish how cells maintain and restrict these determinants and explain how this system is exploited by invading pathogens.     

Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders

Cellular and Molecular Life Sciences - Oligodendrocyte precursor cells (OPCs) account for 5% of the resident parenchymal central nervous system glial cells. OPCs are not only a back-up for the loss...     

Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia.

Advances in genetics and molecular biology have provided an extensive body of information on the structure and function of the elementary building blocks of living systems. Genetic defects in membrane ion channels can disrupt the delicate balance of dynamic interactions between the ion channels and the cellular environment, leading to altered cell function. As ion-channel defects are typically studied in isolated expression systems, away from the cellular environment where they function physiologically, a connection between molecular findings and the physiology and pathophysiology of the cell is rarely established. Here we describe a single-channel-based Markovian modelling approach that bridges this gap. We achieve this by determining the cellular arrhythmogenic consequences of a mutation in the cardiac sodium channel that can lead to a clinical arrhythmogenic disorder (the long-QT syndrome) and sudden cardiac death.     

The magnetic nature of disk accretion onto black holes

Although disk accretion onto compact objects-white dwarfs, neutron stars and black holes-is central to much of high-energy astrophysics, the mechanisms that enable this process have remained observationally difficult to determine. Accretion disks must transfer angular momentum in order for matter to travel radially inward onto the compact object. Internal viscosity from magnetic processes and disk winds can both in principle transfer angular momentum, but hitherto we lacked evidence that either occurs. Here we report that an X-ray-absorbing wind discovered in an observation of the stellar-mass black hole binary GRO J1655 - 40 (ref. 6) must be powered by a magnetic process that can also drive accretion through the disk. Detailed spectral analysis and modelling of the wind shows that it can only be powered by pressure generated by magnetic viscosity internal to the disk or magnetocentrifugal forces. This result demonstrates that disk accretion onto black holes is a fundamentally magnetic process.     

Nuclear-powered millisecond pulsars and the maximum spin frequency of neutron stars

Millisecond pulsars are neutron stars that are thought to have been spun-up by mass accretion from a stellar companion. It is not known whether there is a natural brake for this process, or if it continues until the centrifugal breakup limit is reached at submillisecond periods. Many neutron stars that are accreting mass from a companion star exhibit thermonuclear X-ray bursts that last tens of seconds, caused by unstable nuclear burning on their surfaces. Millisecond-period brightness oscillations during bursts from ten neutron stars (as distinct from other rapid X-ray variability that is also observed) are thought to measure the stellar spin, but direct proof of a rotational origin has been lacking. Here we report the detection of burst oscillations at the known spin frequency of an accreting millisecond pulsar, and we show that these oscillations always have the same rotational phase. This firmly establishes burst oscillations as nuclear-powered pulsations tracing the spin of accreting neutron stars, corroborating earlier evidence. The distribution of spin frequencies of the 11 nuclear-powered pulsars cuts off well below the breakup frequency for most neutron-star models, supporting theoretical predictions that gravitational radiation losses can limit accretion torques in spinning up millisecond pulsars.     

Identification of common variants associated with human hippocampal and intracranial volumes

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).     

Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) has recently been defined based on a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy. LBSL is an autosomal recessive disease, most often manifesting in early childhood. Affected individuals develop slowly progressive cerebellar ataxia, spasticity and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. We performed linkage mapping with microsatellite markers in LBSL families and found a candidate region on chromosome 1, which we narrowed by means of shared haplotypes. Sequencing of genes in this candidate region uncovered mutations in DARS2, which encodes mitochondrial aspartyl-tRNA synthetase, in affected individuals from all 30 families. Enzyme activities of mutant proteins were decreased. We were surprised to find that activities of mitochondrial complexes from fibroblasts and lymphoblasts derived from affected individuals were normal, as determined by different assays.