An AIDS-related cytotoxic autoantibody reacts with a specific antigen on stimulated CD4+ T cells

Patients with the acquired immune deficiency syndrome (AIDS) and AIDS-related conditions are known to have abnormalities of T cell subpopulations, including a decreased helper/inducer (bearing the CD4 antigen) to suppressor/cytotoxic (bearing the CD8 antigen) T cell ratio and decreased absolute numbers of T cells with the CD4+ phenotype. Infection of T cells with a retrovirus, termed human immunodeficiency virus (HIV), is thought to be important in these abnormalities. HIV infection alone does not adequately explain the CD4+ T-cell abnormalities seen in AIDS, however, and the nature of T-cell destruction in this disease remains poorly characterized. Here we describe an AIDS-related serum autoantibody that reacts with an antigen of relative molecular mass 18,000 (Mr 18K) restricted to lectin-stimulated or HIV-infected CD4+ T cells. The antibody also suppresses proliferation of CD4+ T cells in vitro and induces cytotoxicity of these cells in the presence of complement. Its role in the development of AIDS merits attention.     

Retinopathy and attenuated circadian entrainment in Crx-deficient mice

Crx, an Otx-like homeobox gene, is expressed specifically in the photoreceptors of the retina and the pinealocytes of the pineal gland. Crx has been proposed to have a role in the regulation of photoreceptor-specific genes in the eye and of pineal-specific genes in the pineal gland. Mutations in human CRX are associated with the retinal diseases, cone-rod dystrophy-2 (adCRD2; refs 3, 4, 5), retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), which all lead to loss of vision. We generated mice carrying a targeted disruption of Crx. Crx-/- mice do not elaborate photoreceptor outer segments and lacked rod and cone activity as assayed by electroretinogram (ERG). Expression of several photoreceptor- and pineal-specific genes was reduced in Crx mutants. Circadian entrainment was also affected in Crx-/- mice.     

Low strength of deep San Andreas fault gouge from SAFOD core

The San Andreas fault accommodates 28-34 mm?yr(-1) of right lateral motion of the Pacific crustal plate northwestward past the North American plate. In California, the fault is composed of two distinct locked segments that have produced great earthquakes in historical times, separated by a 150-km-long creeping zone. The San Andreas Fault Observatory at Depth (SAFOD) is a scientific borehole located northwest of Parkfield, California, near the southern end of the creeping zone. Core was recovered from across the actively deforming San Andreas fault at a vertical depth of 2.7 km (ref. 1). Here we report laboratory strength measurements of these fault core materials at in situ conditions, demonstrating that at this locality and this depth the San Andreas fault is profoundly weak (coefficient of friction, 0.15) owing to the presence of the smectite clay mineral saponite, which is one of the weakest phyllosilicates known. This Mg-rich clay is the low-temperature product of metasomatic reactions between the quartzofeldspathic wall rocks and serpentinite blocks in the fault. These findings provide strong evidence that deformation of the mechanically unusual creeping portions of the San Andreas fault system is controlled by the presence of weak minerals rather than by high fluid pressure or other proposed mechanisms. The combination of these measurements of fault core strength with borehole observations yields a self-consistent picture of the stress state of the San Andreas fault at the SAFOD site, in which the fault is intrinsically weak in an otherwise strong crust.     

Products of the isoprostane pathway: unique bioactive compounds and markers of lipid peroxidation

We previously reported the discovery of prostaglandin F2-like compounds (F2-isoprostanes) formed by nonenzymatic free-radical-induced peroxidation of arachidonic acid. Quantification of F2-isoprostanes has proven to be a major advance in assessing oxidative stress status in vivo. Central in the pathway of formation of isoprostanes are prostaglandin H2-like endoperoxides, which also undergo rearrangement in vivo to form E-ring, D-ring, and thromboxane-ring compounds. E2- and D2-isoprostanes also undergo dehydration in vivo to form reactive cyclopentenone A2- and J2-isoprostanes, which are susceptible to Michael addition reactions with thiols. Recently, we described the formation of highly reactive gamma-ketoaldehydes (now termed isoketals) as products of isoprostane endoperoxide rearrangement which readily adduct to lysine residues on proteins and induce cross-links at rates that far exceed other aldehyde products of lipid peroxidation. Isoprostane-like compounds (neuroprostanes) and isoketal-like compounds (neuroketals) are formed from oxidation of docosahexaenoic acid, which is enriched in the brain, and measurement of neuroprostanes may provide a unique marker of oxidative neuronal injury.     

Semaphorin 3A is a chemoattractant for cortical apical dendrites

The apical dendrites of pyramidal neurons integrate inputs from various cortical layers and are central to information processing. Here we show that the growth of apical dendrites towards the pial surface is regulated by a diffusible chemoattractant present at high levels near the marginal zone. A major component of this signal is semaphorin 3A (Sema3A), which was previously characterized as a chemorepellant for cortical axons. Soluble guanylate cyclase is asymmetrically localized to the developing apical dendrite, and is required for the chemoattractive effect of Sema3A. Thus the asymmetric localization of soluble guanylate cyclase confers distinct Sema3A responses to axons and dendrites. These observations reveal a mechanism by which a single chemotropic signal can pattern both axons and dendrites during development.     

Myocardial infarction accelerates atherosclerosis

During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.