Induction of AIDS in rhesus monkeys by molecularly cloned simian immunodeficiency virus

Better understanding of the pathogenesis of acquired immunodeficiency syndrome (AIDS) would be greatly facilitated by a relevant animal model that uses molecularly cloned virus of defined sequence to induce the disease. Such a system would also be of great value for AIDS vaccine research. An infectious molecular clone of simian immunodeficiency virus (SIV) was identified that induces AIDS in common rhesus monkeys in a time frame suitable for laboratory investigation. These results provide another strong link in the chain of evidence for the viral etiology of AIDS. More importantly, they define a system for molecular dissection of the determinants of AIDS pathogenesis.     

Role for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus

Genomic imprinting causes parental origin-specific monoallelic gene expression through differential DNA methylation established in the parental germ line. However, the mechanisms underlying how specific sequences are selectively methylated are not fully understood. We have found that the components of the PIWI-interacting RNA (piRNA) pathway are required for de novo methylation of the differentially methylated region (DMR) of the imprinted mouse Rasgrf1 locus, but not other paternally imprinted loci. A retrotransposon sequence within a noncoding RNA spanning the DMR was targeted by piRNAs generated from a different locus. A direct repeat in the DMR, which is required for the methylation and imprinting of Rasgrf1, served as a promoter for this RNA. We propose a model in which piRNAs and a target RNA direct the sequence-specific methylation of Rasgrf1.     

Mutations in dynein link motor neuron degeneration to defects in retrograde transport

Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.     

CTLA-4 control over Foxp3+ regulatory T cell function

Naturally occurring Foxp3+CD4+ regulatory T cells (Tregs) are essential for maintaining immunological self-tolerance and immune homeostasis. Here, we show that a specific deficiency of cytotoxic T lymphocyte antigen 4 (CTLA-4) in Tregs results in spontaneous development of systemic lymphoproliferation, fatal T cell-mediated autoimmune disease, and hyperproduction of immunoglobulin E in mice, and it also produces potent tumor immunity. Treg-specific CTLA-4 deficiency impairs in vivo and in vitro suppressive function of Tregs-in particular, Treg-mediated down-regulation of CD80 and CD86 expression on dendritic cells. Thus, natural Tregs may critically require CTLA-4 to suppress immune responses by affecting the potency of antigen-presenting cells to activate other T cells.     

Cytokinin oxidase regulates rice grain production

Most agriculturally important traits are regulated by genes known as quantitative trait loci (QTLs) derived from natural allelic variations. We here show that a QTL that increases grain productivity in rice, Gn1a, is a gene for cytokinin oxidase/dehydrogenase (OsCKX2), an enzyme that degrades the phytohormone cytokinin. Reduced expression of OsCKX2 causes cytokinin accumulation in inflorescence meristems and increases the number of reproductive organs, resulting in enhanced grain yield. QTL pyramiding to combine loci for grain number and plant height in the same genetic background generated lines exhibiting both beneficial traits. These results provide a strategy for tailormade crop improvement.     

Islet regeneration during the reversal of autoimmune diabetes in NOD mice

Nonobese diabetic (NOD) mice are a model for type 1 diabetes in humans. Treatment of NOD mice with end-stage disease by injection of donor splenocytes and complete Freund's adjuvant eliminates autoimmunity and permanently restores normoglycemia. The return of endogenous insulin secretion is accompanied by the reappearance of pancreatic beta cells. We now show that live donor male or labeled splenocytes administered to diabetic NOD females contain cells that rapidly differentiate into islet and ductal epithelial cells within the pancreas. Treatment with irradiated splenocytes is also followed by islet regeneration, but at a slower rate. The islets generated in both instances are persistent, functional, and apparent in all NOD hosts with permanent disease reversal.     

Protostellar feedback halts the growth of the first stars in the universe

The first stars fundamentally transformed the early universe by emitting the first light and by producing the first heavy elements. These effects were predetermined by the mass distribution of the first stars, which is thought to have been fixed by a complex interplay of gas accretion and protostellar radiation. We performed radiation-hydrodynamics simulations that followed the growth of a primordial protostar through to the early stages as a star with thermonuclear burning. The circumstellar accretion disk was evaporated by ultraviolet radiation from the star when its mass was 43 times that of the Sun. Such massive primordial stars, in contrast to the often-postulated extremely massive stars, may help explain the fact that there are no signatures of the pair-instability supernovae in abundance patterns of metal-poor stars in our galaxy.