HIV-1, lipid rafts,and antibodies to liposomes: implications for anti-viral-neutralizing antibodies (Review)

The human immunodeficiency virus type 1 (HIV-1) is an enveloped virus with a lipid bilayer that contains several glycoproteins that are anchored in, or closely associated with, the membrane surface. The envelope proteins have complex interactions with the lipids both on the host cells and on the target cells. The processes of budding from host cells and entry into target cells occur at sites on the plasma membrane, known as lipid rafts, that represent specialized regions that are rich in cholesterol and sphingolipids. Although the envelope glycoproteins are antigenic molecules that potentially might be used for development of broadly neutralizing antibodies in a vaccine to HIV-1, the development of such antibodies that have broad specificities against primary field isolates of virus has been largely thwarted to date by the ability of the envelope proteins to evade the immune system through various mechanisms. In this review, the interactions of HIV-1 with membrane lipids are summarized. Liposomes are commonly used as models for understanding interactions of proteins with membrane lipids; and liposomes have also been used both as carriers for vaccines, and as antigens for induction of antibodies to liposomal lipids. The possibility is proposed that liposomal lipids, or liposome-protein combinations, could be useful as antigens for inducing broadly neutralizing antibodies to HIV-1.     

Genome-wide analysis of copy number variants in age-related macular degeneration

Age-related macular degeneration (AMD) is a complex genetic disease, with many loci demonstrating appreciable attributable disease risk. Despite significant progress toward understanding the genetic and environmental etiology of AMD, identification of additional risk factors is necessary to fully appreciate and treat AMD pathology. In this study, we investigated copy number variants (CNVs) as potential AMD risk variants in a cohort of 400 AMD patients and 500 AMD-free controls ascertained at the University of Iowa. We used three publicly available copy number programs to analyze signal intensity data from Affymetrix GeneChip SNP Microarrays. CNVs were ranked based on prevalence in the disease cohort and absence from the control group; high interest CNVs were subsequently confirmed by qPCR. While we did not observe a single-locus "risk CNV" that could account for a major fraction of AMD, we identified several rare and overlapping CNVs containing or flanking compelling candidate genes such as NPHP1 and EFEMP1. These and other candidate genes highlighted by this study deserve further scrutiny as sources of genetic risk for AMD.     

Restless legs syndrome

Being of the most frequent causes of insomnia, which in the end leads to chronic fatigue, inadequate performance of daily activities, and serious disruption of quality of living, restless legs syndrome (RLS) is nowadays not only a serious medical problem but a socio-economical one as well. Prevalence of the disorder in general population is estimated at 5 to 15%. Family history is positive in over 50% of idiopathic RLS patients which points to genetic basis of the disorder. The characteristics of the secondary or acquired form of RLS are symptoms that start later in life as well as a rapid progression of the disease. On the other hand, idiopathic RLS more often starts at a younger age and the prognoses are better. Over twenty disorders and conditions are brought in connection with secondary RLS. Although the cause of primary RLS is still unknown, there is a strong connection between central metabolism of iron as well as dopamine levels and RLS manifestation. A differential diagnosis of RLS includes a wide specter of motor and sensory disorders. Diagnosis is based on clinical features and the history of disease. To correctly diagnose idiopathic RLS one must first eliminate secondary causes of RLS and then also exclude any disorders with clinical features that mimic those of RLS. It has been estimated that some 20 to 25% of patients need pharmacological therapy. Best initial therapy is the application of nonergot dopamine agonists. Anticonvulsants, benzodiazepines and opioides can be given to patients who are refractory to dopaminergic therapy, those suffering from RLS with emphasized painful sensory component and those with RLS connected with insomnia.     

Engineered epidermal growth factor mutants with faster binding on-rates correlate with enhanced receptor activation

Receptor tyrosine kinases (RTKs) regulate critical cell signaling pathways, yet the properties of their cognate ligands that influence receptor activation are not fully understood. There is great interest in parsing these complex ligand-receptor relationships using engineered proteins with altered binding properties. Here we focus on the interaction between two engineered epidermal growth factor (EGF) mutants and the EGF receptor (EGFR), a model member of the RTK superfamily. We found that EGF mutants with faster kinetic on-rates stimulate increased EGFR activation compared to wild-type EGF. These findings support previous predictions that faster association rates correlate with enhanced receptor activity.     

SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation

The eukaryotic cell cycle is regulated by multiple ubiquitin-mediated events, such as the timely destruction of cyclins and replication licensing factors. The histone H4 methyltransferase SET8 (Pr-Set7) is required for chromosome compaction in mitosis and for maintenance of genome integrity. In this study, we show that SET8 is targeted for degradation during S phase by the CRL4(CDT2) ubiquitin ligase in a proliferating cell nuclear antigen (PCNA)-dependent manner. SET8 degradation requires a conserved degron responsible for its interaction with PCNA and recruitment to chromatin where ubiquitylation occurs. Efficient degradation of SET8 at the onset of S phase is required for the regulation of chromatin compaction status and cell cycle progression. Moreover, the turnover of SET8 is accelerated after ultraviolet irradiation dependent on the CRL4(CDT2) ubiquitin ligase and PCNA. Removal of SET8 supports the modulation of chromatin structure after DNA damage. These results demonstrate a novel regulatory mechanism, linking for the first time the ubiquitin-proteasome system with rapid degradation of a histone methyltransferase to control cell proliferation.     

Estimating occupancy to monitor northern goshawk in the central Rocky Mountains

Designing monitoring programs to evaluate trends in low-density wildlife species at regional scales is challenging given difficulties detecting uncommon organisms distributed in potential habitats over large spatial extents. The northern goshawk (Accipiter gentilis) has been petitioned for listing under the Endangered Species Act and the review of the petition indicated a need for information on population trend. To evaluate trends in goshawk populations, the U.S. Forest Service developed the Northern Goshawk Bioregional Monitoring Design to estimate goshawk occupancy over broad spatial extents. We adapted and implemented this design to approximately 30,600 km² of 88,128 km² of National Forest System lands in the Forest Service Rocky Mountain Region, including portions of Colorado, Wyoming, and South Dakota. We developed a stratified random design to monitor goshawk occupancy in sampling units, defined by primary and secondary habitat quality as well as accessibility. To define habitat quality, we examined a time series for 58 previously located nesting territories. Using logistic regression, we found that the dominant conifer species and status of aspen in postfledging zones best characterized high-quality goshawk nesting habitat. We applied model results to stratify 4,445 sampling units based on habitat quality and further stratified sampling units based on accessibility into easy and difficult access categories. We conducted field sampling during the goshawk breeding season in the summer of 2006 to estimate detection probabilities and occupancy rates. Within our sampling frame, we sampled 51 sampling units and estimated goshawk occupancy of 0.329 (95% CI: 0.213–0.445). Occupancy within primary strata (high quality) sampling units was 0.811 (SE = 0.113), whereas occupancy in secondary strata (lower quality) sampling units was 0.124 (SE = 0.067). Future implementation of this monitoring program can achieve 0.8 power to detect 30–40% declines in with 140 sampling units. Our implementation of a stratified sampling design to monitor occupancy of goshawks at a region-wide scale reduced the number of sampling units in each administrative unit and focused our efforts on those areas most likely to have goshawks. © 2011 The Wildlife Society.     

Australia's first fossil marsupial mole (Notoryctemorphia) resolves controversies about their evolution and palaeoenvironmental origins

Fossils of a marsupial mole (Marsupialia, Notoryctemorphia, Notoryctidae) are described from early Miocene deposits in the Riversleigh World Heritage Area, northwestern Queensland, Australia. These represent the first unequivocal fossil record of the order Notoryctemorphia, the two living species of which are among the world's most specialized and bizarre mammals, but which are also convergent on certain fossorial placental mammals (most notably chrysochlorid golden moles). The fossil remains are genuinely 'transitional', documenting an intermediate stage in the acquisition of a number of specializations and showing that one of these-the dental morphology known as zalambdodonty-was acquired via a different evolutionary pathway than in placentals. They, thus, document a clear case of evolutionary convergence (rather than parallelism) between only distantly related and geographically isolated mammalian lineages-marsupial moles on the island continent of Australia and placental moles on most other, at least intermittently connected continents. In contrast to earlier presumptions about a relationship between the highly specialized body form of the blind, earless, burrowing marsupial moles and desert habitats, it is now clear that archaic burrowing marsupial moles were adapted to and probably originated in wet forest palaeoenvironments, preadapting them to movement through drier soils in the xeric environments of Australia that developed during the Neogene.