Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy

Latency and ongoing replication have both been proposed to explain the drug-insensitive human immunodeficiency virus (HIV) reservoir maintained during antiretroviral therapy. Here we explore a novel mechanism for ongoing HIV replication in the face of antiretroviral drugs. We propose a model whereby multiple infections per cell lead to reduced sensitivity to drugs without requiring drug-resistant mutations, and experimentally validate the model using multiple infections per cell by cell-free HIV in the presence of the drug tenofovir. We then examine the drug sensitivity of cell-to-cell spread of HIV, a mode of HIV transmission that can lead to multiple infection events per target cell. Infections originating from cell-free virus decrease strongly in the presence of antiretrovirals tenofovir and efavirenz whereas infections involving cell-to-cell spread are markedly less sensitive to the drugs. The reduction in sensitivity is sufficient to keep multiple rounds of infection from terminating in the presence of drugs. We examine replication from cell-to-cell spread in the presence of clinical drug concentrations using a stochastic infection model and find that replication is intermittent, without substantial accumulation of mutations. If cell-to-cell spread has the same properties in vivo, it may have adverse consequences for the immune system, lead to therapy failure in individuals with risk factors, and potentially contribute to viral persistence and hence be a barrier to curing HIV infection.     

Mutant deoxynucleotide carrier is associated with congenital microcephaly

The disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of alpha-ketoglutarate in the urine and premature death. The disorder is inherited in an autosomal recessive pattern and has been observed only in Old Order Amish families whose ancestors lived in Lancaster County, Pennsylvania. Here we show, by using a genealogy database and automated pedigree software, that 23 nuclear families affected with MCPHA are connected to a single ancestral couple. Through a whole-genome scan, fine mapping and haplotype analysis, we localized the gene affected in MCPHA to a region of 3 cM, or 2 Mb, on chromosome 17q25. We constructed a map of contiguous genomic clones spanning this region. One of the genes in this region, SLC25A19, which encodes a nuclear mitochondrial deoxynucleotide carrier (DNC), contains a substitution that segregates with the disease in affected individuals and alters an amino acid that is highly conserved in similar proteins. Functional analysis shows that the mutant DNC protein lacks the normal transport activity, implying that failed deoxynucleotide transport across the inner mitochondrial membrane causes MCPHA. Our data indicate that mitochondrial deoxynucleotide transport may be essential for prenatal brain growth.     

Community Organizations in Venezuela: Toward the Disintegration of the Modern State and the Emergence of a "Community Organized" Society?

This paper argues that Venezuelan community organizations (COs) are playing a substantial role in the building of a new social order in which elements such as rights, equity, and justice are being displaced from a universal narrative toward more local narratives. This displacement is enwrapped in a discourse on the political participation of citizens in the running of public affairs, which implies a redefinition of the role of COs and the state beyond the usually accepted sphere of COs. The need to unfold the sense of COs thus becomes paramount for understanding our present and its current manifestations of an epochal change.     

Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon

Kras is commonly mutated in colon cancers, but mutations in Nras are rare. We have used genetically engineered mice to determine whether and how these related oncogenes regulate homeostasis and tumorigenesis in the colon. Expression of K-Ras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek-dependent manner. N-Ras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc-mutant colonic tumor, activation of K-Ras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This K-Ras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant K-Ras were hypersensitive to inhibition of Raf, but not Mek. These studies demonstrate clear phenotypic differences between mutant Kras and Nras, and suggest that the oncogenic phenotype of mutant K-Ras might be mediated by noncanonical signaling through Ras effector pathways.     

The coconut pathosystem: weed hosts of nymphs of the American palm Cixiid Haplaxius crudus (Hemiptera: Fulgoroidea)

Lethal yellowing (LY) of coconut palm (Cocos nucifera L., Arecaceae) is a disease of economic importance that is caused by the phytoplasma ‘Candidatus Phytoplasma palmae’ and is transmitted by the planthopper Haplaxius crudus (Van Duzee) (Hemiptera: Cixiidae). This study explores the weeds used by H. crudus nymphs and other Cixiidae in a coconut pathosystem in southern Mexico. Nymphs were collected directly from the root system of each weed by hand or with the help of a vacuum after carefully opening the culm. This study included 11 species of weeds: nine Poaceae [Brachiaria decumbens Stapf, B. humidicola (Rendle) Schweick, B. mutica (Forssk.) Stapf, Digitaria abyssinica (Hochst. Ex A. Rich.) Stapf, Eustachys petraea (Sw.) Desv., Leersia hexandra Sw., Panicum laxum Sw., P. maximum Jacq., Paspalum notatum Flüggé]; one Cyperaceae [Cyperus ligularis L.], and one Portulacaceae: [Portulaca pilosa L.]. Brachiaria mutica, E. petraea, B. humidicola, P. maximum were identified as the principal host species for H. crudus nymphs. Brachiaria decumbens, D. abyssinica, and C. ligularis are new host records for the nymphs of H. crudus. Additionally, it was found that H. crudus may coexist with its cogeners H. skarphion Kramer (Cixiidae) and H. caldwelli Kramer (Cixiidae), on B. mutica. On C. ligularis, H. crudus may coexist with Oecleus snowi Ball (Cixiidae) nymphs. These results suggest that in the coconut pathosystem there is a complex of multitrophic interactions that should be considered in integrated management of LY.     

Urbanization impacts on the trophic guild composition of bird communities

Urbanization transforms the landscape and generates loss of pristine habitats. We investigated the urbanization effect on bird communities in a growing South American city (Santa Fe, Argentina) and hypothesized that if habitat structure and human disturbance change along an urban gradient, the richness and abundance of trophic guilds should also vary accordingly. We placed 50 transects 100 m long × 50 m wide in five districts with different levels of urbanization, determined by habitat structure variables. We recorded the number and abundance of species and the amount of pedestrians and vehicles passing through each transect. We recorded 23% of all bird species known for the Santa Fe province and categorized them within 19 trophic guilds. The percentage of area covered by herbaceous vegetation, water bodies and trees and shrubs had a positive relationship with the richness and abundance of most of trophic guilds (hawking aerial, terrestrial, bark and foliage insectivores; terrestrial and generalized granivores; generalized, aquatic diving and foliage omnivores; hawking aerial, aquatic diving and striding carnivores; nectarivores; and aquatic filters). Pavement surface and human disturbance variables had a negative relationship with the richness, and high buildings and pavement surface had a positive relationship with the abundance of terrestrial omnivores and coursing aerial insectivores. Variation partitioning revealed that habitat structure and human disturbance were better predictors of the richness than the abundance of each trophic guild. Results showed that trophic guilds associated to vegetation strata were seen to increase their richness and abundance towards green areas, even if they presented generalist or specialist habits. Urban planners should conserve or manage the surrounded natural spaces when the growth of the city is directed to these areas and increase the availability of environmental features within the urban matrix.     

Birth and Demise of a Social Protection Organization in Venezuela

In this article a context for the study of a social protection organization is presented. This context is based on three ideas: (i) social protection is a requirement for assuming the cohesion and continuation of society; (ii) in an industrialized society, social protection is conceived in connection with salary; and (iii) the organizational form of social protection in Venezuelan society is Social Security guaranteed by a Welfare State. The becoming of our Social Security organization is interpreted with these concepts. The interpretive process consists in the unfolding of the relation between the organizational form and the conceptions about social protection since the birth of the organization 60 years ago. This unfolding simultaneously reveals failure concerning coverage of the risks typical of social security and a radical change in the conception of social protection in Venezuela. These results rest on the non-realization of premise ii of the interpretive context in the case of the Venezuelan society. The article concludes by showing the need to understand the conceptions regarding social protection in contexts different from that of an industrial society (advanced or not).