Effect of cortisone or triiodothyronine administration to pregnant rats on lysosomal hydrolases in fetal forebrain and cerebellum

Triiodothyronine injected daily to pregnant rats for the last week of gestation (50 microgram/100 g b.wt) increased the specific activities of 5 acid glycosidases in the fetal forebrain and cerebellum. Cortisone (50 mg/100 g b.wt) administered in the same period had no effect on cerebellum acid hydrolases, but decreased their activity in the forebrain.     

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.     

Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy

Centronuclear myopathies are characterized by muscle weakness and abnormal centralization of nuclei in muscle fibers not secondary to regeneration. The severe neonatal X-linked form (myotubular myopathy) is due to mutations in the phosphoinositide phosphatase myotubularin (MTM1), whereas mutations in dynamin 2 (DNM2) have been found in some autosomal dominant cases. By direct sequencing of functional candidate genes, we identified homozygous mutations in amphiphysin 2 (BIN1) in three families with autosomal recessive inheritance. Two missense mutations affecting the BAR (Bin1/amphiphysin/RVS167) domain disrupt its membrane tubulation properties in transfected cells, and a partial truncation of the C-terminal SH3 domain abrogates the interaction with DNM2 and its recruitment to the membrane tubules. Our results suggest that mutations in BIN1 cause centronuclear myopathy by interfering with remodeling of T tubules and/or endocytic membranes, and that the functional interaction between BIN1 and DNM2 is necessary for normal muscle function and positioning of nuclei.     

CXorf6 is a causative gene for hypospadias

46,XY disorders of sex development (DSD) refer to a wide range of abnormal genitalia, including hypospadias, which affects approximately 0.5% of male newborns. We identified three different nonsense mutations of CXorf6 in individuals with hypospadias and found that its mouse homolog was specifically expressed in fetal Sertoli and Leydig cells around the critical period for sex development. These data imply that CXorf6 is a causative gene for hypospadias.     

Mutations in dynamin 2 cause dominant centronuclear myopathy

Autosomal dominant centronuclear myopathy is a rare congenital myopathy characterized by delayed motor milestones and muscular weakness. In 11 families affected by centronuclear myopathy, we identified recurrent and de novo missense mutations in the gene dynamin 2 (DNM2, 19p13.2), which encodes a protein involved in endocytosis and membrane trafficking, actin assembly and centrosome cohesion. The transfected mutants showed reduced labeling in the centrosome, suggesting that DNM2 mutations might cause centronuclear myopathy by interfering with centrosome function.     

Variable effects of nitrogen additions on the stability and turnover of soil carbon

Soils contain the largest near-surface reservoir of terrestrial carbon and so knowledge of the factors controlling soil carbon storage and turnover is essential for understanding the changing global carbon cycle. The influence of climate on decomposition of soil carbon has been well documented, but there remains considerable uncertainty in the potential response of soil carbon dynamics to the rapid global increase in reactive nitrogen (coming largely from agricultural fertilizers and fossil fuel combustion). Here, using 14C, 13C and compound-specific analyses of soil carbon from long-term nitrogen fertilization plots, we show that nitrogen additions significantly accelerate decomposition of light soil carbon fractions (with decadal turnover times) while further stabilizing soil carbon compounds in heavier, mineral-associated fractions (with multidecadal to century lifetimes). Despite these changes in the dynamics of different soil pools, we observed no significant changes in bulk soil carbon, highlighting a limitation inherent to the still widely used single-pool approach to investigating soil carbon responses to changing environmental conditions. It remains to be seen if the effects observed here-caused by relatively high, short-term fertilizer additions-are similar to those arising from lower, long-term additions of nitrogen to natural ecosystems from atmospheric deposition, but our results suggest nonetheless that current models of terrestrial carbon cycling do not contain the mechanisms needed to capture the complex relationship between nitrogen availability and soil carbon storage.     

Early human use of marine resources and pigment in South Africa during the Middle Pleistocene

Genetic and anatomical evidence suggests that Homo sapiens arose in Africa between 200 and 100 thousand years (kyr) ago, and recent evidence indicates symbolic behaviour may have appeared approximately 135-75 kyr ago. From 195-130 kyr ago, the world was in a fluctuating but predominantly glacial stage (marine isotope stage MIS6); much of Africa was cooler and drier, and dated archaeological sites are rare. Here we show that by approximately 164 kyr ago (+/-12 kyr) at Pinnacle Point (on the south coast of South Africa) humans expanded their diet to include marine resources, perhaps as a response to these harsh environmental conditions. The earliest previous evidence for human use of marine resources and coastal habitats was dated to approximately 125 kyr ago. Coincident with this diet and habitat expansion is an early use and modification of pigment, probably for symbolic behaviour, as well as the production of bladelet stone tool technology, previously dated to post-70 kyr ago. Shellfish may have been crucial to the survival of these early humans as they expanded their home ranges to include coastlines and followed the shifting position of the coast when sea level fluctuated over the length of MIS6.