Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis

Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.     

Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity

Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders.     

The positional identity of mouse ES cell-generated neurons is affected by BMP signaling

We investigated the effects of bone morphogenetic proteins (BMPs) in determining the positional identity of neurons generated in vitro from mouse embryonic stem cells (ESCs), an aspect that has been neglected thus far. Classical embryological studies in lower vertebrates indicate that BMPs inhibit the default fate of pluripotent embryonic cells, which is both neural and anterior. Moreover, mammalian ESCs generate neurons more efficiently when cultured in a minimal medium containing BMP inhibitors. In this paper, we show that mouse ESCs produce, secrete, and respond to BMPs during in vitro neural differentiation. After neuralization in a minimal medium, differentiated ESCs show a gene expression profile consistent with a midbrain identity, as evaluated by the analysis of a number of markers of anterior–posterior and dorsoventral identity. We found that BMPs endogenously produced during neural differentiation mainly act by inhibiting the expression of a telencephalic gene profile, which was revealed by the treatment with Noggin or with other BMP inhibitors. To better characterize the effect of BMPs on positional fate, we compared the global gene expression profiles of differentiated ESCs with those of embryonic forebrain, midbrain, and hindbrain. Both Noggin and retinoic acid (RA) support neuronal differentiation of ESCs, but they show different effects on their positional identity: whereas RA supports the typical gene expression profile of hindbrain neurons, Noggin induces a profile characteristic of dorsal telencephalic neurons. Our findings show that endogenously produced BMPs affect the positional identity of the neurons that ESCs spontaneously generate when differentiating in vitro in a minimal medium. The data also support the existence of an intrinsic program of neuronal differentiation with dorsal telencephalic identity. Our method of ESC neuralization allows for fast differentiation of neural cells via the same signals found during in vivo embryonic development and for the acquisition of cortical identity by the inhibition of BMP alone.     

Characterisation of burrow architecture under natural conditions in the sand-dwelling wolf spider Allocosa brasiliensis

Allocosa brasiliensis (Petrunkevitch, 1910) is a wolf spider that constructs silk-lined burrows along the coastal sand dunes of Argentina, Brazil and Uruguay. This species shows a reversal in typical sex roles and sexual size dimorphism expected for spiders. Females are the smaller and mobile sex, which initiates courtship at the male burrow entrance. Mating occurs in the male burrow, and when it ends, the male leaves and the female stays inside. Females prefer to mate with those males showing longest burrows, so burrow dimensions would be under strong sexual selection pressures. Previous studies in the laboratory indicated that male burrows are longer than those of virgin females, which were described as simple silk capsules. Preliminary observations suggested that juvenile burrows presented differences from those of adults; however, detailed observations of A. brasilienisis burrow characteristics at the field were lacking. The aim of this study was to characterise the burrows of adults and juveniles of A. brasiliensis under natural conditions. We recorded the dimensions of burrows inhabited by males, females and juveniles (n = 30 for each category) and created beeswax moulds that reflected burrow shape. Juveniles inhabited tubular burrows with two branches and two openings; on the contrary, adults were found in tubular burrows with a single entry. Males and females inhabited burrows of similar length and width, but those of juveniles were shorter and narrower. We discuss the results and their possible functional explanations according to the selective pressures expected for each developmental stage and sex.     

Endoderm contributes to endocardial composition during cardiogenesis

Heart formation commences from a single heart tube, which fuses from bilateral primordial heart fields. The developing heart tube is composed of outerlayer myocardial cells and innerlayer endocardial cells. Several distinct populations of precardiac cells contribute to cardiac morphogenesis. However, it still remains not very clear about the lineage of endocardium at gastrulation stage. Thereby, this study focused on ascertaining the correlation between the hypoblast in gastrulation and endocardium during cardiogenesis. Firstly, the fusing heart tube morphologically is closed to endoderm-derived pharynx floor, implying the possibility that pharynx floor might be wrapped into the formation of endoderm. Secondly, HNK1 is expressed in hypoblast strongly at gastrula stage and subsequently appeared in endocardium of cardiogenesis. Moreover, fate map data displayed that DiI labeled hypoblast was also present in endocardium later on. One more evidence is chickquail chimera of hypoblast transplantation, in which quailhypoblast derivative could be identified in endocardium of cardiogenesis by QCPN antibody. In sum, our current data suggests that endoderrn in gastrula contribute at least partly to the formation of endocardium of cardiogenesis.     

Protein synthesis inhibition induced by dimethylnitrosamine and diethylnitrosamine on isolated rat hepatocytes

Summary Time- and dose-dependent protein synthesis inhibition takes place following exposure to high doses of dimethylnitrosamine (DMN) or diethylnitrosamine (DENA) in isolated rat hepatocytes. The ability of DENA to depress protein synthesis is 5-fold higher than that of DMN. Cells inhibited by 60 min exposure to DMN or DENA, and then incubated in a nitrosamine-free medium, regain their initial rate of protein synthesis. This recovery is faster and more complete for DENA-treated cells.     

The draft genome of the transgenic tropical fruit tree papaya (Carica papaya Linnaeus)

Papaya, a fruit crop cultivated in tropical and subtropical regions, is known for its nutritional benefits and medicinal applications. Here we report a 3x draft genome sequence of 'SunUp' papaya, the first commercial virus-resistant transgenic fruit tree to be sequenced. The papaya genome is three times the size of the Arabidopsis genome, but contains fewer genes, including significantly fewer disease-resistance gene analogues. Comparison of the five sequenced genomes suggests a minimal angiosperm gene set of 13,311. A lack of recent genome duplication, atypical of other angiosperm genomes sequenced so far, may account for the smaller papaya gene number in most functional groups. Nonetheless, striking amplifications in gene number within particular functional groups suggest roles in the evolution of tree-like habit, deposition and remobilization of starch reserves, attraction of seed dispersal agents, and adaptation to tropical daylengths. Transgenesis at three locations is closely associated with chloroplast insertions into the nuclear genome, and with topoisomerase I recognition sites. Papaya offers numerous advantages as a system for fruit-tree functional genomics, and this draft genome sequence provides the foundation for revealing the basis of Carica's distinguishing morpho-physiological, medicinal and nutritional properties.