Shortened duration of drug-induced behavioral excitation in rats with septal lesions

Resumen En las ratas, la reacción elevada de la respuesta evasiva, después de darles iproniazida y tetrabenazina aparentemente está relacionada con el suelto acrecentado de acetylcholina en al parte frontal del cerebro. Cuando las ratas con lesiones septales recibieron estas dos drogas, sus periódos resultantes de excitacion de conducta eran significantamente mas cortos que los de los controles. Como las lesiones septales producen disminución en los niveles de la acetylcholina en el cerebro, estos datos implicaron más el sistema cholinergica en la excitación producida por la iproniziada-tetrabenazina.     

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.     

Genes involved in breast cancer metastasis to bone

Metastasis to bone occurs frequently in advanced breast cancer and is accompanied by debilitating skeletal complications. Current treatments are palliative and new therapies that specifically prevent the spread of breast cancer to bone are urgently required. While our understanding of interactions between breast cancer cells and bone cells has greatly improved, we still know little about the molecular determinants that regulate specific homing of breast cancer cells to the bone. In this review, we focus on genes that have been implicated in migration and adhesion of breast cancer cells to bone, as well as genes that promote tumor cell proliferation in the bone microenvironment. In addition, the review discusses new technologies, including better animal models, that will further assist with the identification of the molecular determinants of bone metastasis and will guide the development of new therapies. Received 25 January 2002; received after revision 27 March 2002; accepted 5 April 2002 RID="*" ID="*"Corresponding author.     

Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria

We used exome sequencing to identify the genetic basis of combined malonic and methylmalonic aciduria (CMAMMA). We sequenced the exome of an individual with CMAMMA and followed up with sequencing of eight additional affected individuals (cases). This included one individual who was identified and diagnosed by searching an exome database. We identify mutations in ACSF3, encoding a putative methylmalonyl-CoA and malonyl-CoA synthetase as a cause of CMAMMA. We also examined a canine model of CMAMMA, which showed pathogenic mutations in a predicted ACSF3 ortholog. ACSF3 mutant alleles occur with a minor allele frequency of 0.0058 in ～1,000 control individuals, predicting a CMAMMA population incidence of ～1:30,000. ACSF3 deficiency is the first human disorder identified as caused by mutations in a gene encoding a member of the acyl-CoA synthetase family, a diverse group of evolutionarily conserved proteins, and may emerge as one of the more common human metabolic disorders.     

Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis

Papillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset. The PLS locus has been mapped to chromosome 11q14-q21 (refs 7, 8, 9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.     

Two-electron dissociation of single molecules by atomic manipulation at room temperature

Using the tip of a scanning tunnelling microscope (STM) to mechanically manipulate individual atoms and molecules on a surface is now a well established procedure. Similarly, selective vibrational excitation of adsorbed molecules with an STM tip to induce motion or dissociation has been widely demonstrated. Such experiments are usually performed on weakly bound atoms that need to be stabilized by operating at cryogenic temperatures. Analogous experiments at room temperature are more difficult, because they require relatively strongly bound species that are not perturbed by random thermal fluctuations. But manipulation can still be achieved through electronic excitation of the atom or molecule by the electron current tunnelling between STM tip and surface at relatively high bias voltages, typically 1-5 V. Here we use this approach to selectively dissociate chlorine atoms from individual oriented chlorobenzene molecules adsorbed on a Si(111)-7 x 7 surface. We map out the final destination of the chlorine daughter atoms, finding that their radial and angular distributions depend on the tunnelling current and hence excitation rate. In our system, one tunnelling electron has nominally sufficient energy to induce dissociation, yet the process requires two electrons. We explain these observations by a two-electron mechanism that couples vibrational excitation and dissociative electron attachment steps.