mTOR signaling in neural stem cells: from basic biology to disease

The mammalian target of rapamycin (mTOR) pathway is a central controller of growth and homeostasis, and, as such, is implicated in disease states where growth is deregulated, namely cancer, metabolic diseases, and hamartoma syndromes like tuberous sclerosis complex (TSC). Accordingly, mTOR is also a pivotal regulator of the homeostasis of several distinct stem cell pools in which it finely tunes the balance between stem cell self-renewal and differentiation. mTOR hyperactivation in neural stem cells (NSCs) has been etiologically linked to the development of TSC-associated neurological lesions, such as brain hamartomas and benign tumors. Animal models generated by deletion of mTOR upstream regulators in different types of NSCs reproduce faithfully some of the TSC neurological alterations. Thus, mTOR dysregulation in NSCs seems to be responsible for the derangement of their homeostasis, thus leading to TSC development. Here we review recent advances in the molecular dissection of the mTOR cascade, its involvement in the maintenance of stem cell compartments, and in particular the implications of mTOR hyperactivation in NSCs in vivo and in vitro.     

The diagrammatic dimension of William Gilbert's De magnete

In De magnete (1600), Gilbert frequently appealed to diagrams. As result of a focus on the experimental methodology of the treatise, its diagrammatic dimension has been overlooked in the scholarship. This paper argues that, in De magnete, at least some diagrams are epistemically relevant; specifically, Gilbert moves from experiments to concepts and theories through diagrams. To show this, I analyze the role that the “Diagram of motions in magnetick orbes” plays in the formulation of Gilbert's rule of alignment of magnetic bodies within the orb of virtue (the space around a magnet where its influence is exerted). If it turns out that diagrams play a genuine role in Gilbert's magnetic investigations, then his investigative strategy goes beyond mere experimentalism.     

Breeding and parental care in the endangered Tehuantepec jackrabbit ( Lepus flavigularis )

We documented date and duration of each breeding phase, breeding rate, nursing behavior, parental care, and leveret survival of the Tehuantepec jackrabbit ( Lepus flavigularis ), a critically endangered lagomorph. Between June 2006 and May 2008, we observed 60 adult radio-collared jackrabbits in Oaxaca, México. Tehuantepec jackrabbits exhibit breeding behaviors 250 days out of the year, with a high-intensity period during the rainy season (May–October). Females give birth to 2 leverets 32 days after copulation. Directly after birth, leverets are put into “beds” or “nests,” which are depressions in the ground covered by prairie grass ( Jouvea pilosa ). Females return to nurse and groom the leverets once per day until the leverets are weaned (12 days after birth). The breeding season and parental care behaviors of Tehuantepec jackrabbits are similar to those of other jackrabbits. Females produced an average of 2 litters per breeding season. The breeding rate for the Tehuantepec jackrabbit (4 leverets per breeding female per breeding season) is lower than the average of other species in the genus Lepus. The survival rate of Tehuantepec jackrabbit leverets (50% at day 19) is higher than that of other leporids. Predation by domestic dogs ( Canis familiaris ) is the main cause of mortality. Understanding reproductive behavior is critical for captive breeding, reintro duction, and conservation efforts for endangered leporids such as the Tehuantepec jackrabbit. Documentamos la fecha y la duración de cada fase de la reproducción, la tasa reproductiva, el amamantamiento, el cuidado parental y los instintos de supervivencia de los lebratos de la liebre de Tehuantepec ( Lepus flavigularis ), un lagomorfo en peligro crítico de extinción. Entre junio de 2006 y mayo de 2008 observamos 60 liebres adultas con collares radiotransmisores en Oaxaca, Mexico. Las liebres de Tehuantepec se reproducen 250 días del año, con un período de alta intensidad durante la estación lluviosa (de mayo a octubre). Las hembras paren 2 lebratos 32 días después de la cópula; colocan a los lebratos en “camas”, o huecos en el suelo cubiertos del pasto Jouvea pilosa, justo después de nacer. Las hembras regresan para amamantar y limpiar a los lebratos una vez cada tarde hasta destetarlos 12 días después de nacer. La temporada de reproducción y el cuidado parental de la liebre de Tehuantepec son parecidos a los de otras liebres. En promedio, las hembras producen 2 crías cada temporada de reproducción. La tasa de reproducción de la liebre de Tehuantepec (4 lebratos por hembra reproductora por temporada de reproducción) está por debajo del promedio de otras especies del género Lepus. La tasa de supervivencia de los lebratos de la liebre de Tehuantepec (50% al día 19) es superior a la que se ha documentado para otros lepóridos, siendo la principal causa de mortalidad la depredación por los perros domésticos ( Canis familiaris ). Es crucial entender el comportamiento reproductor para la crianza en cautiverio, la reintroducción y para los esfuerzos de conservación de lepóridos que están en peligro de extinción tal como occure con la liebre de Tehuantepec.     

Dam-raised fawns, an alternative to bottle feeding

Rearing young ungulates for ecological studies is costly and time consuming. Doe-rearing mule deer ( Odocoileus hemionus ) fawns is a viable alternative to the common method of bottle-feeding. Fawns tamed while nurtured by their tractable dams showed no marked difference in tractability over bottle-reared orphans. The advantages of doe-rearing are better health for the young and convenience for the handler.     

Role of Chk1 in the differentiation program of hematopoietic stem cells

Hematopoietic stem cells (HSC) isolated from umbilical cord blood (UCB) were treated with ionizing radiation (IR) and sensitivity and IR induced checkpoints activation were investigated. No difference in the sensitivity and in the activation of DNA damage pathways was observed between CD133+ HSC and cells derived from them after ex vivo expansion. Chk1 protein was very low in freshly isolated CD133+ cells, and undetectable in ex vivo expanded UCB CD133+ cells. Chk1 was expressed only on day 3 of the ex vivo expansion. This pattern of Chk1 expression was corroborated in CD133+ cells isolated from peripheral blood apheresis collected from an healthy donor. Treatment with a specific Chk1 inhibitor resulted in a strong reduction in the percentage of myeloid precursors (CD33+) and an increase in the percentage of lymphoid precursors (CD38+) compared to untreated cells, suggesting a possible role for Chk1 in the differentiation program of UCB CD133+ HSC.     

Genetic variation in ecophysiological and survival responses to drought in two native grasses: Koeleria macrantha and Elymus elymoides

Genetic variation in ecophysiological and survival responses to drought was studied in 2 northern Arizona native grass species, Koeleria macrantha (Ledeb.) Schult. (prairie Junegrass) and Elymus elymoides (Raf.) Swezey. ssp. elymoides (squirreltail). Low- and high-elevation populations of each species were compared in a greenhouse common garden experiment that included simulated drought. Leaf gas-exchange characteristics were significantly affected by simulated drought and often by population elevation, but gas-exchange responses to drought were similar for high- and low-elevation populations. Compared to high-elevation populations, low-elevation populations of both species had higher net photosynthetic rate and predawn water potential, and for E. elymoides had higher stomatal conductance. Leaf-level water-use efficiency did not differ between populations for either species. Populations also differed significantly in leaf morphological characteristics related to water use. Compared to high-elevation populations, low-elevation populations of both species had smaller leaves. Low-elevation populations of both species survived aboveground longer than high-elevation populations during drought, with a larger difference in K. macrantha than in E. elymoides. These results suggest strong selection for drought adaptation and water use along an elevational and water-availability gradient in native grasses. Se estudió la variación genética en respuestas ecofisiológica y de sobrevivencia a la sequía en dos especies de pasto nativo del norte de Arizona, Koeleria macrantha (Ledeb.) Schult. (“prairie Junegrass”) y Elymus elymoides (Raf.) Swezey. spp. elymoides (“squirreltail”). Se compararon poblaciones de cada especie a elevaciones altas y bajas durante un experimento de jardín común en un invernadero que simulaba condiciones de sequía. Las características relacionadas con el intercambio de gases a nivel de hoja se vieron afectadas significativamente por la sequía simulada y con frecuencia por la elevación de la población, pero la respuesta del intercambio de gases a la sequía fue similar en las poblaciones de alta y baja elevación. En comparación con las poblaciones altas, las poblaciones bajas, en ambas especies, tuvieron una elevada tasa neta de fotosíntesis y un mayor potencial hídrico previo al amanecer; E. elymoides tuvo mayor conductancia estomática. La eficiencia en el uso del agua (EUA) a nivel de hoja no difirió entre poblaciones en ninguna especie. Las poblaciones sí difirieron significativamente en las características de la morfología de la hoja relacionadas con el uso del agua. Comparadas con las poblaciones altas, las poblaciones bajas de ambas especies tuvieron hojas más pequeñas. Durante la sequía, la parte de la planta que estaba encima de la tierra sobrevivió por más tiempo en las poblaciones bajas de ambas especies que en las poblaciones altas, con una mayor diferencia en K. macrantha que en E. elymoides. Estos resultados indican que hay una fuerte selección para la adaptación a la sequía y el uso del agua a lo largo de una gradiente de elevación y de disponibilidad de agua en pastos nativos.     

Temporal and spatial distribution of highway mortality of mule deer on newly constructed roads at Jordanelle Reservoir, Utah

In this paper we evaluated traffic characteristics and vegetation and topographic features associated with mule deer kills on 3 highways (US 40, SR 32, SR 248) in northeastern Utah. We also compared number, and sex and age composition of roadkills to that of the living population observed during spotlight counts. From 15 October 1991 to 14 October 1993 we documented 397 deer roadkills: 51.6% were does, 18.9% bucks, 21.7% fawns, and 7.8% could not be classified. Sixty-seven percent of adult kills were 2.5 yr of age. Kill composition compared closely to spotlight counts. Of 1515 spotlight deer, 65.2% were does, 8.9% bucks, and 25.9% fawns. Spotlight density and deer mortality were strongly correlated from summer 1992 through summer 1993 ( r = 0.94). Traffic conditions, topographic features, and vegetative characteristics contributed to mortality levels. Roadkills were highest along US 40 (68% year 1, 55% year 2) where traffic volume and speed were significantly higher along either state route. Large drainages intersected highways in 78% of designated kill zones. Roads adjacent to agricultural areas along all routes sustained the fewest highway mortalities. Percent cover was higher (40%) in kill zones than in other areas (29%).     

A variant associated with nicotine dependence, lung cancer and peripheral arterial disease

Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.     

Gap junction adhesion is necessary for radial migration in the neocortex

Radial glia, the neuronal stem cells of the embryonic cerebral cortex, reside deep within the developing brain and extend radial fibres to the pial surface, along which embryonic neurons migrate to reach the cortical plate. Here we show that the gap junction subunits connexin 26 (Cx26) and connexin 43 (Cx43) are expressed at the contact points between radial fibres and migrating neurons, and acute downregulation of Cx26 or Cx43 impairs the migration of neurons to the cortical plate. Unexpectedly, gap junctions do not mediate neuronal migration by acting in the classical manner to provide an aqueous channel for cell-cell communication. Instead, gap junctions provide dynamic adhesive contacts that interact with the internal cytoskeleton to enable leading process stabilization along radial fibres as well as the subsequent translocation of the nucleus. These results indicate that gap junction adhesions are necessary for glial-guided neuronal migration, raising the possibility that the adhesive properties of gap junctions may have an important role in other physiological processes and diseases associated with gap junction function.