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.     

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%).     

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.     

Transient FTY720 treatment promotes immune-mediated clearance of a chronic viral infection

For a wide variety of microbial pathogens, the outcome of the infection is indeterminate. In some individuals the microbe is cleared, but in others it establishes a chronic infection, and the factors that tip this balance are often unknown. In a widely used model of chronic viral infection, C57BL/6 mice clear the Armstrong strain of lymphocytic choriomeningitis virus (LCMV), but the clone 13 strain persists. Here we show that the Armstrong strain induces a profound lymphopenia at days 1-3 after infection, but the clone 13 strain does not. If we transiently augment lymphopenia by treating the clone-13-infected mice with the drug FTY720 at days 0-2 after infection, the mice successfully clear the infection by day 30. Clearance does not occur when CD4 T cells are absent at the time of treatment, indicating that the drug is not exerting direct antiviral effects. Notably, FTY720 treatment of an already established persistent infection also leads to viral clearance. In both models, FTY720 treatment preserves or augments LCMV-specific CD4 and CD8 T-cell responses, a result that is counter-intuitive because FTY720 is generally regarded as a new immunosuppressive agent. Because FTY720 targets host pathways that are completely evolutionarily conserved, our results may be translatable into new immunotherapies for the treatment of chronic microbial infections in humans.     

The decline and fate of an iron-induced subarctic phytoplankton bloom

Iron supply has a key role in stimulating phytoplankton blooms in high-nitrate low-chlorophyll oceanic waters. However, the fate of the carbon fixed by these blooms, and how efficiently it is exported into the ocean's interior, remains largely unknown. Here we report on the decline and fate of an iron-stimulated diatom bloom in the Gulf of Alaska. The bloom terminated on day 18, following the depletion of iron and then silicic acid, after which mixed-layer particulate organic carbon (POC) concentrations declined over six days. Increased particulate silica export via sinking diatoms was recorded in sediment traps at depths between 50 and 125 m from day 21, yet increased POC export was not evident until day 24. Only a small proportion of the mixed-layer POC was intercepted by the traps, with more than half of the mixed-layer POC deficit attributable to bacterial remineralization and mesozooplankton grazing. The depletion of silicic acid and the inefficient transfer of iron-increased POC below the permanent thermocline have major implications both for the biogeochemical interpretation of times of greater iron supply in the geological past, and also for proposed geo-engineering schemes to increase oceanic carbon sequestration.     

Neuropsychological impairment: the disturbed effect of self-processing in patients with major depressive disorder

Neuropsychological impairment has long been established as a fundamental characteristic of depression, but a generally accepted, specific pattern of neuropsycho- logical impairment has not been summarized. In this study, we examined the classic neuropsychological paradigm of self-face recognition, to explore whether the self was impaired in major depressive disorder （MDD）. Eighteen MDD patients and 20 healthy subjects were recruited to participate in this study. By using a face morphing tech- nique, we measured the size of processing bias in MDD patients during different face discrimination tasks relative to controls. Results of analysis of variance （ANOVA） showed a significant main effect of Group （F（1, 36） = 7.388, P = 0.01）. Subsequent independent t-tests further revealed that self bias （t = 2.636, P = 0.012） and self-recognition bias（t = 2.190, P = 0.035） observed in self-famous task and self-stranger task respectively for patients were significantly greater than that for controls. Both self-processing and self- recognition were impaired in patients with MDD, indicating that MDD individuals might exist level of self-abnormali- ties. These findings provide a new perspective for further study on the etiological and pathological mechanisms of MDD.     

Potentiation of cortical inhibition by visual deprivation

The fine-tuning of circuits in sensory cortex requires sensory experience during an early critical period. Visual deprivation during the critical period has catastrophic effects on visual function, including loss of visual responsiveness to the deprived eye, reduced visual acuity, and loss of tuning to many stimulus characteristics. These changes occur faster than the remodelling of thalamocortical axons, but the intracortical plasticity mechanisms that underlie them are incompletely understood. Long-term depression of excitatory intracortical synapses has been proposed as a general candidate mechanism for the loss of cortical responsiveness after visual deprivation. Alternatively (or in addition), the decreased ability of the deprived eye to activate cortical neurons could be due to enhanced intracortical inhibition. Here we show that visual deprivation leaves excitatory connections in layer 4 (the primary input layer to cortex) unaffected, but markedly potentiates inhibitory feedback between fast-spiking basket cells (FS cells) and star pyramidal neurons (star pyramids). Further, a previously undescribed form of long-term potentiation of inhibition (LTPi) could be induced at synapses from FS cells to star pyramids, and was occluded by previous visual deprivation. These data suggest that potentiation of inhibition is a major cellular mechanism underlying the deprivation-induced degradation of visual function, and that this form of LTPi is important in fine-tuning cortical circuitry in response to visual experience.     

ATM stabilizes DNA double-strand-break complexes during V(D)J recombination

The ATM (ataxia-telangiectasia mutated) protein kinase mediates early cellular responses to DNA double-strand breaks (DSBs) generated during metabolic processes or by DNA-damaging agents. ATM deficiency leads to ataxia-telangiectasia, a disease marked by lymphopenia, genomic instability and an increased predisposition to lymphoid malignancies with chromosomal translocations involving lymphocyte antigen receptor loci. ATM activates cell-cycle checkpoints and can induce apoptosis in response to DNA DSBs. However, defects in these pathways of the DNA damage response cannot fully account for the phenotypes of ATM deficiency. Here, we show that ATM also functions directly in the repair of chromosomal DNA DSBs by maintaining DNA ends in repair complexes generated during lymphocyte antigen receptor gene assembly. When coupled with the cell-cycle checkpoint and pro-apoptotic activities of ATM, these findings provide a molecular explanation for the increase in lymphoid tumours with translocations involving antigen receptor loci associated with ataxia-telangiectasia.