Molecular Signatures of Proliferation and Quiescence in Hematopoietic Stem Cells

Stem cells resident in adult tissues are principally quiescent, yet harbor enormous capacity for proliferation to achieve self renewal and to replenish their tissue constituents. Although a single hematopoietic stem cell (HSC) can generate sufficient primitive progeny to repopulate many recipients, little is known about the molecular mechanisms that maintain their potency or regulate their self renewal. Here we have examined the gene expression changes that occur over a time course when HSCs are induced to proliferate and return to quiescence in vivo. These data were compared to data representing differences between naturally proliferating fetal HSCs and their quiescent adult counterparts. Bioinformatic strategies were used to group time-ordered gene expression profiles generated from microarrays into signatures of quiescent and dividing stem cells. A novel method for calculating statistically significant enrichments in Gene Ontology groupings for our gene lists revealed elemental subgroups within the signatures that underlie HSC behavior, and allowed us to build a molecular model of the HSC activation cycle. Initially, quiescent HSCs evince a state of readiness. The proliferative signal induces a preparative state, which is followed by active proliferation divisible into early and late phases. Re-induction of quiescence involves changes in migratory molecule expression, prior to reestablishment of homeostasis. We also identified two genes that increase in both gene and protein expression during activation, and potentially represent new markers for proliferating stem cells. These data will be of use in attempts to recapitulate the HSC self renewal process for therapeutic expansion of stem cells, and our model may correlate with acquisition of self renewal characteristics by cancer stem cells

Re-Emergence of Crimean-Congo Hemorrhagic Fever Virus in Central Africa

Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted to humans through tick-bite or contact with infected blood or tissues from livestock, the main vertebrate hosts in a peri-domestic natural cycle. With numerous outbreaks, a high case fatality rate (3%–30%) and a high risk for nosocomial transmission, CCHFV became a public health concern in Europe and Asia. However virus surveillance in Africa is difficult due to the limited sanitary facilities. Especially, CCHFV occurrence in Central Africa is very poorly described and seems highly in contrast with the temperate to dry environments to which the virus is usually associated with. We described a single human infection that occurred in Democratic Republic of the Congo after nearly 50 years of absence. The phylogenetic analysis suggests that CCHFV enzootic circulation in the area is still ongoing despite the absence of notification, and thus reinforces the need for the medical workers and authorities to be aware of the outbreak risk. The source of infection seemed associated with a forest environment while no link with the usual agro-pastoral risk factors could be identified. More accurate ecological data about CCHFV enzootic cycle are required to assess the risk of emergence in developing countries subjected to deforestation

Animal Perception of Seasonal Thresholds: Changes in Elephant Movement in Relation to Rainfall Patterns

Background: The identification of temporal thresholds or shifts in animal movement informs ecologists of changes in an animal\u2019s behaviour, which contributes to an understanding of species\u2019 responses in different environments. In African savannas, rainfall, temperature and primary productivity influence the movements of large herbivores and drive changes at different scales. Here, we developed a novel approach to define seasonal shifts in movement behaviour by examining the movements of a highly mobile herbivore (elephant; Loxodonta africana), in relation to local and regional rainfall patterns. Methodology/Principal Findings: We used speed to determine movement changes of between 8 and 14 GPS-collared elephant cows, grouped into five spatial clusters, in Kruger National Park, South Africa. To detect broad-scale patterns of movement, we ran a three-year daily time-series model for each individual (2007\u20132009). Piecewise regression models provided the best fit for elephant movement, which exhibited a segmented, waveform pattern over time. Major breakpoints in speed occurred at the end of the dry and wet seasons of each year. During the dry season, female elephant are constrained by limited forage and thus the distances they cover are shorter and less variable. Despite the inter-annual variability of rainfall, speed breakpoints were strongly correlated with both local and regional rainfall breakpoints across all three years. Thus, at a multi-year scale, rainfall patterns significantly affect the movements of elephant. The variability of both speed and rainfall breakpoints across different years highlights the need for an objective definition of seasonal boundaries. Conclusions/Significance: By using objective criteria to determine behavioural shifts, we identified a biologically meaningful indicator of major changes in animal behaviour in different years. We recommend the use of such criteria, from an animal\u2019s perspective, for delineating seasons or other extrinsic shifts in ecological studies, rather than arbitrarily fixed definitions based on convention or common practice

An anticyclonic circulation above the Northwest Georgia Rise, Southern Ocean

Data from a variety of sources reveal a warm-core anticyclonic circulation above the Northwest Georgia Rise (NWGR), an similar to2000-m high bathymetric feature north of South Georgia. The sense of the circulation is opposite to the general cyclonic flow in the Georgia Basin. The circulation shows the characteristics of a stratified Taylor column: dimensional analysis shows that the local bathymetry and hydrography are conducive to the formation of such. ERS2 altimeter data show that the column, whilst not fully permanent, is nonetheless a recurring feature. High concentrations of chlorophyll-a are observed at the centre of the circulation, indicating that the modulation of the physical environment has significant consequences for the local biogeochemical system via enhanced primary production. Enhanced chlorophyll-a extends in a long plume from the NWGR along pathways indicated by drifters; this passive redistribution may have consequences for the larger (basin-) scale ecosystem

Model of HSC Activation Cycle

<div><p>(A) Normal HSCs reside in a quiescent niche in a “state of readiness” exemplified by the indicated genes.</p> <p>(B) Upon stress (5FU treatment), HSCs “pause” by remaining quiescent and in their niche while they “prepare” to proliferate. HSCs receive signals from proinflammatory cytokines at this point. The signals induce a proliferative state that is divisible into early (C) and late (D) phases.</p> <p>(C) “Early proliferation” is marked by an increase in expression of genes involved in DNA replication, repair, and cell migration molecules that allow movement of HSCs from the quiescence niche to the proliferative zone.</p> <p>(D) “Late proliferation” is marked by expression of many cell cycle genes as well as many energy pathway molecules.</p> <p>(E) Re-induction of quiescence involves changes in migratory molecule expression, which leads to return of cells to their quiescence niche, as well the expression of antiproliferative genes.</p></div

Gene Expression Profiles Correlate with Protein Expression on HSCs

<div><p>(A) Gene expression over time. The actual observed values of each replicate at each time point are shown in red, and the line connects the predicted expression value at each time point based on our regression analysis.</p> <p>(B) Antigen expression on HSCs measured by flow cytometry. Gray lines represent negative control, red lines represent protein expression at day 0, and blue lines represent protein expression at day 7.</p> <p>(C) Cell cycle analysis of CD48⁻ and CD48⁺ HSCs isolated 6 d post 5FU treatment.</p></div