Human pressure on forests, caused by population growth, diffused poverty and lack of alternatives, is increasing, leading to extensive forest degradation and deforestation (Rijal and Meilby, 2012). Salerno et al. (2010) assessed an average decrease of 38% in forest biomass between 1992 and 2008 in the Khumbu Valley. Nonetheless, the development of sustainable

management plans, taking into account both ecological and socio-economic issues, is often limited by the lack of knowledge on forest structure and of awareness about human impact on the ecosystem (Rijal and Meilby, 2012). The measured effects of forest exploitation on stand structure and tree species composition confirmed the recent hypothesis that forest degradation has a stronger impact than deforestation in SNPBZ (Stevens, 2003 and Byers, 2005). Trekking GSK-3 inhibitor review tourism is still increasing in the SNP and is seriously affecting the Sherpas traditional use of natural resources (Byers, 2009 and Spoon, 2011). Forest degradation and shrub removal (especially Juniperus

wallichiana) are the more evident effects of this socio-cultural change. A land cover change analysis recently performed in the area ( Bajracharya et al., 2010) mTOR inhibitor revealed that between 1992 and 2006 the most significant shifts were the reduction of mixed forest cover, together with an increase of dwarf shrubs at 3000–4000 m a.s.l. and a reduction of shrubland at higher elevations (4000–5000 m a.s.l.). The overall change in forest and shrub communities was negligible (−4% and −9% respectively) compared to the relevant increase (47%) of dwarf shrubs at 3000–4000 m Tacrolimus (FK506) a.s.l. Prior to 1950, the Sherpa people extensively clearcut woodlands

and converted them into pastures and villages. Land use/cover change is a further driver of erosion risk in Himalayas, a region characterized by heavy rainfalls (Valdiya and Bartarya, 1989, Rawat and Rawat, 1994 and Tiwari, 2000). Soil erosion and mass movement are often related to human activities such as deforestation, overgrazing and building construction in vulnerable sites (Shrestha et al., 2004), but natural disturbances can sometimes override human influence (Bruijnzeel and Bremmer, 1989 and Messerli and Hofer, 1992). In the last decades excessive tree felling without any silvicultural rationale, became the most common forest practice and is still widespread. The prohibition to log living trees inside the national park has caused the increasing removal of green limbs and branches (especially of P. wallichiana) causing severe mechanical damage and growth and survival limitations to the trees ( Gautam, 2001, Gautam and Watanabe, 2002, Bhat et al., 2000 and Pandey and Shukla, 2001). In addition, since the removal of deadwood is still allowed within the park, stems are often purposely injured in order to hasten their death.

All other landslides are observed in anthropogenic environments with the majority of landslides (i.e. 70%)

in the matorral and 17% of the landslides in short rotation pine plantations. In contrast, in the Panza subcatchment, 34% of the total number of landslides is located in a (semi-)natural environment (i.e. 13% in páramo and 21% in natural dense forest) while 48% of the landslides is observed in agricultural land. In Llavircay, SCH772984 a quarter of the total landslides are observed in natural environments. The multi-temporal landslide inventories include raw data that are derived from different remote sensing data. To ensure that the data source has no effect on the landslide frequency–area distribution, landslide inventories of

different data sources were compared. Only the (semi-)natural environments were selected for this analysis, to avoid confounding with land use effects. We observe no significant difference in landslide area between the inventory derived from aerial photographs and the one derived from very high resolution remote sensing data (Wilcoxon rank sum test: W = 523, p-value = 0.247). Moreover, the landslide frequency–area distributions are independent of the source of the landslide inventory data (Kolmogorov–Smirnov test: D = 0.206, p-value = 0.380). As Crizotinib research buy the landslide inventory is not biased by the data source, we used the total landslide inventories to analyse the landslide frequency–area distribution. The number of landslide occurrences in the two sites in the Pangor catchment was too low to calculate the probability density functions. Therefore, the landslide inventories from both sites (Virgen Yacu and Panza) were combined to get a complete landslide inventory that is large enough to capture the complexity of land cover dynamics present in the Pangor catchment. However, Llavircay and Pangor (including Virgen Yacu and Panza) are analysed distinctively as to detect potential variations resulting from different climatic regimes. Fig. 5 gives the landslide frequency–area distribution for

the landslide inventories Idoxuridine of the Llavircay and Pangor site. It also shows that the double Pareto distribution of Stark and Hovius (2001) and the Inverse Gamma distribution of Malamud et al. (2004) provide similar results. The probability density for medium and large landslides obeys a negative power law trend. The power law tail exponent (ρ + 1) is equal for the double Pareto distribution and for the Inverse Gamma distribution, respectively 2.28 and 2.43 in Pangor and 2 and 2.18 in Llavircay ( Table 3). The model parameter values are obtained by maximum likelihood estimation, but they are similar to those obtained by alternative fitting techniques such as Kernel Density or Histogram Density estimation. Besides, the model parameter values that we obtain here for the tropical Andes are very similar to previously published parameter estimates ( Malamud et al., 2004 and Van Den Eeckhaut et al., 2007).

Compared to DNA in the intracellular environment, “bare” DNA is quite sensitive and vulnerable to direct damage on exposure to hydrophobic PAHs. These persistent lipophilic organic contaminants with high biological affinity are ubiquitous in the environment [14]. Owing to their strong hydrophobic properties, PAHs have greater affinity for such organic substances as compared to other organic contaminants or heavy metals. Therefore, the PAHs in the same environmental background may be capable of partitioning organic substances. Any “bare” germplasm released into the soil or water is directly

exposed to these hazardous materials. The extracellular interaction of DNA with PAHs is completely different from that in an intracellular environment. C59 wnt price Fig.

1 shows the main pathway by which PAHs affect intracellular DNA. In it, the PAH molecules are first catalyzed into “OH–PAH” by a series of enzymes, and the active “ OH” functional groups in the PAH molecules combine with the bases of DNA by forming chemical “DNA adducts” based on chemical bonds [15]. In contrast, the interaction of PAHs with free DNA in the extracellular environment is based on weak molecular forces. Although changes in the structure, backbone Selleck Etoposide composition, and guanine constituents of DNA induced by PAHs which can be inserted into double strands have been observed, and imidazole-like derivatives are produced from the combination of imidazole rings with pyrene [5] and [17], PAHs lack active

functional groups related to the functional sites of DNA, and no enzyme catalysis occurs in the extracellular environment. Therefore, the changes in DNA seen in the extracellular environment cannot Epothilone B (EPO906, Patupilone) be attributed to the formation of chemical bonds between DNA and PAHs, but are linked to the weak molecular forces between DNA molecules and PAHs. In other words, polar DNA molecules can induce relative displacement between the electron cloud and atomic nucleus of non-polar PAHs, causing the appearance of dipoles with excellent induction forces in PAH molecules. These induction forces of the PAH molecules then attract polar DNA molecules with their innate dipoles [15]. PAHs are inserted into grooves in DNA (Fig. 2A and B) or between bases (Fig. 2C and D) through dispersion force and π–π overlap between PAHs and bases. Free calcium ions enhance the efficiency of DNA transformation into bacterial recipients by forming hydroxyl–calcium phosphate complexes in DNA [6]. The interaction between “bare” DNA and PAH molecules is based on a weak molecular force, which implies that such weak molecular forces are more strongly affected by the chemical bonds of Ca-DNA. Fig. 3 supports this viewpoint. The transformational efficiency of DNA plasmids (pUC19) with no PAHs and Ca2+ is 4.7 (PAHs are exposed to plasmid DNA and did not directly contact with host cell (E. coli DH5a)).

0009) and an interaction of these two factors (F = 4.68, df 1, 14, p < 0.05) by two-way ANOVA for IFNβ. The hippocampal induction of IFN-α was less marked and more variable. Nonetheless, there AZD2281 was an interaction between disease and poly I:C for this gene (F = 5.68, df 1, 14, p < 0.05). TLR3 mRNA was induced in the hippocampus both by poly I:C treatment and by ME7. Two-way ANOVA revealed a main effect of both poly I:C (F = 41.38, df 1, 14, p < 0.0001) and of ME7 (F = 24.3, df 1, 14 p = 0.0002) but there was no significant interaction, although

TLR3 was induced further by poly I:C challenge in ME7 animals (one-way ANOVA, ME7 + poly I:C versus NBH + poly I:C p < 0.01 and versus ME7 + saline p < 0.001). RIG-I showed similar expression to IFNβ, with main effects of disease (F = 59.21, df 1, 14, p < 0.0001) and of poly

I:C (F = 351.86, df 1, 14, p < 0.0001) and a significant interaction of these two factors (F = 9.97, df 1, 14, p < 0.01). Thus anti-viral responses were amplified in ME7 + poly I:C animals with respect to NBH + poly I:C. These transcripts (IFNβ, IFNα, TLR3, RIG-I) were also examined in the hypothalamus since this region is highly sensitive to circulating inflammatory mediators. Poly I:C induced robust transcription of all 4 genes in the hypothalamus, but this transcription was equivalent in ME7 and NBH animals. These data are shown in Fig. 1b. Two-way ANOVAs for these genes showed that there were main effects of poly I:C in all cases, but no effect of ME7 and no interaction between the two factors (F = 1.62, df 1, 14, p > 0.22 Adenosine in all cases). Thus,

the exaggerated anti-viral response of ME7 animals, to poly I:C, is present selleck screening library in the hippocampus, but not in the hypothalamus. The levels of IFNβ, TNF-α and IL-6 were elevated in the plasma of poly I:C-treated animals (6 h post-treatment) but were below detectable levels in both NBH and ME7 animals challenged with sterile saline (Table 1). Poly I:C groups were significantly different to relevant saline controls for IFNβ (p < 0.001), TNF-α (p < 0.01) and IL-6 (p < 0.05) by Bonferroni post hoc tests. Treatment with poly I:C did not produce significantly different cytokine levels in NBH versus ME7 animals (p > 0.05 for all three cytokines). Therefore, systemic cytokine responses to poly I:C are not significantly different in animals with prior neurodegeneration. At the earliest time point examined (14 weeks post-inoculation with ME7, 4 h after poly I:C), poly I:C induced the predicted mild hyperthermic response in normal (NBH) animals but caused hypothermia in prion-diseased (ME7) animals. In addition, the later hypothermic phase was exaggerated in ME7 animals with respect to NBH animals treated with poly I:C (Fig. 2). Repeated measures ANOVA revealed a significant effect of time (F = 5.66, df 4, 160, p < 0.0005), a significant effect of treatment (F = 9.29, df 3, 40, p < 0.0001) and an interaction of treatment and time (F = 6.46, df 12, 160, p < 0.0001).

Most likely, the quantity

of fungal inoculum in the soil would be far less concentrated than the artificial suspensions used to inoculate the roots in the present study. When the maize roots were treated with a moderate level of F. verticillioides inoculum, the resistant lines supported less fungal growth than the susceptible ones. Typical lesions and runner hyphae in mosaic patterns of colonization were readily observed on the roots of susceptible lines, whereas the cells in the roots of resistant lines tended to become necrotic, apparently limiting hyphal extension within the root tissues. The cellular junctions that form between the lateral roots and root hairs are considered to be the entry points for penetration into the root tissues [39]. Verticillium longisporum (C. Stark) Karapapa, Bainbr. & Heale 1997, Fusarium oxysporum Schlecht. Ruxolitinib ic50 emend. Snyder & Hansen, and Klebsiella oxytosa Klebsiella oxytoca (Schroeter 1886) Trevisan 1887 initially enter roots by following the root hairs [40], [41] and [42]. There might exist a common mode of infection used by vascular pathogens to enter root hair zones where they first Selleck AG-14699 attach and then penetrate directly into the epidermal cells, due to a stronger chemical attraction of the fungus to

the root hairs than the root surface [7] and [41]. A similar observation that the root hairs are entry points of F. verticillioides into the inner and upper parts of maize was made in the present study. The roots of resistant maize lines (i.e.,

Qi 319, Dan 340 and Zhongzi 01) had fewer root hairs than susceptible lines (i.e., B73, Lu 9801 and P138), and were less heavily colonized by the pathogen. Analysis of CFU at the same time-points showed that the quantities of F. verticillioides in the roots of susceptible maize lines were higher than in those of resistant lines. Several factors influenced the accumulation of toxin when F. graminearum attacked root system of barley [11]. Factors such as ambient pH, amylopectin concentration, nitrogen limitation, and carbon nutrient specificity also affected FB1 production check details in F. verticillioides infections of maize [14] and [43]. Although acidic conditions are reported to be favorable for the production of FB1, no significant difference in pH of the roots of susceptible and resistant maize lines was observed in the present study. The amount of amylopectin in maize roots was below the limit of detection. The titers of FB1 that accumulated in susceptible maize roots were greater than those in the resistant roots. The CFU values at 144 HAI were significantly associated with the production of FB1. This suggests that the quantity of F. verticillioides seems to be a main factor determining the production of FB1 at the early stages of the plant–fungus interaction. FB1 toxin was shown to induce PCD in Arabidopsis thaliana leaves and in protoplasts of maize leaves [17] and [18].

Findings were not explained by a lack of vividness in imagining the items or by a difference in tendency to use mental imagery in the high dysphoric group. In Study 2, objective ratings confirmed that the descriptions of ambiguous scenarios imagined by a high compared to low dysphoric group were more negative in content. This is consistent with AST-D differences not merely being due to diminished positive affect for the same scenario outcome, but to differing interpretations of the outcome itself. Overall, the AST-D shows promise as a tool to assess interpretation biases for CBT treatment monitoring,

experimental research such as CBM-I paradigms (e.g. Blackwell & Holmes, 2010) learn more and during fMRI studies on similar topics (e.g. Browning, Holmes, Murphy, Goodwin, & Harmer, 2010). These studies have a number of limitations. For example, they were conducted on non-clinical samples of students, and validating the AST-D in a general population as well as a clinical sample would be useful. In Study 2, time passed between the imagination and description of the scenarios. While this may have introduced extra variablity

and weakened the results, a convergence between objective and subjective ratings was still found. Successful use of the AST-D in the environment of a MR scanner, suggests wide applicability. Finally, since some research suggests that lack of positivity bias is not the same as a negativity bias and there are different correlates, albeit in a different information processing framework (e.g. Hayden, Klein, Durbin, & Olino, 2006), further research might seek to develop versions of the AST-D, which could test this possibility. Overall, results suggest the potential Gefitinib research buy utility of the AST-D as a simple and thus pragmatic tool to assess interpretation bias associated with depressed mood. Depression and anxiety are highly comorbid and the relation between the two was beyond the scope of the current study but may be of interest in future studies. Since negative interpretation bias is central to cognitive models of depression, and measures are currently lacking both experimentally and in the clinic, the development of tools such as the AST-D is in high

demand. This research was supported by a Lord GPX6 Florey Scholarship of the Berrow Foundation and an Eugenio Litta scholarship, awarded to Chantal Berna, a Department of Psychiatry Bursary for Overseas students and a Linacre college EPA Cephalosporin Scholarship awarded to Tamara J. Lang, and a Wellcome Trust Clinical Fellowship (WT088217) and a grant from the Lupina Foundation awarded to Emily A Holmes. We thank Irene Tracey, Andrea Reinecke and Louise Acker for their support with the study. We are grateful to Andrew Mathews, Bundy Mackintosh and Laura Hoppit and other CBM colleagues for inspiration and earlier work on related scenarios. “
“In the above article Fig. 4 contains two parts, but only one part appeared in the issue above. The correct Fig. 4 is included here.

If many scenarios and hypotheses are to be explored, it seems more adequate to have a model interface targeted at scientists

rather than stakeholders, i.e., it should be flexible, generic, compute fast, and generate synthetic and clear output. A model interface with buttons, menus, etc. obliges the modelling to follow some fixed and pre-defined lines set up by the original model developer, and this may come at costs in terms of flexibility to address new thoughts and ideas, and may create parameterization issues if data is lacking to fit the model frame [82]. Three out of our four cases (pelagic, Mediterranean, Nephrops) made use of the FLR modelling framework [72]. Based on the R freeware (R development Core Team 2010), this framework is far from what could be considered a user-friendly interface, and requires advanced technical skills and an initial steep learning curve. However, its modular “Lego blocks” approach, where various small pieces www.selleckchem.com/products/KU-60019.html of standard code can be put together by individual modelers within a loose modelling framework, has proven to be flexible and efficient to address widely different questions (cf. e.g., BEZ235 mw tutorials

and publications list on www.flr-project.org). JAKFISH scientists also tested other types of communication tools, developing innovative types of graphs and figures to describe the results and their uncertainties (e.g., Bayesian influence diagrams), and using clear model description tools such as the pedigree matrices. The Baltic case study built on an integrated Bayesian framework, which did include an interactive and attractive interface (Hugin) for the initial conceptual phase of mental modelling [85]. For this particular purpose, the interface proved appropriate and appreciated. Despite its attractiveness, the interface was not operated by the stakeholders themselves but served only to support the discussion around model development.

In summary, there are many ways to communicate around modelling issues triclocarban within a participatory modelling process; different tools have emerged. It is recommended to follow guidelines, or formalized approaches, to facilitate a structured dialogue, because a functioning communication between modelers and stakeholders is important. Although being time-consuming and beyond the traditional scientific tasks, functioning communication constitutes an absolute requirement for successful participatory modelling. So far, participatory modelling is a relatively new approach in European natural resource governance with only few exercises that have been carried out. It is foremost an object of research, not an approved method. The four JAKFISH case studies shed light on possible ways, their pros and cons to put the concept into practice. A variety of types, forms and tools of participatory modelling were identified and tested in case studies over a one to three year time frame.

The copepod Eurytemora americana showed in this year the maximal population abundance registered for the estuary over the last decade ( Berasategui et al., 2009 and Hoffmeyer and Prado Figueroa, 1997). Light availability, although may have played a significant role in bloom initiation, was not a determining factor of bloom selleckchem duration as underwater light penetration remained high over the next two months after the event ended. Dissolved nutrient concentrations were high

all-year round, except during the blooming season (see Fig. 2c). This annual pattern is relatively constant in the inner zone of the Bahía Blanca Estuary, where the nutrients notably decrease in the water column during late winter-early spring in relation to microalgae consumption (Guinder et al., 2010 and Popovich et al., 2008). In the present study, the estimation of nutrient ratios (data not shown) indicated a limitation (Popovich et al., 2008 and references therein) in phosphate (N:P >20–30) and in nitrogen (N:P <10 and Si:N >1) in some dates toward the end of the blooming season. The beginning of the winter bloom was dominated by small diatom species like Chaetoceros

sp. (3–8 μm) and Cyclotella sp. (5–12 μm), which showed a peak of abundance in June–July. The abrupt population decrease of these diatoms in July–August could be related with predation by microzoopankton ( Barria de Cao et al., 2005 and Pettigrosso and Popovich, 2009) and nauplii of E. americana ( Berasategui et al., 2012). Although this small-sized copepod stage was not considered in this study, as we used a net of 200-μm mesh ( Berasategui et al., 2012 and Grice, 1970), it learn more is well known that in the Bahía Blanca Estuary, hatching of resting eggs of E. americana occurs between May–July under conditions of low temperature, high salinity

and high chlorophyll levels and nauplii feed on small sized-phytoplankton ( Berasategui et al., 2012 and Berasategui et al., 2013). The adult stage of E. americana feeds preferentially on large species of the phytoplankton winter assemblage, i.e. Thalassiosira spp. many ( Hoffmeyer and Prado Figueroa, 1997). The selective grazing of the adult of E. americana on large cells might reduce the relative abundances of these diatoms in the mid-late winter bloom. In this study, no fixatives were added to the containers in order to evaluate the accumulation of particulate matter near the bottom over time, embracing also natural processes of production and decomposition (Schloss et al., 1999 and Varela et al., 2004). On the one hand, not using preservatives eliminates the risk of overestimating the sedimentation due to swimmer contamination (i.e. vertically migrating phototrophic micro-organisms) (Heiskanen and Leppänen, 1995 and Heiskanen et al., 1998). On the other hand, when fixatives are not used, the actual sedimentation of organic matter can be slightly underestimated (e.g.

However, it has been proposed that small amounts of Cr(III) enter the cell through the energy intensive process of pinocytosis. Carcinogenic Cr(VI) is commonly present in tetrahedral coordination and thus emulates biological phosphates and sulphates. Therefore it can be readily taken up through channels for the transfer of the isoelectric and isostructural anions into cells. Following oral administration of Cr(VI), it is efficiently detoxified upon reduction by saliva and gastric

juice, and sequestration by intestinal bacteria (De Flora, 2000). Chromium(VI) absorbed by the intestine is effectively reduced in the blood and then in the liver. This is in agreement CT99021 in vitro with rather low genotoxicity and carcinogenicity of Cr(VI), with the exception of long-term exposed individuals to high doses of this carcinogenic metal (De Flora et al., 1990). In the lungs (and also in the liver) Cr(VI) is efficiently reduced probably by the glutathione (Izzotti CX-5461 et al., 1998). Thus the risk of lung cancer increases

only when Cr(VI) doses overwhelm the cellular defense mechanisms. The process of intracellular reduction of Cr(VI) by chelators reduces pools of this potentially carcinogenic metal ion (Fig. 3). Enhanced diffusion of Cr(VI) from plasma to erythrocytes represents a mechanism of depletion of Cr(VI) from blood plasma. In the erythrocytes, in the course of detoxification of Cr(VI), it is reduced to lower oxidation states and forms chromium protein complexes (Kerger

et al., 1997 and Petrilli and De Flora, 1978). Complexed chromium with various ligands, cannot leave the cell and move back into the plasma (Zhitkovich, 2005 and De Flora et al., 1995). It has been estimated, that that the rate of uptake of Cr(VI) by red blood cells is synchronised with the reduction capacity of Cr(VI) to Cr(III) species. The process of reduction of Cr(VI) to Cr(III) by chelation is not absolutely safe, because during this process various free radicals are generated, which will result either in activation or in detoxification depending on the site of the intracellular reduction and its proximity to DNA. The results have shown that ascorbate is the most efficient biological reductant of Cr(VI) in cells under in vivo Baricitinib conditions and plays a dual role in Cr(VI) toxicity: protective-antioxidant outside and prooxidative inside the cell. In fact, reactions utilizing ascorbate in the reduction of chromium(VI) inside the cells generate high levels of chromium–DNA adducts and produce mutation-inducing DNA damage (Fig. 3) (Quievryn et al., 2003, Quievryn et al., 2002 and O’Brien et al., 2002). In addition to primary reduced Cr(VI) by ascorbate, it can be accomplished through non-enzymatic reactions with cysteine and glutathione; however, in the target tissues of chromate toxicity, such as lung, ascorbate is the primary reducer of Cr(VI).

Osteogenesis Imperfecta was the first disease for which a stem cell-based type of intervention was envisioned [43], and in which targeting

the genetic defect in stem cells ex vivo was attempted [44] and [45]. The gene defect causing FD is a dominant, gain-of-function point mutation in a ubiquitously expressed, indispensable gene. Gene correction in FD thus requires silencing of the mutated allele with absolute specificity, which per se is a greater challenge in gene therapy than gene replacement. Nonetheless, the FD-causing mutation can be efficiently and specifically corrected in human stromal progenitor ex vivo using lentivirally expressed shRNAs, resulting in reversion of the fundamental cellular phenotype represented SCH772984 datasheet by excess production of cAMP [46]. Of note, as specific genetic defects can be corrected ex vivo in skeletal stem cells, several systemic, often lethal, skeletal diseases such as Osteogenesis Imperfecta and FD could be cured as of today, if systemic infusion

of skeletal stem cells was at all feasible in the simplistic way in which it was first envisioned. Unfortunately, we are not there yet. Nonetheless, the use of stem cells, including gene-corrected BMS-907351 concentration stem cells for treating systemic diseases of the skeleton remains unfeasible until ways to deliver stem cells systemically to the skeleton becomes feasible. Conversely, stable transduction of normal stromal progenitors with disease genes using last generation lentiviral vectors provides

an additional tool for investigating the functional effects of a disease gene. In the case of FD, this exercise revealed, for example, the induction of RANKL as a robust and specific effect of the GNAS mutation, directly relevant to the origin of excess osteoclastogenesis and remodeling in FD [46], very and made it possible to investigate the transcriptome of newly mutated cells with appropriate controls and statistical robustness, circumventing the unpredictable variability of primary cultures derived from clinical material (manuscript in preparation). Hematopoietic and non-hematopoietic cancer (primary and secondary) is a major determinant of skeletal morbidity, and for this reason, cancer in bone is the source of major clinical, social and healthcare concerns. Until very recently, myeloma and metastatic growth of primary epithelial cancers were the specific focus of interest, reflecting both the occurrence of gross bone lesions as a result of their growth, and of the ease with which such lesions could be traced to an unbalance in remodeling. In this context, interest in the interaction of cancer cells with bone essentially excluded consideration of a potential role for skeletal stem cells as partners or players of the cancer–bone interaction, and in most cases even consideration of a role for bone marrow stromal cells at large.