Kodandaramireddy Nalapareddy

Hong Jiang

Luis Miguel Guachalla Gutierrez

K Lenhard

Determining the influence of telomere dysfunction and DNA damage on stem and progenitor cell aging -what markers can we use?

Telomere dysfunction

Telomeres are repetitive DNA sequences that cap the ends of eukaryotic chromosomes [START_REF] Blackburn | The telomere and telomerase: nucleic acid-protein complexes acting in a telomere homeostasis system[END_REF]. Telomere capping is required to prevent an activation of DNA damage signaling at the chromosome termini. It has been proposed that individuals are born with long telomeres (10-15 kbs in humans), and that aging is in part the result of a decrease in telomere length. In cell culture, telomeres shorten during each cell division [START_REF] Harley | Telomeres shorten during ageing of human fibroblasts[END_REF] due to the "end-replication-problem" of DNA polymerase and due to processing of telomeres during the cell cycle. In response to critical shortening, telomeres lose their capping function at the chromosome ends.

Uncapped, dysfunctional telomeres trigger DNA damage responses that lead to an activation of the p53 pathway [START_REF] Chin | p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis[END_REF]. Two checkpoints limit the lifespan of primary human fibroblast in response to telomere dysfunction: The first checkpoint (first mortality stage = M1) induces a permanent cell cycle arrest named 'senescence' [START_REF] Wright | The two-stage mechanism controlling cellular senescence and immortalization[END_REF]. Cells with impaired p53 checkpoint function can bypass senescence and continue to proliferate despite the presence of dysfunctional telomeres. However, continuous telomere shortening leads to further accumulation of telomere dysfunction inducing a second checkpoint (second mortality stage = M2) named 'crisis'. Crisis is a p53independent event and is characterized by massive chromosomal instability and cell death [START_REF] Wright | The two-stage mechanism controlling cellular senescence and immortalization[END_REF]). Both senescence and crisis limit the replicative lifespan of human cells, thus, acting as tumor suppressor mechanisms that limit the lifespan of transformed cells [START_REF] Wright | The two-stage mechanism controlling cellular senescence and immortalization[END_REF]. As a downside, these checkpoints could also contribute to the exhaustion of cellular functions impairing organ maintenance during ageing.

Most human tissues and organs show significant telomere shortening during ageing including peripheral blood cells, lymphocytes, kidney epithelium, vascular endothelial cells, hepatocytes, intestinal epithelial cells, lung epithelial cells, muscle, and others [START_REF] Jiang | Telomere shortening and ageing[END_REF]. However, there is still a continuous debate whether this level of telomere shortening leads to telomere dysfunction impairing organ maintenance and regeneration during human aging. In the following section we briefly review experimental studies investigating the prevalence of telomere dysfunction, DNA damage, and checkpoint induction (senescence and apoptosis) during organismal aging.

Telomere dysfunction and DNA damage during aging

It has been postulated that accumulation of DNA damage can contribute to human aging [START_REF] Lieber | Ageing, repetitive genomes and DNA damage[END_REF]. Several mechanisms can induce DNA damage in cells including replication errors, telomere shortening and generation of reactive oxygen species (ROS), toxic metabolites, background irradiation, ultraviolet radiations and exposure to environmental toxins among others [START_REF] Vijg | The role of DNA damage and repair in aging: New approaches to an old problem[END_REF]. Different types of DNA lesions occur in response to these different types of damage including the oxidation of nucleotides, single-and double-strand breaks, depurinations, depyrmidations, interstrand crosslinks, and telomere dysfunction. Despite the prevalence of telomere shortening in almost all human tissues during aging [START_REF] Jiang | Telomere shortening and ageing[END_REF], the relative contribution of telomere dysfunction to organismal aging remains under debate. Telomere dysfunction represents a deleterious type of DNA damage due to the limited capacity of cells in repairing telomeric lesions. It has been suggested that micro-homology based mechanisms lead to the induction of chromosomal fusion in response to telomere dysfunction [START_REF] Maser | Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers[END_REF]. However, chromosomal fusions are not stable and are prone to breakage when cells enter the cell cycle. It has also been shown that single dysfunctional telomeres induce repeated fusion/breakage cycles that lead to chromosomal instability [START_REF] Sabatier | The loss of a single telomere can result in instability of multiple chromosomes in a human tumor cell line[END_REF] and may account for increased cancer formation during aging.

DNA damage responses elicited by dysfunctional telomeres appear to be similar to those induced by DNA double strand breaks. The earliest response is the formation of DNA damage foci containing different proteins such as 53bp1, Mdc1, Mre11, Rad50, Nbs1, among others (d' Adda di Fagangna et al. 2003). These proteins have a functional role in detecting and processing damaged DNA and furthermore activate downstream signaling pathways. In addition, DNA damage foci contain γH2AX, a phosphorylated form of the histone H2AX.

As discussed above, it is difficult to discriminate the DNA damage responses elicited by dysfunctional telomeres from that of DNA breaks within the genome. In contrast to the DNA damage foci formed at dysfunctional telomere (d' Adda di Fagangna et al., 2003), extra-telomeric DNA damage involves the formation of DNA damage foci throughout the genome [START_REF] Sedelnikova | Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks[END_REF]. To distinguish telomere dysfunction induced DNA damage foci (TIFs) from DNA breaks within the genome investigators have used co-staining for (i) telomere components (telomere fluorescence in situ hybridization, immunofluorescence against telomere binding proteins: Trf1, Trf2) and (ii) DNA damage foci components. The drawback of this assay is that TIFs normally form at telomere-free chromosome ends containing no or very low amounts of telomeric DNA and telomere binding proteins. Therefore, costaining techniques likely underestimate the contribution of TIFs to the total amount of DNA damage foci in cells or tissues.

Studies on organismal aging have revealed some evidence for an accumulation of DNA damage during ageing (Table 1). In aging mice an increase in the percentage of organ cells containing DNA damage (γH2AX) foci has been seen in various organs like liver (9% of the cells), testis (11% of the cells), kidney (12% of the cells), lung (15% of the cells), and brain (7.4% of the cells, [START_REF] Sedelnikova | Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks[END_REF]. In this study only a minor proportion (10-15%) of DNA damage foci was found to co-localize with telomeric markers (TIFs). However, as discussed above, it is possible that this method underestimates the true co-localization to telomeres. Studies on aging baboons have specifically addressed this question by quantification of γH2AX foci at telomeres [START_REF] Herbig | Cellular senescence in aging primates[END_REF][START_REF] Jeyapalan | Accumulation of senescent cells in mitotic tissue of aging primates[END_REF].These studies revealed an increase in γH2AX foci at telomeres in aging skin, but not in other organs such as muscle.

In humans, an increase in DNA damage foci has been observed in lymphocytes during aging (Sedelnikova et al., 2008) and in intestinal epithelial cells of patients with colitis ulcerosa (Risques et al., 2008) -a chronic inflammatory disease associated with accelerated telomere shortening. In addition, an increase in DNA double strand and single stand breaks was detected in aging sperm (Schmid et al., 2007, Singh et al., 2003) in brain of patients with Alzheimer disease [START_REF] Mullaart | Increased levels of DNA breaks in cerebral cortex of Alzheimer' s disease patients[END_REF], and in peripheral blood lymphocytes (Chicca et al. 1996). Moreover, an increase in DNA damage signals has been observed in some tissues of aging humans including kidney [START_REF] Melk | Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney[END_REF], skeletal muscle (Welle et al., 2004), bone marrow stroma (Zhou et al., 2008), and brain of patients with Alzheimer's disease [START_REF] Cenini | Elevated levels of pro-apoptotic p53 and its oxidative modification by the lipid peroxidation product, HNE, in brain from subjects with amnestic mild cognitive impairment and Alzheimer' s disease[END_REF]. However, there is accumulating evidence for a decline in stem cell function during aging [START_REF] Rando | The immortal strand hypothesis: segregation and reconstruction[END_REF].

Studies on DNA repair deficient mice and telomerase knockout mice have shown that DNA damage [START_REF] Nijnik | DNA repair is limiting for haematopoietic stem cells during ageing[END_REF] and telomere dysfunction [START_REF] Rossi | Stems cells and the pathways to aging and cancer[END_REF], Choudhury et al., 2007) limit the function of adult stem cells. The impaired function of hematopoietic stem cells (HSCs) in response to telomere dysfunction involves both the activation of stem cell intrinsic checkpoints and alterations of the stem cell environment (Ju et al., 2007b). The relative contribution of these mechanisms to human aging remains to be determined (Song, 2008). Studies on aging telomerase deficient mice have also revealed a decrease in HSC maintenance compared to wild type mice [START_REF] Choudhury | Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation[END_REF]. In contrast to the decline in hematopoietic progenitor cells during human aging, the number of HSCs increases during aging in some laboratory inbred mouse strains including the C57Bl/6J strain. In aging telomere dysfunctional mice and in mouse mutants with impaired DNA damage repair this agedependent increase in HSC number is reduced compared to wild type mice (Rossi et al. 2007). Also in absolute number there was a reduction in HSC numbers in bone marrow of aged telomere dysfunctional mice compared to wild type mice [START_REF] Choudhury | Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation[END_REF]). Together, these results indicate that DNA damage and telomere dysfunction can impair the self renewal of HSCs. Similar findings appear to hold true for intestinal stem cells since there is a strong reduction in basal crypts in aging telomere dysfunctional mice compared to wild type mice [START_REF] Choudhury | Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation[END_REF], Schaetzlein et al. 2007). In contrast, there are reports on increased number of label retaining cells in hair bulge of telomere dysfunctional mice compared to wild type mice (Flores et al. 2005). It needs yet to be confirmed with more specific markers whether there is a true increase in stem cell number in the hair bulge of telomere dysfunctional mice. Such results would indicate that telomere dysfunction can have different effects on stem cell maintenance depending on the organ compartment.

Studies on telomere dysfunctional and DNA repair deficient mice have shown that progenitor cells appear to be more sensitive to DNA damage than stem cells. The reduction in hematopoietic progenitor cells in telomere dysfunctional mice was more pronounced than the reduction in HSC number (Ju et al. 2007, Choudhury et al. 2007, Schaetzlein et al. 2007, Rossi et al. 2007). One possible explanation for these findings is that quiescent stem cells may be better protected against DNA damage compared to transient amplifying cells. An alternative explanation is that DNA damage responses are reduced in stem cells compared to progenitor cells. Along these lines, there is evidence for impaired DNA damage checkpoint function in embryonic stem cells compared to somatic cells [START_REF] Hong | Restoration of an absent G1 arrest and protection from apoptosis in embryonic stem cells after ionizing radiation[END_REF]. Moreover, DNA damage signal induction in response to telomere dysfunction is mitogen dependent [START_REF] Satyanarayana | Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling[END_REF]) and DNA damage responses may thus be reduced in quiescent stem cells compared to highly proliferative progenitor cell compartments.

Together, these studies indicate that telomere dysfunction and DNA damage can impair the function and maintenance of stem and progenitor cells. The higher resistance to DNA damage seen in stem cells compared to progenitor cells may lead to an accumulation of DNA damage in aging stem cells, and may thus represent a possible mechanism through which stem cell aging can lead to cancer (Rossi et al. 2007b).

As dysfunctional telomeres and DNA damage can either induce senescence or apoptosis, analysis of the prevalence of apoptosis and senescence could help to identify organs in which telomere dysfunction and DNA damage contribute to the aging process. In the following section we briefly summarize studies on the prevalence of apoptosis and senescence in aging organisms.

Senescence and aging

Studies on human fibroblasts have shown that a sentinel of dysfunctional telomeres induce senescence in response to telomere shortening [START_REF] Harley | Telomeres shorten during ageing of human fibroblasts[END_REF][START_REF] Wright | The two-stage mechanism controlling cellular senescence and immortalization[END_REF]. It was estimated that 4 to 5 dysfunctional telomeres per cell are required to activate cell cycle checkpoints inducing senescence [START_REF] Zou | Does a sentinel or a subset of short telomeres determine replicative senescence?[END_REF]. The formation of DNA damage foci (see above) represents the initial response to telomere dysfunction (d' Adda et al., 2003;[START_REF] Satyanarayana | Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling[END_REF]. DNA damage foci activate ATM/Chk2 and ATR/Chk1 kinases inducing p53 and its downstream target p21 [START_REF] Brown | Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts[END_REF]. Functional studies on human fibroblast senescence have shown that abrogation of ATM, ATR, Chk2, p53, or p21 is sufficient to abrogate or delay the induction of senescence [START_REF] Brown | Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts[END_REF]d' Adda et al., 2003;[START_REF] Gire | DNA damage checkpoint kinase Chk2 triggers replicative senescence[END_REF]. It has been proposed that induction of p53 and p21 represents an early response inducing senescence, whereas the up-regulation of p16 appears to be a late event after the induction of replicative senescence [START_REF] Stein | Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts[END_REF]. Moreover, it has been shown that senescent cells exhibit heterochromatin foci formation associated with an impairment of the canonical Wnt signaling pathway in senescent cells [START_REF] Ye | Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells[END_REF]. Besides these molecular markers, an increased activity of lysosomal β-Galactosidase (at pH6) occurs in senescent cells (senescence associated β-Galactosidase = SA-β-Gal) [START_REF] Lee | Senescenceassociated beta-galactosidase is lysosomal beta-galactosidase[END_REF]). However, this marker has to be analysed with caution since it lacks specificity and shows background activity at a lower PH.

Experimental data indicate that senescence can be induced by various telomere-independent mechanisms including (i) over-activation of oncogenes [START_REF] Serrano | Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a[END_REF], (ii) over-stimulation with mitogens [START_REF] Sherr | Cellular senescence: mitotic clock or culture shock?[END_REF], (ii) oxidative stress [START_REF] Parrinello | Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts[END_REF], (iv) irradiation [START_REF] Suzuki | Stress-induced premature senescence (SIPS)--influence of SIPS on radiotherapy[END_REF], and (v) chemotherapy [START_REF] Haug | Cellular response to irinotecan in colon cancer cell lines showing differential response to 5-fluorouracil[END_REF]. The only specific marker of telomere induced senescence is the formation TIFs, however, this marker has a lack of sensitivity (see above). In conclusion, the current senescence markers are difficult to use for in vivo studies and most of these markers can not discriminate between replicative senescence and other forms of senescence. In addition, non-senescent cells can express senescence markers. For example, γH2AX foci are present in intestinal stem and progenitor cells of telomere dysfunctional mice (Schaetzlein et al., 2007b;Choudhury et al., 2007b). However, only a small subset of these cells are cell cycle arrested [START_REF] Choudhury | Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation[END_REF][START_REF] Schaetzlein | Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice[END_REF]. Together, reports on the prevalence of senescent cells in vivo have to be interpreted with caution.

Many experimental studies have attempted to analyse the prevalence of senescent cells in aging tissues of human and model organisms. These studies revealed some evidence for senescent cells in aging tissues (Table 2). In humans, an increase in SA-β-Gal positive cells was described in skin keratinocytes [START_REF] Dimri | A biomarker that identifies senescent human cells in culture and in aging skin in vivo[END_REF], cornea epithelium [START_REF] Mimura | Replication competence and senescence in central and peripheral human corneal endothelium[END_REF], ischemic heart [START_REF] Minamino | Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction[END_REF], arterosclerotic plaques [START_REF] Gorenne | Vascular smooth muscle cell senescence in atherosclerosis[END_REF], articular chondrocytes (Martin and Buckwalter 2001), and in liver cirrhosis -the end stage of chronic liver disease [START_REF] Wiemann | Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis[END_REF]. In addition, an upregulation of DNA damage pathways associated with senescence has been obersved in various tissue of aging humans including activation of p53, p21 and p16 (see above and Table 1). An increase in SA-β-Gal activity and senescence associated DNA damage signaling has also been observed in aging animals (Table 1,2). However, it remains to be analysed whether this increase in SA-β-Gal activity DNA damage signaling is truly associated with senescence cell cycle arrest in vivo.

There is evidence that upregulation of p16 can limit the regenerative capacity of stem cells in aging mice [START_REF] Janzen | Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a[END_REF][START_REF] Krishnamurthy | p16INK4a induces an age-dependent decline in islet regenerative potential[END_REF][START_REF] Molofsky | Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing[END_REF]. The mechanisms that lead to an activation of p16 in aging mice remain to be elucidated. Given the long telomeres in inbred mouse strains this upregulation of p16 is likely independent of telomere dysfunction.

The most thorough analysis for the detection of replicative senescent cells in vivo was the screening for the prevalence of TIFs (γH2AX-positive DNA damage foci at telomeres) in aging baboons [START_REF] Herbig | Cellular senescence in aging primates[END_REF][START_REF] Jeyapalan | Accumulation of senescent cells in mitotic tissue of aging primates[END_REF]. This study revealed an accumulation of TIFs in skin but not in muscle of aging baboons. It was not analyzed whether the marker-positive cells in the skin were truly senescent in the sense that the cells were cell cycle arrested (non-dividing).

Studies on telomerase knockout mice provided evidence that telomere dysfunction does not lead to strong accumulation of senescent-marker positive cells in different organs [START_REF] Choudhury | Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation[END_REF].

Instead, the mice showed a depletion of intestinal and hematopoietic stem and progenitor cells [START_REF] Choudhury | Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation[END_REF], Rossi et al. 2007). A possible explanation is that -unlike the observation from in vitro cell cultures -senescent cells do not persist in vivo. Along these lines, it has been suggested that senescent cells can be removed by immune responses [START_REF] Xue | Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas[END_REF] or apoptosis [START_REF] Choudhury | Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation[END_REF].

All together, it appears that the currently available markers of senescence lack specificity and likely underestimate the influence of telomere dysfunction on organismal aging.

Apoptosis and aging

Apoptosis is the cellular response to an accumulation of macromolecular damage. Cell intrinsic and extrinsic pathways can trigger apoptosis, which common endpoint is the activation of effector proteases called caspases. Apoptotic cells can be detected by their characteristic apoptotic nuclear morphology including fragmentation of genomic DNA by endonucleases. Similar to the senescence checkpoint, apoptosis is regarded as a tumor suppressor mechanism preventing the accumulation and spread of damaged cells. In contrast, increasing rates of apoptosis could contribute to impaired organ maintenance during aging. Some of the studies on the prevalence of apoptosis in aging tissues are summarized in Table 3.

Studies on telomerase knockout mice have confirmed that telomere dysfunction increases apoptosis in lymphocytic progenitor cells, intestinal progenitor cells and germ cells [START_REF] Choudhury | Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation[END_REF]Ju et al., 2007b;[START_REF] Lee | Comparative analysis of DNA mutations in lacI transgenic mice with age[END_REF]. An age dependent increase in apoptosis rates has also been observed in wild type mice and rats. Liver, muscle, testis and heart from old wild type mice displayed increased rates of cleaved caspase-3 as compared to young controls [START_REF] Kujoth | Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging[END_REF]. In addition, the gastric epithelium of aging rats displayed an increased expression of caspase-3 and -9 [START_REF] Tarnawski | Aging gastropathy-novel mechanisms: hypoxia, up-regulation of multifunctional phosphatase PTEN, and proapoptotic factors[END_REF].

In humans, an increased expression of pro-apoptotic signaling molecules and caspases was found in patients with Alzheimer's disease [START_REF] Albrecht | Activation of caspase-6 in aging and mild cognitive impairment[END_REF] and in various tissues including peripheral blood lymphocytes (Aggarawal andGupta, 1998), brain (Gua et al., 2004), lung [START_REF] Healy | Intravascular coagulation activation in a murine model of thrombomodulin deficiency: effects of lesion size, age, and hypoxia on fibrin deposition[END_REF], and pancreas [START_REF] Maedler | Aging correlates with decreased beta-cell proliferative capacity and enhanced sensitivity to apoptosis: a potential role for Fas and pancreatic duodenal homeobox-1[END_REF]. Increased rates of apoptosis have also been found in sarcopenia and there is ongoing discussion that increased rates of apoptosis may cause the progression of muscle loss during human aging [START_REF] Marzetti | Skeletal muscle apoptosis, sarcopenia and frailty at old age[END_REF]. However, apoptosis rates do not increase in the wall of coronary arteries during human aging [START_REF] Boddaert | Age and gender effects on apoptosis in the human coronary arterial wall[END_REF] and are decreased in aging sperm (Singh et al., 2003). In addition, it was reported that lymphocytes from aged individuals were resistant to pro-apoptotic effects of inflammatory cytokines [START_REF] Larbi | Oxidative stress modulation and T cell activation[END_REF].

Together, the data on modulation of apoptosis during aging are not uniform and require further analysis. In addition, the mechanisms that increase apoptosis during aging remain to be defined.

Biomarkers of telomere dysfunction and DNA damage

The above studies illustrate that telomere dysfunction and DNA damage likely contribute to the pathophysiology of human aging. However, it is difficult to determine the true impact of DNA damage and telomere dysfunction to aging because of following limitations:

(i) Traditional markers of telomere dysfunction and DNA damage are not easy to detect in vivo and are not applicable for clinical routine diagnostics.

(ii) There is evidence that cells with higher levels of telomere dysfunction or DNA damage are cleared in vivo. Especially, stem cells are very sensitive to DNA and telomere damage and are depleted in response to such lesion. Thus, analyzing the prevalence of DNA damage and telomere dysfunction likely underestimates the true impact of these lesion on aging.

(iii) It is difficult to quantify the activation of checkpoints induced by telomere dysfunction and DNA damage (apoptosis and senescence). In addition, these checkpoints can be induced by a variety of different stimuli making it difficult to determine the underlying cause of checkpoint activation.

Sensitive biomarkers that indicate low rates of DNA and/or telomere damage could help to determine the influence of DNA damage on aging and disease. To identify marker proteins of telomere dysfunction in pre-senescent cells we have recently used a knockout mouse lacking the RNA component of telomerase (Terc-/-). Late generation (G3-G4) Terc-/-mice show evidence of telomere dysfunction and premature aging of high-turnover organs but lack an accumulation of senescent cells (Choudhury et al., 2007). An unbiased proteomic approach (CE-TOF-MS analysis) has identified 4 marker proteins that were up-regulated in aging G3-G4 Terc-/-mice with dysfunctional telomeres but not in wildtype mice with long telomeres: CRAMP, stathmin, EF-1α, chitinase [START_REF] Jiang | Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease[END_REF]. The study showed that the same marker proteins were up-regulated in culture medium of human fibroblast in response to telomere-induced senescence and γ-irradiation. Of note, an analysis of these marker proteins in human blood and tissue samples revealed an increased expression of these marker proteins in human aging, age associated disease, and in chronic diseases that have previously been associated with telomere dysfunction, e.g., cirrhosis, myelodysplastic syndromes. Together, this study provides further support for the concept that telomere dysfunction and DNA damage contribute to human aging. The identified biomarkers are easily detectable in blood samples and thus provide a powerful tool to better analyze the influence of telomere dysfunction and DNA damage on disease processes associated with human aging.

Moreover, these biomarkers could be useful to develop prevention strategies slowing the accumulation of DNA damage and the evolution of age associated disease. It is also conceivable that secreted proteins from damaged cells directly influence the aging process. Along these lines it has been shown that systemic acting factors impair the function of adult stem cells during aging [START_REF] Conboy | Rejuvenation of aged progenitor cells by exposure to a young systemic environment[END_REF].

Therefore, a better understanding of the molecular markers induced by telomere dysfunction and DNA damage may not only provide novel diagnostic tools but could point to targets for future therapies aiming to improve organismal fitness during aging.

Conclusions

There is accumulating evidence that telomere dysfunction and DNA damage contribute to the pathophysiology of human aging. The development of novel biomarkers will help to better characterize this interconnection. The currently available biomarkers cannot distinguish telomere dysfunction and intra-chromosomal DNA damage and thus cannot determine the relative contribution of each of these lesions to human aging. A discrimination between these lesion is further complicated because telomere dysfunction increases the amount of intra-chromosomal DNA damage by induction of fusion-bridgebreakage cycles [START_REF] Sabatier | The loss of a single telomere can result in instability of multiple chromosomes in a human tumor cell line[END_REF].

The contribution of DNA damage to aging may continuously be underestimated because damaged cells, specifically stem and progenitor cells, are depleted in response to DNA damage. The loss of adult stem and progenitor cells could have major contributions to the impairment of organ maintenance and regeneration during aging and chronic disease. The identification of specific markers of adult stem cells (Barker et al., 2007) will help to analyze stem cell reserve in aging organs and tissues.

Responses to DNA damage in adult stem cells may differ from those in somatic cells. A careful characterization of such differences could lead to the identification of biomarkers specifically indicating DNA damage in stem cell compartments. Together, the identification of both stem cell markers and biomarkers for damage accumulation should help to develop prevention strategies and therapies aiming to improve stem and progenitor cell function, tissues maintenance, and healthy aging. (Sedelnikova et al., 2008) Increase in ulcerative colitis (Risques et al., 2008) Increase in skin but not muscle [START_REF] Herbig | Cellular senescence in aging primates[END_REF][START_REF] Jeyapalan | Accumulation of senescent cells in mitotic tissue of aging primates[END_REF] Increase in liver, testis, kidney, lung, brain [START_REF] Sedelnikova | Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks[END_REF] Increase in liver [START_REF] Panda | Modification of the ATM/ATR directed DNA damage response state with aging and long after hepatocyte senescence induction in vivo[END_REF] Fragmented DNA (double strand breaks) Human rat mouse Increase in brain of patients with Alzheimer or cognitive impairment [START_REF] Mullaart | Increased levels of DNA breaks in cerebral cortex of Alzheimer' s disease patients[END_REF] Increase in sperm (Schmid et al., 2007, Singh et al., 2003) Increase in muscle (Sundaram et al., 2006), liver (Higami et al., 1994) Increase in kidney (Singh et al. 2001) fluorometric analysis of DNA unwinding (single strand breaks) human rat mouse No significant increase in peripheral blood lymphocytes (Singh et al., 1991) Increase in peripheral blood lymphocytes (Chicca et al. 1996) Increase in liver but not in brain [START_REF] Mullaart | Increased levels of DNA breaks in cerebral cortex of Alzheimer' s disease patients[END_REF] No increase in brain, liver, and kidney (Fu et al., 1991 [START_REF] Cenini | Elevated levels of pro-apoptotic p53 and its oxidative modification by the lipid peroxidation product, HNE, in brain from subjects with amnestic mild cognitive impairment and Alzheimer' s disease[END_REF] Increase in bone marrow derived stroma cells (Zhou et al., 2008) Increase in kidney [START_REF] Melk | Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney[END_REF] Increase in skeletal muscle (Welle et al., 2004) Increase in skeletal muscle (Tamilselvan et al., 2007) Increase in kidney (Ding et al., 2001, Melk et al., 2003) Increase in skeletal muscle (Edwards et al., 2007)

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Table 2. Evidence for an accumulation of senescent cells in aged tissues

Marker of senescence species

Affected organ DNA damage foci at telomere (TIFs) baboons Increase in skin but not in muscle [START_REF] Herbig | Cellular senescence in aging primates[END_REF][START_REF] Jeyapalan | Accumulation of senescent cells in mitotic tissue of aging primates[END_REF] SA-β-Gal human rhesus monkey rat

Increase in skin [START_REF] Dimri | A biomarker that identifies senescent human cells in culture and in aging skin in vivo[END_REF] No increase in skin (Severino et al. 2000) Increase in cornea [START_REF] Mimura | Replication competence and senescence in central and peripheral human corneal endothelium[END_REF] Increase in ischemic heart [START_REF] Minamino | Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction[END_REF] Increase in endarterectomy plaque [START_REF] Gorenne | Vascular smooth muscle cell senescence in atherosclerosis[END_REF] No increase in gastrointestinal epithelium (Going et al., 2002) Increase in articular chondrocytes (Martin and Buckwalter, 2001) Increase in chronic hepatitits and cirrhosis (Paradis et al., 2001[START_REF] Wiemann | Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis[END_REF] Increase in retina [START_REF] Hjelmeland | Senescence of the retinal pigment epithelium[END_REF] Increase in kidney [START_REF] Melk | Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney[END_REF], Ding et al., 2001 [START_REF] Aggarwal | Increased apoptosis of T cell subsets in aging humans: altered expression of Fas (CD95), Fas ligand, Bcl-2, and Bax[END_REF] Increase in brain [START_REF] Guo | Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer' s disease[END_REF] Increase in lung [START_REF] Healy | Intravascular coagulation activation in a murine model of thrombomodulin deficiency: effects of lesion size, age, and hypoxia on fibrin deposition[END_REF] Increase in pancreas [START_REF] Maedler | Aging correlates with decreased beta-cell proliferative capacity and enhanced sensitivity to apoptosis: a potential role for Fas and pancreatic duodenal homeobox-1[END_REF] Increase in Alzheimer's disease (Rohn et al., 2001) Increase in skeletal muscle (Tamilselvan et al., 2007) Increase in heart (Phaneuf and Leeuwenburgh, 2002) Increase in liver (Ando et al. 2002) Increase in skeletal muscle, testis, liver, and heart [START_REF] Kujoth | Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging[END_REF] Thymus involution is Fas-dependent (Yajima et al., 2004 (Singh et al., 2003) Increase in chondrocytes of articular knee (Adams and Horton, 1998) Increase in chondrocytes of articular knee (Adams and Horton, 1998)

  The decline in organ maintenance and function is one of the major problems limiting quality of life during aging. The accumulation of telomere dysfunction and DNA damage appears to be one of the underlying causes. Uncapping of chromosome ends in response to critical telomere shortening limits the proliferative capacity of human cells by activation of DNA damage checkpoints inducing senescence or apoptosis. Telomere shortening occurs in the vast majority of human tissues during aging and in chronic diseases that increase the rate of cell turnover. There is emerging evidence that telomere shortening can limit the maintenance and function of adult stem cells -a cell type of utmost importance for organ maintenance and regeneration. In mouse models, telomere dysfunction leads to a depletion of adult stem cell compartments suggesting that stem cells are very sensitive to DNA damage. Both the rarity of stem and progenitor cells in adult organs and their removal in response to damage make it difficult to assess the impact of telomere dysfunction and DNA damage on stem and progenitor cell aging. Such approaches require the development of sensitive biomarkers recognizing low levels of telomere dysfunction and DNA damage in stem and progenitor cells. Here, we review experimental data on the prevalence of telomere dysfunction and DNA damage during aging and its possible impact on stem and progenitor cell aging.

  It remains an open question to what extend dysfunctional teloemres contribute to the total amount of DNA damage accumulating during human aging. Another open question is to what extent telomere dysfunction and DNA damage occurs in aging stem cells. Experimental studies on neurodegenerative disorders have suggested that non-proliferative cells may be particularly prone to the accumulation of DNA damage(for review see Rass et al., 2007).

Table 3 . Evidence for an increase in apoptosis in aged tissues

 3

	Marker	of	species	affected organ
	apoptosis
	Pro-apoptosis		human	Increase in peripheral blood T-lymphocytes
	signaling:
	Fas,	p53,
	cytochrome	c,
	bax, caspases
			rat
			mouse


Alan W Harris
email: alan.harris@dlr.de

Michael Mueller

Marco Delbó

Physical Characterization of the Potentially-Hazardous High-Albedo Asteroid (33342) 1998 WT 24 from Thermal-Infrared Observations 1

Keywords: Asteroids, Infrared Observations, Photometry, Spectrophotometry

The potentially-hazardous asteroid (33342) 1998 WT 24 approached the Earth within 0.0125 AU on 2001 Dec. 16 and was the target of a number of optical, infrared, and radar observing campaigns. Interest in 1998 WT 24 stems from its having an orbit with an unusually low perihelion distance, which causes it to cross the orbits of the Earth, Venus, and Mercury, and its possibly being a member of the E spectral class, which is rare amongst near-Earth asteroids (NEAs). We present the results of extensive thermal-infrared observations of 1998 WT 24 obtained in December 2001 with the 3-m NASA Infrared Telescope Facility (IRTF) on Mauna Kea, Hawaii and the ESO 3.6-m telescope in Chile. A number of thermal models have been applied to the data, including thermophysical models that give best-fit values of 0.35 ± 0.04 km for the effective diameter, 0.56 ± 0.2 for the geometric albedo, p v , and 100 -300 J m -2 s -0.5 K -1 for the thermal inertia. Our values for the diameter and albedo are consistent with results derived from radar and polarimetric observations. The albedo is one of the highest values obtained for any asteroid and, since no other taxonomic type is associated with albedos above 0.5, supports the suggested rare E-type classification for 1998 WT 24 . The thermal inertia is an order of magnitude higher than values derived for large main-belt asteroids but consistent with the relatively high values found for other near-Earth asteroids. A crude pole solution inferred from a combination of our observations and published radar results is β = -52˚, λ = 355˚ (J2000), but we caution that this is uncertain by several tens of degrees.

Introduction

In recent years near-Earth asteroids (NEAs) have become targets both for Earth-based astronomical observation campaigns and in situ investigations via space missions. The recent missions NEAR-Shoemaker to (433) Eros and Hayabusa to (25143) Itokawa have provided a wealth of fascinating information on two very different NEAs. The results of studies to date have demonstrated that the NEA population has extremely diverse physical characteristics. In particular, NEAs appear to vary widely in terms of shape, mineralogy, albedo, regolith, and other surface properties.

Interest in NEAs arises not only from the potential impact hazard they present to Earth but also from their relation to main-belt asteroids. Most NEAs are thought to be fragments from collisions in the main asteroid belt and are at the large end of a size continuum of material delivered into near-Earth space, which includes meteoroids and interplanetary dust. NEAs are vehicles by means of which material can be transported from the main belt to the inner Solar System and, together with comets, are thought to have played a major role in the development of the surfaces of the inner planets, including the delivery of materials to the Earth that may have contributed to the development of life.

A combination of dynamical processes, including the Yarkovsky effect (see [START_REF] Bottke | The effect of Yarkovsky thermal forces on the dynamical evolution of asteroids and meteoroids[END_REF] and references therein) and mean-motion resonances, enables collisional fragments from different regions of the main belt to reach the inner Solar System. The diversity of the NEA population therefore largely reflects the diversity of the main-belt population. However, NEAs display a particularly broad range of albedo (published values range from 0.02 to 0.6, e.g. see [START_REF] Delbó | Keck observations of near-Earth asteroids in the thermal infrared[END_REF], which may be due to there being a significant number of dormant or extinct cometary nuclei with very low geometric albedos (p v = 0.02 -0.05) amongst the NEAs (e.g.

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A N U S C R I P T ACCEPTED MANUSCRIPT 5 [START_REF] Binzel | Observed spectral properties of near-Earth objects: results for population distribution, source regions, and space weathering processes[END_REF], and the possibility that NEAs that are fragments from collisions in the main belt are younger and have generally fresher, less space-weathered (and therefore brighter) surfaces than observable main-belt asteroids (space weathering appears to lead to a darkening of, in particular, olivine-rich surfaces -see Clark et al., 2002, and references therein).

However, the taxonomic class associated with the highest albedos is the E class, members of which have albedos typically in the range p v = 0.3 -0.6. Examples of main-belt E-types are 44 Nysa (IRAS p v = 0.55, Tedesco et al., 2002b), 64 Angelina (p v = 0.40, Tedesco et al., 2002a) and 214 Aschera (IRAS p v = 0.52, Tedesco et al., 2002b); the NEA 3103 Eger has E-type spectral properties [START_REF] Clark | E-type asteroid spectroscopy and compositional modeling[END_REF], Gaffey et al., 1992), and on the basis of their thermalinfrared determinations of size and albedo [START_REF] Delbó | Keck observations of near-Earth asteroids in the thermal infrared[END_REF] suggest E-type classifications for the NEAs 4660 Nereus (p v = 0.55) and 5751 Zao (p v = 0.36). Furthermore, NEA (10302) 1989 ML, previously classed as an X type, has E-type spectral properties and an E-type albedo of p v = 0.4 [START_REF] Mueller | Size, albedo, and taxonomic type of potential spacecraft target asteroid[END_REF].

(33342) 1998 WT 24 was discovered on 1998 Nov. 25 by the LINEAR [START_REF] Stokes | Lincoln near-Earth asteroid program (LINEAR)[END_REF] search program. Observations of physical characteristics published to date suggest that 1998

WT 24 is a rare E-type Aten NEA with a high polarimetric albedo of around 0.4 [START_REF] Lazzarin | Visible and nearinfrared spectroscopic investigation of near-Earth objects at ESO: first results[END_REF][START_REF] Kiselev | Synthetic phase angle dependence of polarization for the E-type asteroids[END_REF]. [START_REF] Krugly | CCD photometry of near-Earth asteroids in 2001[END_REF] report a rather short rotation period of 3.697 h and a lightcurve amplitude measured at solar phase angles between 50˚ and 60˚ of 0.26 mag.

The absolute magnitude at maximum brightness derived by [START_REF] Kiselev | Synthetic phase angle dependence of polarization for the E-type asteroids[END_REF] is 18.69 ± 0.08 mag, or 18.39 ± 0.08 mag if a brightness opposition effect is assumed similar to that observed for the E-type asteroids (44) Nysa and (64) Angelina. Given the reported 0.53 mag lightcurve amplitude at the time of the Kiselev et al. photometric observations (2001 Dec. 2 -9), the Kiselev at al. result of H max = 18.39 ± 0.08 mag is compatible with H (lightcurve mean) = 18.54 ± 0.1 mag derived independently by Delbó (2004) using the method of [START_REF] Bowell | Application of photometric models to asteroids[END_REF] on observations made at ESO on 2001 Dec. 2 and 4, taking G = 0.4. Taking H = 18.5 ±

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3, the diameter of (33342) 1998 WT 24 inferred from an albedo of p v = 0.4 is D = 0.42 ± 0.06 km. It should be noted, however, that the derivation of albedos from polarimetric observations is based on a method that depends on empirically derived relations between the polarization parameters and the solar phase angle and albedo and that different calibrations of this method have been published, most recently by [START_REF] Cellino | Polarimetric observations of small asteroids: preliminary results[END_REF]. [START_REF] Kiselev | Synthetic phase angle dependence of polarization for the E-type asteroids[END_REF] used the relations of [START_REF] Lupishko | A new calibration of the polarimetric albedo scale of asteroids[END_REF]. If we take the Kiselev et al. value of h v = 0.039 % deg -1 for the slope of the linear part of the polarization-phase curve and apply the appropriate relation of [START_REF] Cellino | Polarimetric observations of small asteroids: preliminary results[END_REF], we find a higher albedo of p v = 0.62. Assuming H = 18.5 ± 0.3, the implied diameter is reduced to D = 0.34 ± 0.05 km.

Goldstone radar images of 1998 WT 24 made available on the web by S. Ostro and colleagues (http://neo.jpl.nasa.gov/images/1998wt24.html) suggest a slightly elongated body with a possible concavity. However, no formal report of the Goldstone observations is available at the time of writing. [START_REF] Zaitsev | Radar detection of NEA 33342 (1998 WT24) with Evpatoria -Medicina System at 6 cm[END_REF] made radar observations of 1998 WT 24 on 2001 Dec. 16 and 17 and derived lower limits for the maximum pole-on breadth of the asteroid of D max = 0.42 and 0.40 km, respectively, from observations of the Doppler-broadened echo bandwidth, B, on the two dates. B is proportional to D max x sin φ, where φ is the angle between the spin vector and the radar line of sight. Since the pole orientation of 1998 WT 24 is unknown, only a lower limit for the maximum pole-on dimension can be determined from the radar data.

Further information on the diameter and albedo of 1998 WT 24 can be obtained from thermalinfrared observations and the application of suitable thermal models. Furthermore, thermalinfrared observations can provide insight into the near-surface thermal inertia and regolith structure, information relevant to modeling the Yarkovsky effect and impact-hazard mitigation techniques. [START_REF] Delbó | Keck observations of near-Earth asteroids in the thermal infrared[END_REF] used the 10-m Keck-1 telescope for a study of the thermal emission from NEAs. They derived diameters and albedos for 20 NEAs in the size range 0.1 -

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7 10 km and found evidence that most of the observed objects have a significant insulating regolith, rather than a high-thermal-inertia surface characteristic of bare rock. [START_REF] Harris | The surface properties of small asteroids: peculiar Betulia -a case study[END_REF] derived the size, albedo, and thermal inertia of the NEA (1580) Betulia from 7 -21 μm observations with the NASA Infrared Telescope Facility (IRTF). In the case of Betulia the thermal inertia was found to be intermediate between that of main belt asteroids (5 -25 J m -2 s - 0.5 K -1 , e.g. [START_REF] Müller | Asteroids as far-infrared photometric standards for ISOPHOT[END_REF] and bare rock (~ 2500 J m -2 s -0.5 K -1 , Jakosky, 1986), i.e. consistent with the findings of [START_REF] Delbó | Keck observations of near-Earth asteroids in the thermal infrared[END_REF].

We observed (33342) 1998 WT 24 with the ESO 3.6-m telescope and the IRTF in December 2001. Thermal-infrared flux measurements were obtained at wavelengths in the range 7 -21 μm. The objective of these measurements was to observe 1998 WT 24 over the very wide range of solar phase angle (α = 10˚ -90˚) available for this asteroid during its close approach in December 2001. Observations over this period could provide a valuable database for testing thermal models and enabling the surface thermal inertia of a very small asteroid to be determined. However, the first two out of a total of five observing sessions at the IRTF were lost due to bad weather, consequently no observations at │α│ < 60˚ could be made. The remaining three IRTF nights were partially compromised by poor weather and instrument problems but the availability of independent data sets from four nights in total with a broad range of observing geometries (see Table 1) has nevertheless enabled substantial, selfconsistent results to be derived. We have fitted the resulting flux data with a number of different thermal models, including a thermophysical model, to obtain the size, albedo and magnitude of the thermal inertia. Furthermore, our results combined with published observations constrain the asteroid's spin axis orientation.

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Observations and data reduction

Observations were performed on 2001 December 4 at the ESO 3.6 m telescope with the Thermal-Infrared Multimode Instrument (TIMMI 2, Reimann et al., 2000) in imaging mode, and on 2001 December 18, 19 and 21 with the IRTF and JPL's 128 x 128 pixel, 7 -25 μm infrared astronomical camera, MIRLIN. For details of MIRLIN see [START_REF] Ressler | The JPL deep-well midinfrared array camera[END_REF] and http://cougar.jpl.nasa.gov/mirlin.html. The ESO measurements were made in filters centered at 8. 73, 10.38, and 11.66 μm with bandwidths of around 10%. The IRTF measurements were made in filters centered at 7.91, 10.27, and 11.7 μm with bandwidths of around 10% and at 17.93 and 20.81 μm with bandwidths of 2.5% and 7.8%, respectively. At each observing site the telescope was tracked at the rates predicted from the ephemerides of the target and the usual chop-nod procedure was used. In each case calibration stars were chosen to be close on the sky to the target asteroid. Standard synthetic aperture procedures were used for the derivation of raw signal counts from the camera images. Absolutely calibrated fluxes for the target asteroids were obtained by multiplying the integrated in-band absolute fluxes of the calibration stars by the ratios of the target/calibration star raw counts in each filter. Absolutely calibrated infrared spectra for the calibration stars β And, α Tau (Dec. 18,19,21) and HD 81420 (Dec. 4) were taken from the database of [START_REF] Cohen | Spectral irradiance calibration in the infrared. X. A self-consistent radiometric all-sky network of absolutely calibrated stellar spectra[END_REF]. Color corrections for the different flux distributions of the calibration stars and asteroids in the narrow filter pass bands were found to be no more than a few percent and were not applied.

Table 1 lists the observing geometry. The resulting fluxes are listed in Table 2. The quoted uncertainties in the flux measurements refer to the formal statistical uncertainties in the synthetic aperture procedure only. The quality of the data is variable due to fluctuating atmospheric and instrumental circumstances. In particular, the Dec. 18 observations were affected by partially non-photometric conditions and problems with the filter wheel. The 1) reveals the presence of non-statistical variability in the data, which is probably due mainly to rotation of the asteroid and variable atmospheric conditions. However, our model fitting routines effectively take account of the scatter in multiple measurements, in addition to the statistical uncertainties, and weight the data accordingly, which mitigates against serious errors due to non-statistical variability.

Thermal-model fitting

Simple models

The high solar phase angles of the observations imply that simple models, such as the standard thermal model (STM, see Lebofsky et al. 1986, and references therein), are likely to give erroneous results. The STM is the basic and most widely used asteroid thermal model; it is based on spherical geometry and was designed for use with main-belt asteroids at solar phase angles α ≤ 30˚. The STM may be an appropriate model if the asteroid is rotating slowly and has a low thermal inertia (or its rotation axis points to the Sun) so that each surface element can be considered to be in instantaneous thermal equilibrium with insolation. In the case of 1998 WT 24 the relatively short rotation period of 3.697 h (e.g. [START_REF] Krugly | CCD photometry of near-Earth asteroids in 2001[END_REF], and the high values of thermal inertia (relative to those of main-belt asteroids) found recently for NEAs (e.g. see [START_REF] Harris | The surface properties of small asteroids: peculiar Betulia -a case study[END_REF], together with the high phase angles at which the observations were made, indicate that the STM is not an appropriate thermal model.

A corresponding simple model for the extreme case of high thermal inertia and/or fast rotation is the so-called fast rotating or isothermal latitude model [START_REF] Veeder | Radiometry of near-Earth asteroids[END_REF]; Lebofsky and

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10 Spencer, 1989), hereafter FRM, in which the surface temperature distribution is a function of latitude only. An asteroid with a surface of bare rock would be expected to have a high thermal inertia. For objects with significant thermal inertia the FRM can give a useful indication of diameter, especially at high phase angles (see [START_REF] Harris | The surface properties of small asteroids from thermal-infrared observations[END_REF]. The FRM assumes the Sun is in the equatorial plane; if the sub-Earth latitude is also zero, as is normally assumed in the FRM, no phase-angle correction is required.

The near-Earth asteroid thermal model, NEATM [START_REF] Harris | A thermal model for near-Earth asteroids[END_REF], can provide useful estimates of diameter and albedo when parameters are intermediate to those for which the STM and FRM are applicable. The STM and the NEATM both incorporate a so-called "beaming parameter", η, which was originally introduced to allow the model temperature distribution to be modified from that of a smooth, zero-thermal-inertia sphere to take account of the observed enhancement of thermal emission at small solar phase angles due to surface roughness. In the STM η has the fixed value of 0.756, whereas in the NEATM η is treated as a modeling parameter that allows a first-order correction for effects such as beaming, thermal inertia and rotation that influence the surface temperature distribution presented to the observer. Changing η causes the effective color temperature, or flux distribution, of the model thermal continuum to change. In the case of the NEATM the value of η giving the best fit to the measured continuum flux distribution is found via an iterative procedure. Unlike the STM and FRM, the NEATM requires measurements of the thermal flux at more than one wavelength because the NEATM treats η as an additional variable (in the cases of the STM and the FRM the only free parameters are diameter and geometric albedo, therefore one measurement in the thermal infrared and one in the visible suffice for a solution).

The value of η resulting from application of the NEATM can be considered a measure of the extent to which the surface temperature distribution departs from that of a perfect STM-type

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11 asteroid (i.e. smooth, with zero thermal inertia), for which η =1. At small phase angles η > 1 indicates significant thermal inertia, whereas η < 1 indicates significant beaming due to surface roughness. At large phase angles, however, thermal inertia and roughness can both lead to increased η, and detailed thermophysical modeling is required to unravel their contributions.

The NEATM takes account of the phase angle by numerically integrating the observable thermal emission from the spherical surface that is illuminated by the Sun, assuming that surface emits with a Lambertian angular distribution. Since the NEATM and the STM assume that no emission originates on the night side of the object, these models would be expected to lead to overestimation of diameters and underestimation of albedos at very high solar phase angles for objects with high thermal inertia. In such cases the FRM may be the more appropriate model to use.

For more detailed discussions of the NEATM and other thermal models outlined here see [START_REF] Harris | A thermal model for near-Earth asteroids[END_REF], [START_REF] Delbó | Physical properties of near-Earth asteroids from thermal infrared observations and thermal modeling[END_REF], [START_REF] Harris | Asteroids in the thermal infrared[END_REF], [START_REF] Delbó | Keck observations of near-Earth asteroids in the thermal infrared[END_REF], and [START_REF] Harris | The surface properties of small asteroids from thermal-infrared observations[END_REF], and references therein. [START_REF] Delbó | Physical properties of near-Earth asteroids from thermal infrared observations and thermal modeling[END_REF] give the mathematical expressions for calculating the wavelength-dependent observable thermal-infrared fluxes for all three models.

Thermophysical models

We find it instructive to apply various types of thermal model to thermal-infrared asteroid data to probe the relative accuracies of the different modeling approaches, especially when estimates of size and albedo are available from other techniques such as radar and optical polarimetry. Thermophysical models include phenomena such as thermal inertia, surface roughness (the "beaming effect"), and rotational state explicitly as model parameters and are

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12 potentially more accurate than the simple models described above. However, the extra complexity of thermophysical models is rarely warranted unless a realistic shape model of the object is available. Unfortunately, this is not currently the case for 1998 WT 24 . Information from radar observations and optical lightcurve observations is available, however, from which some inferences about shape can be made.

Given the variable data quality in the case of 1998 WT 24 , and the large increases in phase angle between successive observing runs, we decided to take a cautious approach initially and analyze the data on a night-to-night basis to check the data set for consistency and to monitor the performance of the thermophysical approach. For a first thermophysical analysis we adopted a smooth sphere as a shape model (for convenience we refer to this model as the "smooth-sphere" thermophysical model). In the case of 1998 WT 24 , as with most asteroids, we have no knowledge of detailed topographical structure, which could influence shadowing patterns and the temperature distribution on the surface, and which would be more significant at high phase angles, such as those at which our IRTF observations were made. The standard idealistic treatment of roughness as a uniform distribution of hemispherical craters may be appropriate for large main-belt asteroids, but in the case of very small asteroids its validity is questionable, particularly at high phase angles. In any case, [START_REF] Lagerros | Thermal physics of asteroids III. Irregular shapes and albedo variegations[END_REF] found that the effects of shape tend to dominate those of surface roughness in thermophysical models. In the absence of a more appropriate alternative approach, we chose to ignore surface roughness in the first stage of our thermophysical analysis.

In the second stage of the analysis we explored the effect on the results of a distribution of hemispherical craters by application of our independently developed general thermophysical model, which has been used in earlier studies (e.g. [START_REF] Harris | The surface properties of small asteroids: peculiar Betulia -a case study[END_REF]. The smooth-sphere thermophysical model and the more detailed general thermophysical model both include a

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13 treatment of thermal inertia: the temperature of each surface element is determined by numerically solving the one-dimensional heat diffusion equation. In the more detailed model, which is based on the work of [START_REF] Lagerros | Thermal physics of asteroids I. Effects of shape, heat conduction and beaming[END_REF][START_REF] Lagerros | Thermal physics of asteroids IV. Thermal infrared beaming[END_REF], the surface temperature distribution is further modified by a distribution of hemispherical craters over the surface, with shadowing and multiple reflections of incident solar and thermally emitted radiation inside craters taken account of. The total observable thermal emission is calculated by summing the contributions from each surface element visible to the observer. Model parameters are adjusted until good agreement is obtained with the observational data, thereby constraining the physical properties of the asteroid.

Results

Rotational variability

Due to rotation the observed reflected and emitted radiation from an asteroid vary with time. It is important to take account of the rotational variability in observational data when applying thermal models. When simple models based on spherical geometry are used, optical lightcurves are often used as the basis for correcting thermal-infrared data, a practice that can introduce errors if the optical and thermal-infrared lightcurves are out of phase or differ in structure. Differences in the lightcurves of reflected and emitted radiation can arise from the effects of shape, surface structure and thermal inertia. A further effect, which is important in our study, is the change in the nature of the lightcurve with increasing solar phase angle. [START_REF] Krugly | CCD photometry of near-Earth asteroids in 2001[END_REF] observed a modest lightcurve amplitude of 0.26 mag at solar phase angle α = 50˚ -60˚, while [START_REF] Kiselev | Synthetic phase angle dependence of polarization for the E-type asteroids[END_REF] observed a lightcurve amplitude of 0.53 mag at α = 83˚.

To our knowledge no studies of the phase-dependence of thermal-infrared lightcurves have

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A N U S C R I P T ACCEPTED MANUSCRIPT 14 been carried out. In the case of (1580) Betulia the optical and thermal-infrared lightcurves at α = 53˚ appear to be quite similar, especially in terms of amplitude [START_REF] Harris | The surface properties of small asteroids: peculiar Betulia -a case study[END_REF], but comparisons at very high phase angles are lacking. In the case of our IRTF observations of 1998 WT 24 the solar phase angle was very high and changed significantly from night to night.

Rotational variability of the flux values can alter the relative measurements obtained at different wavelengths and therefore influence the results from the model fitting, e.g. lead to erroneous values of η in the case of the NEATM. We note that in the case of the IRTF observations on 2001 Dec. 18, 19, 21 the duration of the observing period on each night was comparable to the time difference between maxima and minima in the lightcurve (see Table 2; a quarter of the period ≈ 55 min), therefore observations probably spanned a large part of the lightcurve amplitude. However, the fact that in general observations in each filter were repeated on each night tends to reduce the chance of non-statistical variability between measurements in different filters causing serious errors in color temperature. The approach we have taken is to apply the various thermal models to the independent uncorrected data sets obtained on each of the four nights and review the consistency of the results.

Spin vector

An important input parameter for thermophysical modeling of asteroids is the orientation of the rotation axis. In the case of 1998 WT 24 the rotation rate is well established but no pole solution has been published to date. However, some clues concerning the pole direction can be derived from our data and the published results of other observers. For instance, the value given by [START_REF] Zaitsev | Radar detection of NEA 33342 (1998 WT24) with Evpatoria -Medicina System at 6 cm[END_REF] for the lower bound on the maximum pole-on breadth of the asteroid from observations of the Doppler-broadened radar echo bandwidth (0.41 km) is very similar to the effective diameter of the asteroid (0.40 km) derived from the polarimetric data of [START_REF] Kiselev | Synthetic phase angle dependence of polarization for the E-type asteroids[END_REF] using the [START_REF] Lupishko | A new calibration of the polarimetric albedo scale of asteroids[END_REF] calibration, which gives the larger size (see

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15 Section 1). The result of Zaitsev et al. is a lower bound because the actual value of the maximum pole-on breadth is given by 0.41/sin φ km, where φ is the angle between the spin vector and the radar line of sight. Given the similarity between the radar lower bound and the maximum size determined via polarimetry, and the fact that the radar data seem to indicate a near spherical shape, we can infer that the spin vector was not far from being perpendicular to the radar line of sight (or, equivalently, the sub-radar latitude was small). Furthermore, the results of our analyses of the thermal-infrared data obtained over a broad phase-angle range indicate (see Section 4.3) that the rotation axis was oriented nearly perpendicular to the solar direction, that is the sub-solar latitude was small. To simultaneously satisfy the conditions of small sub-Earth and sub-solar latitudes at the time of the radar observations (2001 Dec. 17.0 UT), the coordinates of the pole solution of 1998 WT 24 must be around β = 52˚, λ = 175˚ or β = -52˚, λ = 355˚ (J2000), depending on whether the rotation is prograde or retrograde, respectively. Note, however, that the above reasoning allows only very crude indications of the pole orientation to be inferred; the quoted solutions may be in error by several tens of degrees.

Simple models

The results of fitting the NEATM and FRM to the four 2001 December data sets are presented in Table 3. The FRM best-fit diameter is reasonably consistent in all cases, while the NEATM best-fit diameter varies between 0.31 km and 0.62 km. The FRM assumes that the rotation axis is perpendicular to the plane containing the Sun, asteroid and observer, so consistency of the FRM results leads us to infer that the sub-solar latitude was small throughout the period of the infrared observations. If this were not the case, we would expect the FRM to give erroneously large diameters at lower phase angles due to the increased visibility from the Earth of warm surface areas at high asteroidal latitudes (see [START_REF] Harris | The surface properties of small asteroids from thermal-infrared observations[END_REF]. For an FRM-type asteroid, i.e. fast

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16 rotating with low sub-solar and sub-Earth latitudes, the thermal emission observed is independent of solar phase angle.

As discussed in Section 3.1, for objects with significant thermal inertia the NEATM would be expected to overestimate diameters at large phase angles due to emission arising from the night side of the object (the NEATM assumes observed thermal emission is from the day side only, which is approximately true if the object is observed at a moderate phase angle, or has low thermal inertia/is a slow rotator, or the sub-solar latitude is near 90˚).

The above considerations allow constraints to be applied to the size of 1998 WT 24 from the NEATM and FRM results. In the case of NEATM the lower phase angle (60˚, 79˚) results of Dec. 4 and Dec. 19 can be taken as an upper limit, i.e. D NEATM < 0.41 km (note that the results of Dec. 18 may have been compromised by poor quality data due to weather and instrument problems -see Section 2). In the case of the FRM the highest phase angle (93˚) results, which should be the most reliable, give D FRM = 0.36 km.

Thermophysical models

We initially applied the smooth-sphere thermophysical model described in Section 3.2.

An example of the scatter of the flux values and the difficulty in determining best-fit parameters for a single data set is shown in Fig. 1. We assumed the pole direction discussed in Section 4.2 and tried both prograde and retrograde rotation states, in each case calculating best fit diameters for 7 different values of thermal inertia in the range 10 -1000 J m -2 s -0.5 K -1 . For comparison, values of thermal inertia measured to date for large main-belt asteroids are around 5 -25 J m -2 s -0.5 K -1 [START_REF] Müller | Asteroids as far-infrared photometric standards for ISOPHOT[END_REF], while the highest value published to date is 750 J m -2 s -0.5 K -1 for the NEA (25143) Itokawa [START_REF] Müller | Thermal infrared observations of the Hayabusa spacecraft target asteroid 25143 Itokawa[END_REF]. Note that the sense of the

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A N U S C R I P T solar phase angle changed on Dec. 15. For example, if rotation is retrograde the cooler morning side of the asteroid was observed prior to Dec. 15 and the warmer afternoon side after Dec. 15.

The converse applies in the prograde case.

For each value of thermal inertia and each of the four nights of observations the value of diameter minimizing reduced χ 2 was calculated (see Table 4), where

reduced χ 2 = ∑ [(F n (obs) -F n (model))/σ n ] 2 / (n-2) (1)
and n is the number of flux measurements, 2 is the number of free parameters in the fit (diameter and thermal inertia), and σ n are the statistical uncertainties in the photometry,

F n (obs). In the following χ 2 refers to reduced χ 2 . Note that the scatter of the flux values about the best-fit model thermal continua (see Fig. 1) reflects atmospheric variability and lightcurve effects, in addition to the statistical errors given in Table 2, so the values of χ 2 min in Table 4 are generally well above unity. The mean diameters and corresponding standard deviations for each value of thermal inertia are listed in the respective columns of Table 4. In addition, we list the value of ΣΔχ 2 , which is the sum over the four data sets of the differences between χ 2 min for each value of thermal inertia and the overall lowest χ 2 min for the corresponding date. Taking the results for Dec. 19 (retrograde case) for example, the overall lowest χ 2 min , 10.2, is obtained for a thermal inertia value of 50 J m -2 s -0.5 K -1 , so Δχ 2 in the case of thermal inertia = 1000 J m -2 s -0.5 K -1 is 16.4 -10.2 = 6.2, so the relatively poor fit obtained with the high value of thermal inertia incurs a relatively large penalty (Δχ 2 = 6.2). In contrast, for Dec. 4 the corresponding value of Δχ 2 is only 0.14, because the poorer data set of Dec. 4 does not allow confident discrimination between different values of thermal inertia.

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18

The minimum value of ΣΔχ 2 , i.e. 2.22, corresponds to the overall best-fitting thermal inertia of 100 J m -2 s -0.5 K -1 for the combined data of all four nights (Fig. 2). The corresponding mean diameter is 0.33 km (0.34 km if the poor quality data of Dec. 18 are excluded) and we see that this value also corresponds to the minimum scatter in diameter for the four dates (Fig. 3), i.e.

this value of diameter, with a thermal inertia of 100 J m -2 s -0.5 K -1 , and retrograde rotation, appears to give the most consistent fits to the data. Considering the results for prograde rotation in the lower part of Table 4, it is clear that no combination of thermal inertia and diameter gives a comparably convincing overall result.

In summary, the results from the smooth-sphere thermophysical model are: D eff = 0.34 ± 0.02 km, p v = 0.60 ± 0.2 (assuming H = 18.5 ± 0.3), and thermal inertia ~ 100 J m -2 s -0.5 K -1 , which are consistent with those from the FRM and NEATM. In Finally we applied the more detailed general thermophysical model, which explicitly takes account of the shape, spin vector and surface roughness, in addition to thermal inertia, as described in Section 3.2. This model, or a similar one, has been applied in the analysis of thermal-infrared data for ( 25143) Itokawa (Mueller et al., 2006a;[START_REF] Müller | Thermal infrared observations of the Hayabusa spacecraft target asteroid 25143 Itokawa[END_REF] and ( 1580) Betulia [START_REF] Harris | The surface properties of small asteroids: peculiar Betulia -a case study[END_REF]. Since no shape model has yet been published for 1998

WT 24 , we first tried modeling the asteroid as a biaxial ellipsoid spinning about one of the two shorter axes. The ellipsoid was modeled as a mesh of 6144 triangular facets. Several types of ellipsoid were tried, all of which were consistent with published optical lightcurves, but the results turned out to be largely independent of the shape of the ellipsoid. In fact, it was found that no ellipsoid fitted the thermal data significantly better than a sphere. Therefore, we pursued our analysis using the general thermophysical model, based on a sphere, to test the

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19 effects of surface roughness and to check the results obtained with the completely independent smooth-sphere thermophysical model described above. Surface roughness is modeled as a uniform distribution of craters (hemispherical sections); the degree of roughness is varied by changing the crater density and the crater opening angle. Shadowing and multiple reflections of incident solar and thermally emitted radiation inside craters are taken into account.

For both possible spin directions (see Section 4.2) surface roughness, thermal inertia, and size were adjusted until the best agreement was obtained with the full set of observational results listed in Table 2, i.e. χ² was minimized. It was found that the fit significantly improved when the data from Dec. 18 were excluded, which is consistent with these data being of inferior quality, as discussed above.

As in the case of the smooth-sphere thermophysical model, the retrograde pole solution was found to fit the data significantly better than the prograde solution. For the retrograde pole solution, and different degrees of surface roughness, the best-fit thermal inertia is about 200 J m -2 s -0.5 K -1 , with an uncertainty of some 100 J m -2 s -0.5 K -1 (Fig. 4). Zero roughness and the highest degree of roughness (saturated crater coverage) give slightly worse fits to the data. In the case of zero roughness we note that the more detailed general thermophysical model gives very similar results to those of the independently developed smooth-sphere model. The corresponding best-fit values of diameter and albedo are 0.35 ± 0.02 km and p v = 0.56 ± 0.2 (assuming H = 18.5 ± 0.3). Figure 5 illustrates the dependence of diameter on roughness and thermal inertia.

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Uncertainties

The error bars in the plot of Fig. 1 reflect only the statistical uncertainties in the flux derivation from the synthetic aperture procedure. Absolute calibration uncertainties, differences in atmospheric transmission between measurements of the target and calibration star, and lightcurve effects, also contribute to the error budget.

Uncertainties in thermal modeling usually exceed the formal errors resulting from the scatter of the flux measurements. In the case of NEATM, comparison with results from other sources, such as radar, indicate that overall errors are normally less than 15% in diameter and 30% in albedo. In the case of a very irregularly shaped object, or one with complex large-scale surface topography, errors may be larger; at large phase angles an additional error arises due to radiation emitted on the night side, as discussed in Section 3.1. The uncertainty in the adopted H-value increases the uncertainty in derived values of albedo but has relatively little effect on the uncertainty in the diameter.

Comparison with independent results for D eff in the cases of (433) Eros and (25143) Itokawa suggests the uncertainty in diameter determinations with the more detailed general thermophysical model is around 10%. Further testing of the model is required to refine the uncertainty estimates.

Discussion

The results of the more detailed general thermophysical model should be the most robust, although the accuracy of thermophysical modeling depends crucially on the accuracy and

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21 resolution of the shape model used. Unresolved topographic structure, such as large concavities or boulders, could influence the temperature distribution on the surface, and would be more significant at the high phase angles of our observations. So we caution that the modeling uncertainties in our results are considerable. Nevertheless, despite the fact that all the thermal models used have their shortcomings and have not been thoroughly tested at the high phase angles of our 1998 WT 24 observations, the overall agreement of the results from the various models is good. [START_REF] Zaitsev | Radar detection of NEA 33342 (1998 WT24) with Evpatoria -Medicina System at 6 cm[END_REF] derived lower limits for the maximum pole-on breadth of 0.42 and 0.40 km, respectively, from observations of the Doppler-broadened radar echo bandwidth on two consecutive dates. Zaitsev et al. interpret the constancy of their radar echo bandwidths as indicating a roughly spherical shape. The lightcurve amplitude of 0.26 mag peak to peak reported by [START_REF] Krugly | CCD photometry of near-Earth asteroids in 2001[END_REF] at phase angles between 50˚ and 60˚, suggests an axial ratio of roughly a/b = 1.15, after reducing the lightcurve amplitude by a factor of 1.7 to crudely correct for the phase-angle dependence [START_REF] Zappala | An analysis of the amplitude-phase relationship among asteroids[END_REF]. Given the effective diameter of 0.35 km derived in this work, the corresponding dimensions of a biaxial ellipsoid would be a = 0.38 km and b = 0.33 km. The larger dimension is consistent with the results of [START_REF] Zaitsev | Radar detection of NEA 33342 (1998 WT24) with Evpatoria -Medicina System at 6 cm[END_REF],

given the uncertainties. We conclude that our results are consistent with published values for the diameter and albedo derived using independent techniques (Table 5), which increases our confidence in the thermal inertia and approximate pole solution derived in this work.

An interesting result from this work is that neglecting surface roughness in the thermal modeling does not alter the results substantially (cf. the entries in Table 5 for the two thermophysical models used). In this respect the thought-provoking images of (25143) Itokawa from the Hayabusa mission (e.g. [START_REF] Saito | Detailed images of asteroid 25143 Itokawa from Hayabusa[END_REF], which reveal a boulder-strewn surface virtually devoid of craters, leads one to question the validity of the idealistic treatment of However, in the absence of high-resolution shape models there is currently no alternative. An important area for future work is to study how the accuracy of thermophysical models might be influenced by the presence of intermediate-scale topographic structure, e.g. large concavities and other features intermediate in scale between craters and the whole body that are not normally included in shape models.

Our albedo for 1998 WT 24 of p v = 0.56 ± 0.2 is at the high end of the range associated with E types in general and means that this object has one of the highest albedos measured for any asteroid. The uncertainty in our derived albedo is, however, relatively large, due to modeling uncertainties and the uncertainty in the H value. A fainter H value would lead to a lower albedo but would have little influence on the derived diameter. E-type spectra are flat and largely featureless and are thought to be indicative of the spectrally neutral mineral enstatite or other iron-poor silicates. E-type asteroids may have an origin in the crust or exposed mantle of a differentiated parent body [START_REF] Gaffey | BB) to the enstatite achondrite meteorites and the Hungaria asteroids[END_REF] ). An absolute magnitude of H = 18.5 ± 0.3 mag was adopted (see Section 1). D eff is the diameter of a sphere of equivalent projected area to that of the asteroid at the mean level of the lightcurve. The uncertainties are dominated by modeling uncertainties, especially at the high solar phase angles of our observations, at which NEATM may overestimate the diameter by 10% or more; the error increases with increasing thermal inertia and phase angle (see [START_REF] Harris | The surface properties of small asteroids from thermal-infrared observations[END_REF]. On the other hand, the accuracy of the FRM would be expected to improve with increasing thermal inertia and phase angle. Notes: ΣΔχ 2 is the sum over the four data sets of the differences between χ 2 min for each value of thermal inertia and the overall lowest χ 2 min for the corresponding date. The formal definition of χ 2 is given in Eq. (1). The curves were derived from a spherical thermophysical model, in which retrograde rotation is assumed and surface roughness is ignored, with thermal inertia set at 10 J m -2 s -0.5 K -1 (dotted curve), 100 J m -2 s -0.5 K -1 (dashed curve), and 1000 J m -2 s -0.5 K -1 (continuous curve). The model curves are best fits generated by finding the values of diameter that minimize χ 2 . The error bars reflect only the statistical uncertainties in the flux derivation from the synthetic aperture procedure: the scatter of the data points is probably largely due to varying atmospheric transmission and rotational variability (lightcurve effects).

Figure 2. Smooth-sphere thermophysical model: ΣΔχ 2 versus thermal inertia, where ΣΔχ 2 is the sum over the four data sets of the differences between χ 2 min for each value of thermal inertia and the overall lowest χ 2 min for the corresponding date (see text and Table 4). The overall minimum in ΣΔχ 2 is obtained with a thermal inertia of 100 J m -2 s -0.5 K -1 and retrograde rotation.

Figure 3. Smooth-sphere thermophysical model: Standard deviation of the best-fit diameters for the four observation dates (see Table 4) as a function of thermal inertia. The least dispersion in best-fit diameter over the four dates is obtained with a thermal inertia of 100 J m -2 s -0.5 K -1 and retrograde rotation.

  measurements made in the same filter (e.g. see Fig.

  Fig. 1 best-fit model thermal continua for thermal inertia values of 10, 100, and 1000 J m -2 s -0.5 K -1 are shown superimposed on the flux measurements of 2001 Dec. 19.

  uniform distribution of hemispherical craters in the case of very small asteroids.

Figure 1 .

 1 Figure 1. Weighted best fits of thermal-model continua to the flux data of 2001 December 19.

Figure 4 .Figure 5 .

 45 Figure 4. General thermophysical model: Goodness of fit (χ²) as a function of thermal inertia

  Various models applied to thermal-infrared flux measurements of the near-Earth asteroid 1998WT 24 obtained at ESO and the NASA IRTF result in an effective diameter of 0.35 ± 0.04 km and an albedo of p v = 0.56 ± 0.2 (the conservative uncertainties allow for modeling errors and, in the case of p v , the uncertainty in H) and indicate that the surface thermal inertia is around 100 -300 J m -2 s -0.5 K -1 , or a few times the lunar value. The high albedo is consistent with the suggestion that 1998 WT 24 is a member of the E spectral class; so this NEA, which is a potentially hazardous object with a minimum orbit intersection distance (MOID) of only 0.0097 AU and a modest orbital inclination of 7.3°, should be considered, together with 4660 Nereus, a prime candidate source of the aubrite meteorites. The thermal inertia is much lower than that expected for a bare-rock surface and implies that 1998 WT 24 has significant areas of thermally insulating regolith. Our results suggest that 1998 WT 24 is a retrograde rotator. A crude pole solution inferred from a combination of our results and the radar observations of

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	7. Conclusions
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	M
	and are relatively rare; only a handful of NEAs have characteristics suggestive of E-class membership, including 3103 Eger, 4660 Nereus, 5751 Zao, and (10302) 1989 ML. E-type asteroids may be sources of the aubrite meteorites, which have similar spectral characteristics (e.g. Lazzarin et al., 2004), although Clark et al. (2004) argue on the basis of spectroscopic observations and compositional modeling that 3103 Eger is unlikely to be a source of the aubrites. 4660 Nereus and 1998 WT 24 are potentially hazardous objects with inclinations of 1.4° and 7.3°, respectively, that have made close approaches to the Earth in the past. These two NEAs have physical and dynamical Zaitsev et al. (2002) is β = -52˚, λ = 355˚ (J2000), but we caution that this is uncertain by several tens of degrees. Our results are consistent with those of Delbó et al. (2003), Mueller et al. (2006a), and Harris et al. (2005), which indicate that near-Earth asteroids generally have moderate thermal inertias, indicative of surfaces with some exposed rock but largely covered in thermally insulating A C C E P T E D regolith or dust.
	characteristics that make them prime candidate sources of the aubrite meteorites.
	23

  Note: The sense of the solar phase angle changed on Dec. 15. For example, if rotation is retrograde (see Section 4), the cooler morning side of the asteroid was observed prior to Dec. 15 and the warmer afternoon side after Dec. 15.

		TABLE 1
		Observing geometry
	33342 1998 WT 24	2001 Dec. 04 2001 Dec. 18 2001 Dec. 19 2001 Dec. 21
	Telescope	ESO	IRTF	IRTF	IRTF
	Heliocentric distance, r (AU)	1.0148	0.9901	0.9874	0.9817
	Geocentric distance, Δ (AU)	0.0621	0.0162	0.0198	0.0284
	Solar phase angle, αº	-60.4	67.5	79.3	93.4

TABLE 3

 3 Diameter and albedo determinations from the application of the NEATM and the FRM to the data listed in Table2

	Data set	αº	No. flux points	D eff (km) NEATM	p v NEATM	η NEATM	Deff (km) FRM	p v FRM
	2001 Dec. 04	-60.4	3	0.40	0.43	1.86	0.38	0.49
	2001 Dec. 18	67.5	10	0.31	0.75	0.61	0.39	0.46
	2001 Dec. 19	79.3	12	0.41	0.42	1.25	0.38	0.48
	2001 Dec. 21	93.4	8	0.62	0.18	2.70	0.355	0.58
	Note: The unusually low value of η for Dec. 18 may be indicative of poor quality data or lightcurve effects (see
	Sections 2 and 4.1

Acknowledgments

The comments and suggestions of the reviewers, anonymous and Stephan Price, are gratefully acknowledged. Most of the data presented herein were obtained with the Infrared Telescope Facility, which is operated by the University of Hawaii under Cooperative Agreement no. NCC 5-538 with the National Aeronautics and Space Administration, Office of Space Science, Planetary Astronomy Program. The work of M. Delbó and M. Mueller was partly supported by the Deutsche Forschungsgemeinschaft (DFG). Liberal use was made of the excellent JPL Horizons System for generating ephemerides.

Thermal inertia (J m -2 s -0.5 K -1 ) Notes [START_REF] Kiselev | Synthetic phase angle dependence of polarization for the E-type asteroids[END_REF] 0.40 ± 0.13 0.43 ± 0.15 -p v from polarimetry (Lupishko and Mohamed, 1996, calibration). [START_REF] Kiselev | Synthetic phase angle dependence of polarization for the E-type asteroids[END_REF] 0.34 ± 0.10 0.62 ± 0.17 -p v from polarimetry (Cellino et al., 1999, calibration). Note: The value of the absolute magnitude assumed is H = 18.5 ± 0.3. We estimated uncertainties for the polarimetric albedos from the uncertainties in the coefficients of the albedo-polarimetric slope relations (see [START_REF] Cellino | Polarimetric observations of small asteroids: preliminary results[END_REF]. The NEATM would be expected to overestimate diameters at large phase angles due to its assumption that all observed thermal emission is from the day side, therefore an upper limit is quoted here derived from the data taken on Dec. 4 and 19. In contrast to the NEATM, the reliability of the FRM should improve with increasing solar phase angle (see [START_REF] Harris | The surface properties of small asteroids from thermal-infrared observations[END_REF], thus the entry for the FRM is based on the data from Dec. 21 (α = 93.4˚). The effective diameter, D eff , is the diameter of a sphere of equivalent projected area to that of the asteroid at the mean level of the lightcurve. D max refers to the maximum dimension perpendicular to the rotation axis.

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