Skeletal and Dental Health of Precontact Marquesans: The Bioarchaeology of the Human Skeletons from Ha‘atuatua, Nuku Hiva, Marquesas Islands

Skeletal and dental indicators (e.g., stature, linear enamel hypoplasia, cribra orbitalia, trauma, dental pathologies, and other evidence of disease) recorded in 45 subadult and 36 adult skeletons from the NHaa 1 site at Ha‘atuatua, Nuku Hiva, northern Marquesas, are used to examine the health, diet, and lifestyle of precontact Marquesans during the Expansion Period (ca. A.D. 1300–1600). Limited comparisons with skeletons from Hane on Ua Huka and other Pacific Island series augment this study. In addition to elevated numbers of subadult deaths, many during the first year of life, significant palaeopathology suggestive of infection, anemia, or metabolic disease was noted for seven subadults. In contrast, very little palaeopathology was noted in the adults and no significant sex differences for most indicators of health. With few exceptions, the skeletal and dental indicators of health in the Ha‘atuatua and Hane series were very similar. Compared to other precontact Pacific series, the Ha‘atuatua males were tall and similar to other East Polynesians. Higher frequencies of stress fracture in the lower back at Ha‘atuatua may be linked to activities associated with landscape changes and the construction of stone megalithic structures. The skeletal and dental indicators of health observed in the Ha‘atuatua burials are most like those reported for other East Polynesian series. The precontact inhabitants of the Marquesas were generally healthy, contrary to expectations of increased disease frequencies and evidence of warfare during the Expansion Period at Ha‘atuatua. These new bioarchaeological data broaden our understanding of the health and lifestyle of precontact Polynesians

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Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45645/1/11199_2004_Article_BF00287975.pd

Magma chamber detected beneath an arc volcano with high-resolution velocity images

Arc volcanoes are underlain by complex systems of molten-rock reservoirs ranging from melt-poor mush zones to melt-rich magma chambers. Petrological and satellite data indicate that eruptible magma chambers form in the topmost few kilometres of the crust. However, very few chambers have ever been definitively located, suggesting that most are too short-lived or too small to be imaged, which has direct implications for hazard assessment and modelling of magma differentiation. Here we use a high-resolution technology based on inverting full seismic waveforms to image a small, high-melt-fraction magma chamber that was not detected with standard seismic tomography. The melt reservoir extends from ~2 to at least 4 km below sea level (b.s.l.) at Kolumbo – a submarine volcano near Santorini, Greece. The chamber coincides with the termination point of the recent earthquake swarms and may be a missing link between a deeper melt reservoir and the high-temperature hydrothermal system venting at the crater floor. The chamber poses a serious hazard as it could produce a highly explosive, tsunamigenic eruption in the near future. Our results suggest that similar reservoirs (relatively small but high melt-fraction) may have gone undetected at other active volcanoes, challenging the existing eruption forecasts and reactive-flow models of magma differentiation

EBV MicroRNAs in Primary Lymphomas and Targeting of CXCL-11 by ebv-mir-BHRF1-3

EBV-encoded microRNAs (miRNAs) have been identified and their functions are being studied. The expression pattern of these miRNAs in clinical samples of EBV-associated non–Hodgkin’s lymphomas is unknown. We analyzed five primary “endemic” pediatric Burkitt’s lymphomas (BL), two acquired immunodeficiency syndrome (AIDS)-related type I latency BL lines, a type III latency line, three EBV+ primary effusion lymphomas (PEL), and three AIDS-related diffuse large B-cell lymphomas (DLBCL) for expression of EBV-encoded miRNAs. A markedly elevated expression of miRNA BHRF1-3 in type III relative to its parental type I BL line was found. Primary unmanipulated type I BLs and EBV+ PELs expressed high levels of BART2 miRNA, whereas DLBCLs expressed both BART2 and BHRF1-3 species. BHRF1-3 miRNA expression inversely correlated with levels of a putative cellular target, the IFN-inducible T-cell attracting chemokine CXCL-11/I-TAC, and suppression of this factor was reversed by transfection of an antisense oligo to the EBV miRNA BHRF1-3. EBV-encoded miRNAs are expressed in primary lymphomas classically linked to the virus and are associated with the viral latency status. Targeted suppression of CXCL-11/I-TAC by a viral-encoded miRNA may serve as an immunomodulatory mechanism in these tumors

The Orphan Receptor CRF2-4 Is an Essential Subunit of the Interleukin 10 Receptor

The orphan receptor CRF2-4 is a member of the class II cytokine receptor family (CRF2), which includes the interferon receptors, the interleukin (IL) 10 receptor, and tissue factor. CRFB4, the gene encoding CRF2-4, is located within a gene cluster on human chromosome 21 that comprises three interferon receptor subunits. To elucidate the role of CRF2-4, we disrupted the CRFB4 gene in mice by means of homologous recombination. Mice lacking CRF2-4 show no overt abnormalities, grow normally, and are fertile. CRF2-4 deficient cells are normally responsive to type I and type II interferons, but lack responsiveness to IL-10. By ∼12 wk of age, the majority of mutant mice raised in a conventional facility developed a chronic colitis and splenomegaly. Thus, CRFB4 mutant mice recapitulate the phenotype of IL-10–deficient mice. These findings suggest that CRF2-4 is essential for IL-10–mediated effects and is a subunit of the IL-10 receptor

The Combination of AZT/Interferon-α Therapy with the HDAC Inhibitor Valproic Acid for the Treatment of Adult T-Cell Leukemia/Lymphoma

Abstract Abstract 4877 Adult T-cell leukemia/lymphoma (ATLL) carries a dismal long-term prognosis and is generally chemotherapy resistant. We and other groups have demonstrated that the combination of AZT and interferon (IFN) alpha can effectively suppress ATLL long-term; however, these drugs fail to eradicate malignant ATLL clones as patients ultimately progress. We recently tested our hypothesis that histone deacelytase (HDAC) inhibitors would re-activate latent HTLV-I in ATLL cells harboring intact provirus thus helping to eliminate residual disease after cytoreductive treatment. Histone acetylation can result in HTLV-I promoter activation and viral transcription. We found that HDAC inhibitors, including the inexpensive drug valproic acid (VPA), reactivated HTLV-I expression in ATLL cells and caused apoptosis. Based on these concepts, we recently completed a pilot trial for ATLL using AZT/IFN and adding VPA during the maintenance treatment phase. Thirteen subjects with aggressive acute-type ATLL were enrolled in the study, including 11 treatment-naïve patients. The estimated 12-month overall survival rate was 46%. In 12 evaluable subjects (10 naïve) the complete response (CR) rate was 33% and overall response 42% (5 patients). A total of eight subjects (66%) had a hematologic response, including 5 complete hematologic responses (38%). VPA was added at the beginning of month 3 during AZT/IFN maintenance in 3 subjects. One subject achieved a molecular remission and clearance of ATLL after adding VPA as measured by serial multiplex PCR studies. This subject remains disease-free 2.5 years later. Our findings were surprising, as previous studies performed on long-term responders treated with AZT/IFN alone had not demonstrated any molecular remissions. Our data suggest that VPA could potentially eradicate ATLL clones in vivo. The dual anti-neoplastic and viral inducing roles of HDAC inhibitors can be exploited in the treatment of ATLL. This exciting approach may help advance the cure for this disease. We will present our updated interim clinical trial results at the conference. Disclosures: No relevant conflicts of interest to declare

Zidovudine Blocks NF-κB activity in Vivo in Adult T-Cell Leukemia

Abstract Adult T-cell leukemia (ATL) is a lymphoid malignancy caused by the human T-cell leukemia virus type I (HTLV-I), which carries a poor prognosis. A hallmark of ATL is the high constitutive expression of NF-κB, which predominantly exerts an anti-apoptotic effect contributing to chemotherapy resistance. Many of the elegant studies about the pathogenesis of ATL have focused on Tax, a viral transactivator of NF-κB, using HTLV-I expressing cell lines and mouse models, however in primary tumors the virus remains latent and Tax is not detected. We and other investigators have demonstrated the clinical efficacy of Zidovudine (AZT) and interferon-alpha (IFNα) combination therapy in both chronic and acute ATL subtypes with some patients achieving clinical remission or stable disease for many years while on maintenance therapy. The exact mechanisms of these antiviral drugs in ATL remain unclear. In a recent analysis of primary ATL tumors, we implicated the expression of both c-Rel and the NF-κB target gene product IRF-4/MUM-1 in AZT/IFN resistant disease. We have recently opened to accrual a Phase II clinical trial titled Prospective Study of the Molecular Characteristics of Sensitive and Resistant Disease in Patients with HTLV-I Associated Adult T Cell Leukemia Treated with Zidovudine Plus Interferon alpha-2b, which includes the novel use of pegylated interferon-alpha and valproic acid (as HDAC inhibitor) in the maintenance phase as an attempt to eradicate residual ATL clones, which usually occurs after AZT and IFNα therapy even after longterm remission. Our goals are also to study the anti-tumor mechanisms of these drugs in ATL, and define molecular criteria for response. As part of the correlative studies in our Phase II trial, we have analyzed leukemic ATL cells collected from patients during the first 48 hours of treatment (AZT given alone prior to IFN) and found in vivo stabilization of IκB (the repressor protein of NF-κB) by Western Blot in patients responding to the treatment, suggesting a role for this antiviral drug in blocking NF-κB activity as previously hypothesized in our laboratory. We also examined the expression of NF-κB related genes using a custom designed gene expression array by a novel technology (NanoString Inc.) of selected NF-κB target genes and found downregulation of most these genes in vivo by AZT alone. So far, all ATL tumors analyzed exhibited high expression of many NF-κB target genes, and over forty of these are differentially overexpressed in ATL specimens as compared to normal CD4+ T-cells. Some the differentially expressed genes include those encoding NF-κB/Rel, interferon regulatory factor (IRF), and bcl-2 related proteins. A comprehensive analysis of over forty ATL tumors, including specimens collected in both Miami and Brazil, is ongoing and expected to be completed soon. Baseline tumor characteristics and prognostic variables of previously collected tumors, as well interim results of our clinical and molecular studies will be reported

RASP: Optimal Single Puncta Detection in Complex Cellular Backgrounds

Super-resolution and single-molecule microscopy are increasingly applied to complex biological systems. A major challenge of this approach is that fluorescent puncta must be detected in the low signal, high noise, heterogeneous background environments of cells and tissue. We present RASP, Radiality Analysis of Single Puncta, a bioimaging-segmentation method that solves this problem. RASP removes false positive puncta that other analysis methods detect, and detects features over a broad range of spatial scales: from single proteins to complex cell phenotypes. RASP outperforms the state-of-the-art in precision and speed, using image gradients to separate Gaussian-shaped objects from background. We demonstrate RASP's power by showing it can extract spatial correlations between microglia, neurons, and alpha-synuclein oligomers in the human brain. This sensitive, computationally efficient approach enables fluorescent puncta and cellular features to be distinguished in cellular and tissue environments with a sensitivity down to the level of the single protein. Python and MATLAB codes, enabling users to perform this RASP analysis on their own data, are provided as supplementary files and links to third-party repositories.Aligning Science Across Parkinson's [ASAP-000509

RASP: Optimal Single Puncta Detection in Complex Cellular Backgrounds

Publication status: PublishedSuper-resolution and single-molecule microscopy are increasingly applied to complex biological systems. A major challenge of this approach is that fluorescent puncta must be detected in the low signal, high noise, heterogeneous background environments of cells and tissue. We present RASP, Radiality Analysis of Single Puncta, a bioimaging-segmentation method that solves this problem. RASP removes false positive puncta that other analysis methods detect, and detects features over a broad range of spatial scales: from single proteins to complex cell phenotypes. RASP outperforms the state-of-the-art in precision and speed, using image gradients to separate Gaussian-shaped objects from background. We demonstrate RASP's power by showing it can extract spatial correlations between microglia, neurons, and alpha-synuclein oligomers in the human brain. This sensitive, computationally efficient approach enables fluorescent puncta and cellular features to be distinguished in cellular and tissue environments with a sensitivity down to the level of the single protein. Python and MATLAB codes, enabling users to perform this RASP analysis on their own data, are provided as supplementary files and links to third-party repositories.Aligning Science Across Parkinson's [ASAP-000509