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In this issue, three groups (Hewitt et al. 2010. J. Cell Biol. doi:10.1083/jcb.201002133; Maciejowski et al. 2010. J. Cell Biol. doi:10.1083/jcb.201001050; Santaguida et al. 2010. J. Cell Biol. doi:10.1083/jcb.201001036) use chemical inhibitors to analyze the function of the mitotic checkpoint kinase Mps1. These studies demonstrate that Mps1 kinase activity ensures accurate chromosome segregation through its recruitment to kinetochores of mitotic checkpoint proteins, formation of interphase and mitotic inhibitors of Cdc20, and correction of faulty microtubule attachments.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti–dsDNA autoantibody production, a SLE–related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti–dsDNA autoantibody positive (anti–dsDNA +, n = 811) and anti–dsDNA autoantibody negative (anti–dsDNA –, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti–dsDNA + SLE. Far fewer and weaker associations were observed for anti–dsDNA – SLE. For example, rs7574865 in STAT4 had an OR for anti–dsDNA + SLE of 1.77 (95% CI 1.57–1.99, p = 2.0E-20) compared to an OR for anti–dsDNA – SLE of 1.26 (95% CI 1.12–1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti–dsDNA + SLE and were not associated with anti–dsDNA – SLE. In conclusion, we identified differential genetic associations with SLE based on anti–dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti–dsDNA – SLE.

Author Summary

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can involve virtually any organ system. SLE patients produce antibodies that bind to their own cells and proteins (autoantibodies) which can cause irreversible organ damage. One particular SLE–related autoantibody directed at double-stranded DNA (anti–dsDNA) is associated with kidney involvement and more severe disease. Previous genome-wide association studies (GWAS) in SLE have studied SLE itself, not particular SLE manifestations. Therefore, we conducted this GWAS of anti–dsDNA autoantibody production to identify genetic associations with this clinically important autoantibody. We found that many previously identified SLE–associated genes are more strongly associated with anti–dsDNA autoantibody production than SLE itself, and they may be more accurately described as autoantibody propensity genes. No strong genetic associations were observed for SLE patients who do not produce anti–dsDNA autoantibodies, suggesting that other factors may have more influence in developing this type of SLE. Further investigation of these autoantibody propensity genes may lead to greater insight into the causes of autoantibody production and organ damage in SLE.

British Journal of Cancer (2002) 87, 813–814. doi:10.1038/sj.bjc.6600568 www.bjcancer.com

© 2002 Cancer Research UK

A new approach to depth of interaction (DOI) encoding for a pixelated LSO array using a single multi-channel PMT was investigated. In this method the DOI information was estimated by taking advantage of optical crosstalk between LSO elements and examining the standard deviation (spread) of signals on all channels of the PMT. Unpolished and polished 6×6 LSO arrays with a crystal size of 1.3×1.3×20 mm3 were evaluated on a Hamamatsu H7546 64-channel PMT. The arrays were placed on the center of the PMT and the central 16 channels of the PMT were individually read out and digitized. For the unpolished array, all crystals were resolved in the flood histogram. An average DOI resolution of 8 mm was obtained. The energy resolution was ∼25% after the signal amplitude was corrected using the measured DOI information. For the polished array, the flood histogram was superior to the unpolished array, however no DOI information could be measured. Using unpolished crystals, this method could be a practical way to achieve limited DOI information in PET detectors. The standard deviation of all PMT channels can be readily obtained using a resistor network. Only five signals (four signals to determine the x-y position and one signal measuring the standard deviation) need to be digitized, and this method only requires a single photon detector to read out the array. Unlike phoswich detectors, the method does not require segmenting the scintillator array into layers. The measured DOI resolution was much worse than that obtained with the dual-ended readout method, however, it was similar to that obtained with a two-layer phoswich detector.

Background

There are few data on the prevalence of schistosomiasis in Darfur. We conducted this study in response to reports of 15 laboratory confirmed cases of schistosomiasis and visible haematuria among children from two communities in South Darfur. The aim of the study was to estimate the prevalence of schistosomiasis in the area and to decide on modalities of intervention.

Methods

A cross-sectional survey involving 811 children and adults from schools and health facilities was conducted in two communities of South Darfur in March 2010. Urine samples were collected and examined for ova of Schistosoma haematobium using a sedimentation technique. A semi-structured format was used to collect socio-demographic characteristics of the participants.

Results

Eight hundred eleven (811) urine samples were collected, 415 from Alsafia and 396 from Abuselala. Of the collected samples in 56.0% (95% Confidence Interval (CI); 52.6-59.4) Schistosoma eggs were found. The prevalence was high in both Abuselala 73.3% (95% CI; 68.9-77.6) and Alsafia 39.5% (95% CI; 34.8-44.2). More males (61.7%, 95%CI; 56.5-64.9) were infected than females (52.1%, 95%CI; 48.2-56.0). Children in the age group 10-14 has the highest (73.0%, 95%CI; 68.7-77.2) infection rate. School age children (6-15 years) are more likely to be infected than those >15 years (Adjusted Odds Ratio (AOR) = 2.70, 95% CI; 1.80-4.06). Individuals in Abuselala are more likely to be infected than those who live in Alsafia (AOR = 4.3, 95% CI; 3.2-5.9).

Conclusion

The findings of this study indicate that S. hematobium is endemic in Alsafia and Abuselala South Darfur in Sudan with a high prevalence of infection among older children. This signifies the importance of urgent intervention through Mass Drug Administration (MDA) to halt the infection cycle and tailored health messages to targeted groups. Based on the findings MDA was conducted in the villages.

In this issue, Duran et al. (2010. J. Cell Biol. doi: 10.1083/jcb.200911154) and Manjithaya et al. (2010. J. Cell Biol. doi: 10.1083/jcb.200911149) use yeast genetics to reveal a role for autophagosome intermediates in the unconventional secretion of an acyl coenzyme A (CoA)–binding protein that lacks an endoplasmic reticulum signal sequence. Medium-chain acyl CoAs are also required and may be important for substrate routing to this pathway.

Chaperones help proteins fold in all cellular compartments, and many associate directly with ribosomes, capturing nascent chains to assist their folding and prevent aggregation. In this issue, new data from Koplin et al. (2010. J. Cell Biol. doi: 10.1083/jcb.200910074) and Albanèse et al. (2010. J. Cell Biol. doi: 10.1083/jcb.201001054) suggest that in addition to promoting protein folding, the chaperones ribosome-associated complex (RAC), nascent chain–associated complex (NAC), and Jjj1 also help in the assembly of ribosomes.

In contrast to what has been reported previously, endo-lysosomal dysfunction in presenilin-deficient cells does not arise from improper glycosylation of the lysosomal V-ATPase but rather from defective lysosomal calcium homeostasis.

Presenilin (PSEN) deficiency is accompanied by accumulation of endosomes and autophagosomes, likely caused by impaired endo-lysosomal fusion. Recently, Lee et al. (2010. Cell. doi: http://dx.doi.org/10.1016/j.cell.2010.05.008) attributed this phenomenon to PSEN1 enabling the transport of mature V0a1 subunits of the vacuolar ATPase (V-ATPase) to lysosomes. In their view, PSEN1 mediates the N-glycosylation of V0a1 in the endoplasmic reticulum (ER); consequently, PSEN deficiency prevents V0a1 glycosylation, compromising the delivery of unglycosylated V0a1 to lysosomes, ultimately impairing V-ATPase function and lysosomal acidification. We show here that N-glycosylation is not a prerequisite for proper targeting and function of this V-ATPase subunit both in vitro and in vivo in Drosophila melanogaster. We conclude that endo-lysosomal dysfunction in PSEN−/− cells is not a consequence of failed N-glycosylation of V0a1, or compromised lysosomal acidification. Instead, lysosomal calcium storage/release is significantly altered in PSEN−/− cells and neurons, thus providing an alternative hypothesis that accounts for the impaired lysosomal fusion capacity and accumulation of endomembranes that accompanies PSEN deficiency.

Background

The study objectives were to compare and examine mammography use trends among ethnic/racial women in the context of United States Healthy People 2010 goals.

Methods

We analyzed pooled, multistage probability sample data from the 1996–2007 Medical Expenditure Panel Survey. Included in the sample were female respondents ages 40–75 years (n=64,811) from six ethnic/racial groups (Black, White, Mexican, Other Latinas, Puerto Rican and Cuban). The primary outcome was self-reported, past two-year mammography use consistent with screening practice guidelines.

Results

We found that for most U.S. women, the Healthy People 2010 mammography goal (70%) was achieved between 1996 and 2007. Puerto Rican and White women, respectively, had the highest mammography rates, and Black and Cuban women had rates that approached the 2010 goal.

Conclusion

Mexican Latinas reported the lowest rates of past two-year mammography; however, factors enabling healthcare access markedly moderated this lower likelihood. From 2000, Mexican Latinas’ mammography use was markedly below (10%) the Healthy People 2010 goal and remained there for the duration.

Impact

Our findings indicate that healthcare equity goals are attainable if efforts are made to reach a sizeable portion of vulnerable populations.

Using antibodies raised with chlamydial fusion proteins, we have localized a protein encoded by hypothetical open reading frame CT813 in the inclusion membrane of Chlamydia trachomatis. The detection of the C. trachomatis inclusion membrane by an anti-CT813 antibody was blocked by the CT813 protein but not unrelated fusion proteins. The CT813 protein was detected as early as 12 h after chlamydial infection and was present in the inclusion membrane during the entire growth cycle. All tested serovars from C. trachomatis but not other chlamydial species expressed the CT813 protein. Exogenously expressed CT813 protein in HeLa cells displayed a cytoskeleton-like structure similar to but not overlapping with host cell intermediate filaments, suggesting that the CT813 protein is able to either polymerize or associate with host cell cytoskeletal structures. Finally, women with C. trachomatis urogenital infection developed high titers of antibodies to the CT813 protein, demonstrating that the CT813 protein is not only expressed but also immunogenic during chlamydial infection in humans. In all, the CT813 protein is an inclusion membrane protein unique to C. trachomatis species and has the potential to interact with host cells and induce host immune responses during natural infection. Thus, the CT813 protein may represent an important candidate for understanding C. trachomatis pathogenesis and developing intervention and prevention strategies for controlling C. trachomatis infection.

Akin to functional magnetic resonance imaging (fMRI), diffuse optical imaging (DOI) is a noninvasive method for measuring localized changes in hemoglobin levels within the brain. When combined with fMRI methods, multimodality approaches could offer an integrated perspective on the biophysics, anatomy, and physiology underlying each of the imaging modalities. Vital to the correct interpretation of such studies, control experiments to test the consistency of both modalities must be performed. Here, we compare DOI with blood oxygen level-dependent (BOLD) and arterial spin labeling fMRI-based methods in order to explore the spatial agreement of the response amplitudes recorded by these two methods. Rather than creating optical images by regularized, tomographic reconstructions, we project the fMRI image into optical measurement space using the optical forward problem. We report statistically better spatial correlation between the fMRI-BOLD response and the optically measured deoxyhemoglobin (R=0.71, p=1 × 10−7) than between the BOLD and oxyhemoglobin or total hemoglobin measures (R=0.38, p=0.04|0.37, p=0.05, respectively). Similarly, we find that the correlation between the ASL measured blood flow and optically measured total and oxyhemoglobin is stronger (R=0.73, p=5 × 10−6 and R=0.71, p=9 × 10−6, respectively) than the flow to deoxyhemoglobin spatial correlation (R=0.26, p=0.10).