The NMR restraints grid at BMRB for 5,266 protein and nucleic acid PDB entries

Several pilot experiments have indicated that improvements in older NMR structures can be expected by applying modern software and new protocols (Nabuurs et al. in Proteins 55:483–186, 2004; Nederveen et al. in Proteins 59:662–672, 2005; Saccenti and Rosato in J Biomol NMR 40:251–261, 2008). A recent large scale X-ray study also has shown that modern software can significantly improve the quality of X-ray structures that were deposited more than a few years ago (Joosten et al. in J. Appl Crystallogr 42:376–384, 2009; Sanderson in Nature 459:1038–1039, 2009). Recalculation of three-dimensional coordinates requires that the original experimental data are available and complete, and are semantically and syntactically correct, or are at least correct enough to be reconstructed. For multiple reasons, including a lack of standards, the heterogeneity of the experimental data and the many NMR experiment types, it has not been practical to parse a large proportion of the originally deposited NMR experimental data files related to protein NMR structures. This has made impractical the automatic recalculation, and thus improvement, of the three dimensional coordinates of these structures. We here describe a large-scale international collaborative effort to make all deposited experimental NMR data semantically and syntactically homogeneous, and thus useful for further research. A total of 4,014 out of 5,266 entries were ‘cleaned’ in this process. For 1,387 entries, human intervention was needed. Continuous efforts in automating the parsing of both old, and newly deposited files is steadily decreasing this fraction. The cleaned data files are available from the NMR restraints grid at http://restraintsgrid.bmrb.wisc.edu

Lactate-Dehydrogenase 5 is overexpressed in non-small cell lung cancer and correlates with the expression of the transketolase-like protein 1

<p>Abstract</p> <p>Aims</p> <p>As one of the five Lactate dehydrogenase (LDH) isoenzymes, LDH5 has the highest efficiency to catalyze pyruvate transformation to lactate. LDH5 overexpression in cancer cells induces an upregulated glycolytic metabolism and reduced dependence on the presence of oxygen. Here we analyzed LDH5 protein expression in a well characterized large cohort of primary lung cancers in correlation to clinico-pathological data and its possible impact on patient survival.</p> <p>Methods</p> <p>Primary lung cancers (n = 269) and non neoplastic lung tissue (n = 35) were tested for LDH5 expression by immunohistochemistry using a polyclonal LDH5 antibody (ab53010). The results of LDH5 expression were correlated to clinico-pathological data as well as to patient's survival. In addition, the results of the previously tested Transketolase like 1 protein (TKTL1) expression were correlated to LDH5 expression.</p> <p>Results</p> <p>89.5% (n = 238) of NSCLC revealed LDH5 expression whereas LDH5 expression was not detected in non neoplastic lung tissues (n = 34) (p < 0.0001). LDH5 overexpression was associated with histological type (adenocarcinoma = 57%, squamous cell carcinoma = 45%, large cell carcinoma = 46%, p = 0.006). No significant correlation could be detected with regard to TNM-stage, grading or survival. A two sided correlation between the expression of TKTL1 and LDH5 could be shown (p = 0.002) within the overall cohort as well as for each grading and pN group. A significant correlation between LDH5 and TKTL1 within each histologic tumortype could not be revealed.</p> <p>Conclusions</p> <p>LDH5 is overexpressed in NSCLC and could hence serve as an additional marker for malignancy. Furthermore, LDH5 correlates positively with the prognostic marker TKTL1. Our results confirm a close link between the two metabolic enzymes and indicate an alteration in the glucose metabolism in the process of malignant transformation.</p

The Periotest Method: Implant-Supported Framework Precision of Fit Evaluation

: In this study, the Periotest instrument was used to measure the precision of fit between cast high noble-metal frameworks and the supporting implants in a patient-simulation model. Three framework conditions and three implant-location variables were used to evaluate the rigidity of the assembly as measured by the Periotest method. The framework variables were (1) one-piece castings (OPC); (2) sectioned-soldered inaccurate castings (SSIC); and (3) sectioned-soldered accurate castings (SSAC). The implant-location variables were right anterior (RA), center (C), and left anterior (LA). Materials and Methods : The patient simulation model used consisted of three self-tapping BrÅnemark implants in a reasonable arch curvature in bovine bone. Three working casts were fabricated from the patient-simulation model using polyvinyl siloxane and tapered impression copings. From the working casts, three sets of three frameworks were fabricated as OPCs, SSICs, and SSACs using type 3 high noble alloy. The SSICs were fabricated with a quantitative misfit of 101.6 Μm at the facial surface, between the abutment-to-gold cylinder interface at the C implant location. Periotest value (PTV) measurements were made at the midfacial surface of the frameworks directly above each abutment-to-gold cylinder interface. Three measurements were made for each test condition. The data were analyzed to compare framework condition(s) and implant location(s) using ANOVA and Fisher's Protected Least Significant Difference Comparison Test. Results : The ANOVA showed that significant differences exist between the mean PTV data for framework condition and for implant location (p < .01). Significant differences were shown between the mean PTV data for the SSAC assemblies and the OPC and SSIC assemblies. The SSICs displayed a more positive (+) mean PTV than the OPCs. The OPC assemblies had a more positive mean PTV than the SSAC assemblies. The mean PTV data for the SSAC assemblies had a significantly different PTV (p < .01) than the other two framework condition assemblies. The OPC and the SSIC assemblies had PTVs that were not significantly different. The C implant location was significantly different from the RA and the LA implant locations (p < .01). The RA and the LA implant locations were not significantly different from each other. The C implant location always demonstrated the most positive mean PTV regardless of the framework condition being tested. Conclusions : The Periotest instrument quantified differences in the precision of fit between three framework conditions. The SSAC assemblies were significantly more rigid than the OPC and SSIC assemblies. The OPC and SSIC assemblies' mean PTVs were not significantly different. The mean PTVs for the C implant location and the RA and LA implant locations were significantly different (p < .01). The mean PTVs of the RA and LA implant locations were not significantly different. The implant-location PTVs followed the same rank order for all three framework conditions. The procedures used to fabricate a more precise fit between the framework and the supporting implants is influenced by the skill of the clinician and technician.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75096/1/j.1532-849X.1996.tb00298.x.pd

Impaired Heat Shock Response in Cells Expressing Full-Length Polyglutamine-Expanded Huntingtin

The molecular mechanisms by which polyglutamine (polyQ)-expanded huntingtin (Htt) causes neurodegeneration in Huntington's disease (HD) remain unclear. The malfunction of cellular proteostasis has been suggested as central in HD pathogenesis and also as a target of therapeutic interventions for the treatment of HD. We present results that offer a previously unexplored perspective regarding impaired proteostasis in HD. We find that, under non-stress conditions, the proteostatic capacity of cells expressing full length polyQ-expanded Htt is adequate. Yet, under stress conditions, the presence of polyQ-expanded Htt impairs the heat shock response, a key component of cellular proteostasis. This impaired heat shock response results in a reduced capacity to withstand the damage caused by cellular stress. We demonstrate that in cells expressing polyQ-expanded Htt the levels of heat shock transcription factor 1 (HSF1) are reduced, and, as a consequence, these cells have an impaired a heat shock response. Also, we found reduced HSF1 and HSP70 levels in the striata of HD knock-in mice when compared to wild-type mice. Our results suggests that full length, non-aggregated polyQ-expanded Htt blocks the effective induction of the heat shock response under stress conditions and may thus trigger the accumulation of cellular damage during the course of HD pathogenesis

Search for Dark Matter Annihilation in the Galactic Center with IceCube-79

The Milky Way is expected to be embedded in a halo of dark matter particles, with the highest density in the central region, and decreasing density with the halo-centric radius. Dark matter might be indirectly detectable at Earth through a flux of stable particles generated in dark matter annihilations and peaked in the direction of the Galactic Center. We present a search for an excess flux of muon (anti-) neutrinos from dark matter annihilation in the Galactic Center using the cubic-kilometer-sized IceCube neutrino detector at the South Pole. There, the Galactic Center is always seen above the horizon. Thus, new and dedicated veto techniques against atmospheric muons are required to make the southern hemisphere accessible for IceCube. We used 319.7 live-days of data from IceCube operating in its 79-string configuration during 2010 and 2011. No neutrino excess was found and the final result is compatible with the background. We present upper limits on the self-annihilation cross-section, \left, for WIMP masses ranging from 30 GeV up to 10 TeV, assuming cuspy (NFW) and flat-cored (Burkert) dark matter halo profiles, reaching down to $\simeq 4 \cdot 10^{-24}$ cm$^3$ s$^{-1}$, and $\simeq 2.6 \cdot 10^{-23}$ cm$^3$ s$^{-1}$ for the $\nu\overline{\nu}$ channel, respectively.Comment: 14 pages, 9 figures, Submitted to EPJ-C, added references, extended limit overvie

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation