Coherent diffraction of single Rice Dwarf virus particles using hard X-rays at the Linac Coherent Light Source

Single particle diffractive imaging data from Rice Dwarf Virus (RDV) were recorded using the Coherent X-ray Imaging (CXI) instrument at the Linac Coherent Light Source (LCLS). RDV was chosen as it is a wellcharacterized model system, useful for proof-of-principle experiments, system optimization and algorithm development. RDV, an icosahedral virus of about 70 nm in diameter, was aerosolized and injected into the approximately 0.1 mu m diameter focused hard X-ray beam at the CXI instrument of LCLS. Diffraction patterns from RDV with signal to 5.9 angstrom ngstrom were recorded. The diffraction data are available through the Coherent X-ray Imaging Data Bank (CXIDB) as a resource for algorithm development, the contents of which are described here.11Ysciescopu

Angiostatin generating capacity and anti-tumour effects of D-penicillamine and plasminogen activators

BACKGROUND: Upregulation of endogenous angiostatin levels may constitute a novel anti-angiogenic, and therefore anti-tumor therapy. In vitro, angiostatin generation is a two-step process, starting with the conversion of plasminogen to plasmin by plasminogen activators (PAs). Next, plasmin excises angiostatin from other plasmin molecules, a process requiring a donor of a free sulfhydryl group. In previous studies, it has been demonstrated that administration of PA in combination with the free sulfhydryl donor (FSD) agents captopril or N-acetyl cysteine, resulted in angiostatin generation, and anti-angiogenic and anti-tumour activity in murine models. METHODS: In this study we have investigated the angiostatin generating capacities of several FSDs. D-penicillamine proved to be most efficient in supporting the conversion of plasminogen to angiostatin in vitro. Next, from the optimal concentrations of tPA and D-penicillamine in vitro, equivalent dosages were administered to healthy Balb/c mice to explore upregulation of circulating angiostatin levels. Finally, anti-tumor effects of treatment with tPA and D-penicillamine were determined in a human melanoma xenograft model. RESULTS: Surprisingly, we found that despite the superior angiostatin generating capacity of D-penicillamine in vitro, both in vivo angiostatin generation and anti-tumour effects of tPA/D-penicillamine treatment were impaired compared to our previous studies with tPA and captopril. CONCLUSION: Our results indicate that selecting the most appropriate free sulfhydryl donor for anti-angiogenic therapy in a (pre)clinical setting should be performed by in vivo rather than by in vitro studies. We conclude that D-penicillamine is not suitable for this type of therapy

German translation and external validation of the Radboud Skills Questionnaire in patients suffering from Complex Regional Pain Syndrome 1

BACKGROUND: Patients suffering from Complex Regional Pain Syndrome commonly complain of substantial limitations in their activities of daily living. The Radboud Skills Questionnaire measures alterations in the level of disability of patients with Complex Regional Pain Syndrome, but this instrument is currently not available in German. The goals of our study were to translate the Dutch Radboud Skills Questionnaire into German and to assess its external criterion validity with the German version of the Disabilities of the Arm, Shoulder and Hand Questionnaire. METHODS: We translated the Radboud Skills Questionnaire according to published guidelines. Demographic data and validity were assessed in 57 consecutive patients with Complex Regional Pain Syndrome 1 of the upper extremity. Information on age, duration of symptoms, type of Complex Regional Pain Syndrome 1 and type of initiating event was obtained. We assessed the external criterion validity by comparing the German Radboud Skills Questionnaire and the German Disabilities of the Arm, Shoulder and Hand Questionnaire and calculated the prediction intervals. RESULTS: Score values ranged from 55.4 +/- 22.0 for the Disabilities of the Arm, Shoulder and Hand Questionnaire score and 140.1 +/- 39.2 for the Radboud Skills Questionnaire. We found a high correlation between the Radboud Skills Questionnaire and the Disabilities of the Arm, Shoulder and Hand Questionnaire (R2 = 0.83). CONCLUSION: This validation of the Radboud Skills Questionnaire demonstrates that this German version is a simple and accurate instrument to assess and quantify disabilities of patients suffering from Complex Regional Pain Syndrome 1 of the upper extremity for clinical and research purposes

SRT1720 improves survival and healthspan of obese mice

Sirt1 is an NAD+-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1α-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals

Intergenerational impacts of maternal mortality: Qualitative findings from rural Malawi

Background: Maternal mortality, although largely preventable, remains unacceptably high in developing countries such as Malawi and creates a number of intergenerational impacts. Few studies have investigated the far-reaching impacts of maternal death beyond infant survival. This study demonstrates the short- and long-term impacts of maternal death on children, families, and the community in order to raise awareness of the true costs of maternal mortality and poor maternal health care in Neno, a rural and remote district in Malawi. Methods: Qualitative in-depth interviews were conducted to assess the impact of maternal mortality on child, family, and community well-being. We conducted 20 key informant interviews, 20 stakeholder interviews, and six sex-stratified focus group discussions in the seven health centers that cover the district. Transcripts were translated, coded, and analyzed in NVivo 10. Results: Participants noted a number of far-reaching impacts on orphaned children, their new caretakers, and extended families following a maternal death. Female relatives typically took on caregiving responsibilities for orphaned children, regardless of the accompanying financial hardship and frequent lack of familial or governmental support. Maternal death exacerbated children’s vulnerabilities to long-term health and social impacts related to nutrition, education, employment, early partnership, pregnancy, and caretaking. Impacts were particularly salient for female children who were often forced to take on the majority of the household responsibilities. Participants cited a number of barriers to accessing quality child health care or support services, and many were unaware of programming available to assist them in raising orphaned children or how to access these services. Conclusions: In order to both reduce preventable maternal mortality and diminish the impacts on children, extended families, and communities, our findings highlight the importance of financing and implementing universal access to emergency obstetric and neonatal care, and contraception, as well as social protection programs, including among remote populations

Matrix Metalloproteinases in Human Melanoma

SummaryCutaneous melanoma is a highly invasive and metastatic tumor. Degradation of basement membranes and extracellular matrix is an essential step in melanoma cell migration, invasion, and metastasis formation. Matrix metalloproteinases and their tissue inhibitors play a crucial role in these complex multistep processes. Melanoma cells may express a number of matrix metalloproteinase family members (MMP-1, MMP-2, MMP-9, MMP-13, and MT1-MMP) as well as their tissue inhibitors (TIMP-1, TIMP-2, and TIMP-3). Numerous studies have examined matrix metalloproteinases, their tissue inhibitors, and the molecules that regulate their expression and/or activation in melanoma cell lines in vitro and in vivo, and in human melanocytic lesions. Recent results have indicated that adhesion molecules such as CD44 and integrin αvβ3 are involved in positioning activated matrix metalloproteinase molecules on the cell surface of invasive tumor cells. In this review we evaluate these novel aspects of the role of matrix metalloproteinases and their tissue inhibitors in melanoma progression. We conclude that the balance between levels of activated matrix metalloproteinases and expression levels of their tissue inhibitors, and the coexpression of activated matrix metalloproteinases and adhesion molecules are important factors in determining melanoma cell invasion, tumor growth, and metastasis formation

The angiopoietin-like factor cornea-derived transcript 6 is a putative morphogen for human cornea.

The human cornea-specific protein cornea-derived transcript 6 (CDT6) is a member of the angiopoietin gene family. We report the structural and functional characterization of CDT6. We demonstrate that CDT6 is a secreted protein that folds into disulfide-linked homotetramers by coiled-coil interactions. The finding that CDT6 is expressed at high levels in the avascular corneal stromal layer suggested that the protein, similar to certain angiopoietins, acts as a negative regulator of angiogenesis. To test this hypothesis and to assay the effect of the protein on a growing tissue with high vascular density, CDT6 was expressed in a mouse xenograft model. Expression of CDT6 led to a reduction in tumor growth and aberrant blood vessel formation by inducing massive fibrosis. Interestingly, expression of CDT6 also resulted in the deposition of extracellular matrix components typical for the mature corneal stromal layer. These observations strongly suggest a role as morphogen for CDT6 in inducing a corneal phenotype in vivo