The C-Terminal Domain of the MutL Homolog from Neisseria gonorrhoeae Forms an Inverted Homodimer

The mismatch repair (MMR) pathway serves to maintain the integrity of the genome by removing mispaired bases from the newly synthesized strand. In E. coli, MutS, MutL and MutH coordinate to discriminate the daughter strand through a mechanism involving lack of methylation on the new strand. This facilitates the creation of a nick by MutH in the daughter strand to initiate mismatch repair. Many bacteria and eukaryotes, including humans, do not possess a homolog of MutH. Although the exact strategy for strand discrimination in these organisms is yet to be ascertained, the required nicking endonuclease activity is resident in the C-terminal domain of MutL. This activity is dependent on the integrity of a conserved metal binding motif. Unlike their eukaryotic counterparts, MutL in bacteria like Neisseria exist in the form of a homodimer. Even though this homodimer would possess two active sites, it still acts a nicking endonuclease. Here, we present the crystal structure of the C-terminal domain (CTD) of the MutL homolog of Neisseria gonorrhoeae (NgoL) determined to a resolution of 2.4 Å. The structure shows that the metal binding motif exists in a helical configuration and that four of the six conserved motifs in the MutL family, including the metal binding site, localize together to form a composite active site. NgoL-CTD exists in the form of an elongated inverted homodimer stabilized by a hydrophobic interface rich in leucines. The inverted arrangement places the two composite active sites in each subunit on opposite lateral sides of the homodimer. Such an arrangement raises the possibility that one of the active sites is occluded due to interaction of NgoL with other protein factors involved in MMR. The presentation of only one active site to substrate DNA will ensure that nicking of only one strand occurs to prevent inadvertent and deleterious double stranded cleavage

Uncovering mechanisms of transcriptional regulations by systematic mining of cis regulatory elements with gene expression profiles

<p>Abstract</p> <p>Background</p> <p>Contrary to the traditional biology approach, where the expression patterns of a handful of genes are studied at a time, microarray experiments enable biologists to study the expression patterns of many genes simultaneously from gene expression profile data and decipher the underlying hidden biological mechanism from the observed gene expression changes. While the statistical significance of the gene expression data can be deduced by various methods, the biological interpretation of the data presents a challenge.</p> <p>Results</p> <p>A method, called CisTransMine, is proposed to help infer the underlying biological mechanisms for the observed gene expression changes in microarray experiments. Specifically, this method will predict potential cis-regulatory elements in promoter regions which could regulate gene expression changes. This approach builds on the MotifADE method published in 2004 and extends it with two modifications: up-regulated genes and down-regulated genes are tested separately and in addition, tests have been implemented to identify combinations of transcription factors that work synergistically. The method has been applied to a genome wide expression dataset intended to study myogenesis in a mouse C2C12 cell differentiation model. The results shown here both confirm the prior biological knowledge and facilitate the discovery of new biological insights.</p> <p>Conclusion</p> <p>The results validate that the CisTransMine approach is a robust method to uncover the hidden transcriptional regulatory mechanisms that can facilitate the discovery of mechanisms of transcriptional regulation.</p

A treatment applying a biomechanical device to the feet of patients with knee osteoarthritis results in reduced pain and improved function: a prospective controlled study

<p>Abstract</p> <p>Background</p> <p>This study examined the effect of treatment with a novel biomechanical device on the level of pain and function in patients with knee OA.</p> <p>Methods</p> <p>Patients with bilateral knee OA were enrolled to active and control groups. Patients were evaluated at baseline, at 4 weeks and at the 8-week endpoint. A novel biomechanical device was individually calibrated to patients from the active group. Patients from the control group received an identical foot-worn platform without the biomechanical elements. Primary outcomes were the WOMAC Index and ALF assessments.</p> <p>Results</p> <p>There were no baseline differences between the groups. At 8 weeks, the active group showed a mean improvement of 64.8% on the WOMAC pain scale, a mean improvement of 62.7% on the WOMAC function scale, and a mean improvement of 31.4% on the ALF scale. The control group demonstrated no improvement in the above parameters. Significant differences were found between the active and control groups in all the parameters of assessment.</p> <p>Conclusions</p> <p>The biomechanical device and treatment methodology is effective in significantly reducing pain and improving function in knee OA patients.</p> <p>The study is registered at clinicaltrials.gov, identifier NCT00457132, <url>http://www.clinicaltrials.gov/ct/show/NCT00457132?order=1</url></p

Agalsidase beta treatment is associated with improved quality of life in patients with Fabry disease: Findings from the Fabry Registry

Purpose: To evaluate the effect of agalsidase beta on longitudinal health-related quality of life in patients with Fabry disease. Methods: the SF-36 (R) Health Survey was used to measure health-related quality of life in Fabry Registry patients. Seventy-one men and 59 women who were treated with agalsidase beta (median dose: 1.0 mg/kg/2 weeks) and who had baseline and at least 2 yearly posttreatment health-related quality of life measurements were included in these analyses. A repeated measures model was used to analyze change in score from baseline. Results: Men improved in the physical component summary and in all eight scales of the SF-36 after 1 and 2 years and in the mental component summary after 1 year of agalsidase beta treatment (P < 0.05). Women improved in the mental component summary and in six of the eight scales after 1 and/or 2 years of treatment. Patients whose baseline SF-36 scores were below the median showed the greatest improvements. These responses were comparable with or greater than the published effects of various treatments for multiple sclerosis, rheumatoid arthritis, central neuropathic pain, and Gaucher disease. Conclusion: Long-term treatment with agalsidase beta resulted in substantial improvements in health-related quality of life in both men and women; the effect was more pronounced in men. Genet Med 2010:12(11):703 712.Genzyme CorporationGenzymeNatl Univ Hosp, Dept Endocrinol, DK-2100 Copenhagen, DenmarkSan Bassano Hosp, Dept Neurol, Bassano Del Grappa, ItalyUniv Padua, Dept Neurosci, Padua, ItalyUniv Wurzburg, Dept Med, Wurzburg, GermanyColumbia Univ, Dept Pediat, Div Clin Genet, Coll Phys & Surg, New York, NY 10027 USACincinnati Childrens Hosp, Div Human Genet, Cincinnati, OH USAUniversidade Federal de São Paulo, Inatos Metab CREIM, São Paulo, BrazilMassachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USAGenzyme Corp, Dept Biomed Data Sci & Informat, Cambridge, MA USAUniversidade Federal de São Paulo, Inatos Metab CREIM, São Paulo, BrazilWeb of Scienc

Structure and evolutionary origin of Ca2+-dependent herring type II antifreeze protein

10.1371/journal.pone.0000548PLoS ONE26

Reduced expression of a gene proliferation signature is associated with enhanced malignancy in colon cancer

The association between cell proliferation and the malignant potential of colon cancer is not well understood. Here, we evaluated this association using a colon-specific gene proliferation signature (GPS). The GPS was derived by combining gene expression data obtained from the analysis of a cancer cell line model and a published colon crypt profile. The GPS was overexpressed in both actively cycling cells in vitro and the proliferate compartment of colon crypts. K-means clustering was used to independantly stratify two cohorts of colon tumours into two groups with high and low GPS expression. Notably, we observed a significant association between reduced GPS expression and an increased likelihood of recurrence (P<0.05), leading to shorter disease-free survival in both cohorts. This finding was not a result of methodological bias as we verified the well-established association between breast cancer malignancy and increased proliferation, by applying our GPS to public breast cancer data. In this study, we show that reduced proliferation is a biological feature characterizing the majority of aggressive colon cancers. This contrasts with many other carcinomas such as breast cancer. Investigating the reasons underlying this unusual observation may provide important insight into the biology of colon cancer progression and putative novel therapy options

Minimal changes in health status questionnaires: distinction between minimally detectable change and minimally important change

Changes in scores on health status questionnaires are difficult to interpret. Several methods to determine minimally important changes (MICs) have been proposed which can broadly be divided in distribution-based and anchor-based methods. Comparisons of these methods have led to insight into essential differences between these approaches. Some authors have tried to come to a uniform measure for the MIC, such as 0.5 standard deviation and the value of one standard error of measurement (SEM). Others have emphasized the diversity of MIC values, depending on the type of anchor, the definition of minimal importance on the anchor, and characteristics of the disease under study. A closer look makes clear that some distribution-based methods have been merely focused on minimally detectable changes. For assessing minimally important changes, anchor-based methods are preferred, as they include a definition of what is minimally important. Acknowledging the distinction between minimally detectable and minimally important changes is useful, not only to avoid confusion among MIC methods, but also to gain information on two important benchmarks on the scale of a health status measurement instrument. Appreciating the distinction, it becomes possible to judge whether the minimally detectable change of a measurement instrument is sufficiently small to detect minimally important changes

The Generic Short Patient Experiences Questionnaire (GS-PEQ): identification of core items from a survey in Norway

<p>Abstract</p> <p>Background</p> <p>Questionnaires are commonly used to collect patient, or user, experiences with health care encounters; however, their adaption to specific target groups limits comparison between groups. We present the construction of a generic questionnaire (maximum of ten questions) for user evaluation across a range of health care services.</p> <p>Methods</p> <p>Based on previous testing of six group-specific questionnaires, we first constructed a generic questionnaire with 23 items related to user experiences. All questions included a "not applicable" response option, as well as a follow-up question about the item's importance. Nine user groups from one health trust were surveyed. Seven groups received questionnaires by mail and two by personal distribution. Selection of core questions was based on three criteria: applicability (proportion "not applicable"), importance (mean scores on follow-up questions), and comprehensiveness (content coverage, maximum two items per dimension).</p> <p>Results</p> <p>1324 questionnaires were returned providing subsample sizes ranging from 52 to 323. Ten questions were excluded because the proportion of "not applicable" responses exceeded 20% in at least one user group. The number of remaining items was reduced to ten by applying the two other criteria. The final short questionnaire included items on outcome (2), clinician services (2), user involvement (2), incorrect treatment (1), information (1), organisation (1), and accessibility (1).</p> <p>Conclusion</p> <p>The Generic Short Patient Experiences Questionnaire (GS-PEQ) is a short, generic set of questions on user experiences with specialist health care that covers important topics for a range of groups. It can be used alone or with other instruments in quality assessment or in research. The psychometric properties and the relevance of the GS-PEQ in other health care settings and countries need further evaluation.</p

The rise of consumer health wearables: promises and barriers

Will consumer wearable technology ever be adopted or accepted by the medical community? Patients and practitioners regularly use digital technology (e.g., thermometers and glucose monitors) to identify and discuss symptoms. In addition, a third of general practitioners in the United Kingdom report that patients arrive with suggestions for treatment based on online search results. However, consumer health wearables are predicted to become the next “Dr Google.” One in six (15%) consumers in the United States currently uses wearable technology, including smartwatches or fitness bands. While 19 million fitness devices are likely to be sold this year, that number is predicted to grow to 110 million in 2018. As the line between consumer health wearables and medical devices begins to blur, it is now possible for a single wearable device to monitor a range of medical risk factors. Potentially, these devices could give patients direct access to personal analytics that can contribute to their health, facilitate preventive care, and aid in the management of ongoing illness. However, how this new wearable technology might best serve medicine remains unclea