A Non-Motor Microtubule Binding Site Is Essential for the High Processivity and Mitotic Function of Kinesin-8 Kif18A

BACKGROUND: Members of the kinesin-8 subfamily are plus end-directed molecular motors that accumulate at the plus-ends of kinetochore-microtubules (kt-MTs) where they regulate MT dynamics. Loss of vertebrate kinesin-8 function induces hyperstable MTs and elongated mitotic spindles accompanied by severe chromosome congression defects. It has been reported that the motility of human kinesin-8, Kif18A, is required for its accumulation at the plus tips of kt-MTs. METHODOLOGY/FINDINGS: Here, we investigate how Kif18A localizes to the plus-ends of kt-MTs. We find that Kif18A lacking its C-terminus does not accumulate on the tips of kt-MTs and fails to fulfill its mitotic function. In vitro studies reveal that Kif18A possesses a non-motor MT binding site located within its C-proximal 121 residues. Using single molecule measurements we find that Kif18A is a highly processive motor and, furthermore, that the C-terminal tail is essential for the high processivity of Kif18A. CONCLUSION/SIGNIFICANCE: These results show that Kif18A like its yeast orthologue is a highly processive motor. The ability of Kif18A to walk on MTs for a long distance without dissociating depends on a non-motor MT binding site located at the C-terminus of Kif18A. This C-proximal tail of Kif18A is essential for its plus-end accumulation and mitotic function. These findings advance our understanding of how Kif18A accumulates at the tips of kt-MTs to fulfill its function in mitosis

Enteroaggregative Escherichia coli as a Potential Cause of Diarrheal Disease in Adults Infected with Human Immunodeficiency Virus

Stools of 68 human immunodeficiency virus (HIV)-infected adults with diarrhea and 60 without diarrhea were examined for enteroaggregative Escherichia coli (EAggEc) by HeLa cell adherence assay. EAggEc were present in stools of 30 patients with and 18 without diarrhea (P = .05). CD4 cell counts of patients with EAggEc and diarrhea were significantly lower than those of patients with EAggEc without diarrhea (P = .02). There was no difference in the mean duration of diarrheal symptoms or in the number of stools per day between patients with EAggEc and those without. None of the EAggEc strains were positive by polymerase chain reaction for adherence fimbria, but 11 strains were positive for EAggEc heat-stable toxin EAST/1. Of the EAggEc strains, 51% were resistant to trimethoprim-sulfamethoxazole and 65% were resistant to ampicillin. EAggEc may be a pathogen in HIV-infected patients with diarrhea; HIV-infected patients with EAggEc appear to be more symptomatic when HIV disease is more advance

Assessing the discordance rate between local and central HER2 testing in women with locally determined HER2-negative breast cancer.

BackgroundThe importance of human epidermal growth factor receptor 2 (HER2) as a prognostic and predictive marker in invasive breast cancer is well established. Accurate assessment of HER2 status is essential to determine optimal treatment options.MethodsBreast cancer tumor tissue samples from the VIRGO observational cohort tissue substudy that were locally HER2-negative were retested centrally with both US Food and Drug Administration (FDA)-approved immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, using FDA-approved assay cutoffs; results were compared.ResultsOf the 552 unique patient samples centrally retested with local HER2-negative results recorded, tumor samples from 22 (4.0%) patients were determined to be HER2-positive (95% confidence interval [CI] = 2.5%-5.7%). Of these, 18 had been tested locally by only one testing methodology; 15 of 18 were HER2-positive after the central retesting, based on the testing methodology not performed locally. Compared with the 530 patients with centrally confirmed HER2-negative tumors, the 22 patients with centrally determined HER2-positive tumors were younger (median age 56.5 versus 60.0 years) and more likely to have ER/PR-negative tumors (27.3% versus 22.3%). These patients also had shorter median progression-free survival (6.4 months [95% CI = 3.8-15.9 months] versus 9.1 months [95% CI = 8.3-10.3 months]) and overall survival (25.9 months [95% CI = 13.8-not estimable] versus 27.9 months [95% CI = 25.0-32.9 months]).ConclusionsThis study highlights the limitations of employing just one HER2 testing methodology in current clinical practice. It identifies a cohort of patients who did not receive potentially efficacious therapy because their tumor HER2-positivity was not determined by the test initially used. Because of inherent limitations in testing methodologies, it is inadvisable to rely on a single test to rule out potential benefit from HER2-targeted therapy

Pooled safety analysis from phase III studies of trifluridine/tipiracil in patients with metastatic gastric or gastroesophageal junction cancer and metastatic colorectal cancer

Metastatic colorectal cancer; Renal impairment; SafetyCáncer colorrectal metastásico; Insuficiencia renal; SeguridadCàncer colorectal metastàtic; Insuficiència renal; SeguretatBackground Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment. Patients and methods Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function. Results TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function. Conclusions These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.This work was supported by Taiho Oncology, Inc. and Taiho Pharmaceutical (no grant number). This analysis was funded by Taiho Oncology, Inc. Professional medical writing and editorial assistance were provided by Vasupradha Vethantham, Meredith Kalish, and Jennifer L. Robertson at Ashfield MedComms, an Inizio company, funded by Taiho Oncology, Inc

A memory efficient user interface for CLIPS micro-computer applications

The goal of the Integrated Southern Pine Beetle Expert System (ISPBEX) is to provide expert level knowledge concerning treatment advice that is convenient and easy to use for Forest Service personnel. ISPBEX was developed in CLIPS and delivered on an IBM PC AT class micro-computer, operating with an MS/DOS operating system. This restricted the size of the run time system to 640K. In order to provide a robust expert system, with on-line explanation, help, and alternative actions menus, as well as features that allow the user to back up or execute 'what if' scenarios, a memory efficient menuing system was developed to interface with the CLIPS programs. By robust, we mean an expert system that (1) is user friendly, (2) provides reasonable solutions for a wide variety of domain specific problems, (3) explains why some solutions were suggested but others were not, and (4) provides technical information relating to the problem solution. Several advantages were gained by using this type of user interface (UI). First, by storing the menus on the hard disk (instead of main memory) during program execution, a more robust system could be implemented. Second, since the menus were built rapidly, development time was reduced. Third, the user may try a new scenario by backing up to any of the input screens and revising segments of the original input without having to retype all the information. And fourth, asserting facts from the menus provided for a dynamic and flexible fact base. This UI technology has been applied successfully in expert systems applications in forest management, agriculture, and manufacturing. This paper discusses the architecture of the UI system, human factors considerations, and the menu syntax design

Effects of Maraviroc and Efavirenz on Markers of Immune Activation and Inflammation and Associations with CD4+ Cell Rises in HIV-Infected Patients

Maraviroc treatment for HIV-1 infected patients results in larger CD4(+) T cell rises than are attributable to its antiviral activity alone. We investigated whether this is due to modulation of T cell activation and inflammation.Thirty maraviroc-treated patients from the Maraviroc versus Efavirenz Regimens as Initial Therapy (MERIT) study were randomly selected from among those who had CCR5-tropic (R5) HIV on screening and achieved undetectable HIV RNA (<50 copies/mL) by Week 48. Efavirenz-treated controls were matched for baseline characteristics to the maraviroc-treated patients selected for this substudy. Changes in immune activation and inflammation markers were examined for associations with CD4(+) T cell changes. Maraviroc treatment tended to result in more rapid decreases in CD38 expression on CD4(+) T cells and in plasma D-dimer concentrations than did treatment with efavirenz. The proportion of patients with high-sensitivity C-reactive protein >2 µg/mL increased from 45% to 66% in the efavirenz arm, but remained constant in the maraviroc arm (P = 0.033). Decreases in CD38 expression on CD8(+) T cells were correlated with CD4(+) T cell rises for maraviroc treatment (r = -0.4, P = 0.048), but not for treatment with efavirenz.Maraviroc-treated patients had earlier, modest decreases in certain markers of immune activation and inflammation, although in this small study, many of the differences were not statistically significant. Levels of high-sensitivity C-reactive protein remained constant in the maraviroc arm and increased in the efavirenz arm. Decreases in immune activation correlated with increased CD4(+) T cell gains.ClinicalTrials.gov NCT00098293

The PHASES Differential Astrometry Data Archive. V. Candidate Substellar Companions to Binary Systems

The Palomar High-precision Astrometric Search for Exoplanet Systems monitored 51 subarcsecond binary systems to evaluate whether tertiary companions as small as Jovian planets orbited either the primary or secondary stars, perturbing their otherwise smooth Keplerian motions. Six binaries are presented that show evidence of substellar companions orbiting either the primary or secondary star. Of these six systems, the likelihoods of two of the detected perturbations to represent real objects are considered to be "high confidence", while the remaining four systems are less certain and will require continued observations for confirmation.Comment: 16 Pages, Accepted to A

Model Independent Approach to Focus Point Supersymmetry: from Dark Matter to Collider Searches

The focus point region of supersymmetric models is compelling in that it simultaneously features low fine-tuning, provides a decoupling solution to the SUSY flavor and CP problems, suppresses proton decay rates and can accommodate the WMAP measured cold dark matter (DM) relic density through a mixed bino-higgsino dark matter particle. We present the focus point region in terms of a weak scale parameterization, which allows for a relatively model independent compilation of phenomenological constraints and prospects. We present direct and indirect neutralino dark matter detection rates for two different halo density profiles, and show that prospects for direct DM detection and indirect detection via neutrino telescopes such as IceCube and anti-deuteron searches by GAPS are especially promising. We also present LHC reach prospects via gluino and squark cascade decay searches, and also via clean trilepton signatures arising from chargino-neutralino production. Both methods provide a reach out to m_{\tg}\sim 1.7 TeV. At a TeV-scale linear e^+e^- collider (LC), the maximal reach is attained in the \tz_1\tz_2 or \tz_1\tz_3 channels. In the DM allowed region of parameter space, a \sqrt{s}=0.5 TeV LC has a reach which is comparable to that of the LHC. However, the reach of a 1 TeV LC extends out to m_{\tg}\sim 3.5 TeV.Comment: 34 pages plus 36 eps figure

An approach to assess actor's preferences and social learning to enhance participatory forest management planning

Forest management planning is often challenged by the need to address contrasting preferences from several actors. Participatory approaches may help integrate actors’ preferences and demands and thus address this chal- lenge. Workshops that encompass a participatory approach may further influence actors’ opinions and knowledge through social interaction and facilitate the development of collaborative landscape-level planning. Nevertheless, there is little experience of formal assessment of impacts of workshops with participatory approaches. This re- search addresses this gap. The emphasis is on the development of an approach (a) to quantify actors’ preferences for forest management models, post-fire management options, forest functions, and ecosystem services; (b) to assess the impact of participatory discussions on actors’ opinions; and (c) to evaluate the effect of social interac- tion on the actors’ learning and knowledge. The methodology involves a workshop with participatory approach, matched pre- and post-questionnaires, a non-parametric test, the Wilcoxon Signed-rank test for paired samples, and a self-evaluation questionnaire. We report results from an application to a joint forest management area in Vale do Sousa, in North-Western Por- tugal. Findings suggest that workshop and participatory discussions do contribute to social knowledge and learn- ing about forest management models. Actors debated alternatives that can address their financial and wildfire risk-resistance concerns. Also, during the participatory discussions, actors expressed their interest in multifunc- tional forestry. These findings also suggest an opportunity to enhance forest management planning by promoting landscape-level collaborative forest management plans that may contribute to the diversification of forest man- agement models and to the provision of a wider range of ecosystem services. However, more research is needed to strengthen the pre- and post-questionnaire approach, giving more time to actors to reflect on their preferences, to improve methods for quantifying social learning and to develop actors’ engagement strategiesinfo:eu-repo/semantics/publishedVersio

Interventions to improve hand hygiene compliance in patient care

Four studies met the criteria for the review: two from the original review and two from the update. Two studies evaluated simple education initiatives, one using a randomized clinical trial design and the other a controlled before and after design. Both measured hand hygiene compliance by direct observation. The other two studies were both interrupted times series studies. One study presented three separate interventions within the same paper: simple substitutions of product and two multifaceted campaigns, one of which included involving practitioners in making decisions about choice of hand hygiene products and the components of the hand hygiene program. The other study also presented two separate multifaceted campaigns, one of which involved application of social marketing theory. In these two studies follow-up data collection continued beyond 12 months, and a proxy measure of hand hygiene compliance (product use) was recorded. Microbiological data were recorded in one study. Hand hygiene compliance increased for one of the studies where it was measured by direct observation, but the results from the other study were not conclusive. Product use increased in the two studies in which it was reported, with inconsistent results reported for one initiative. MRSA incidence decreased in the one study reporting microbiological data