Toward a Unified Genetic Map of Higher Plants, Transcending the Monocot-Dicot Divergence

Closely related (confamilial) genera often retain large chromosomal tracts in which gene order is colinear, punctuated by structural mutations such as inversions and translocations 1. To explore the possibility that conservation of gene order might extrapolate to more distantly related taxa, we first estimated an average structural mutation rate. Nine pairs of taxa, for which there exist both comparative genetic maps and plausible estimates of divergence time, showed an average of0.14 (±0.06) structural mutations per chromosome per million years of divergence (Myr; Table 1). This value is offered as a first approximation, acknowledging that refined comparative data and/or divergence estimates may impel revision

VHE γ\gamma-ray observations of Markarian 501

Markarian 501, a nearby (z=0.033) X-ray selected BL Lacertae object, is a well established source of Very High Energy (VHE, E>=300 GeV) gamma rays. Dramatic variability in its gamma-ray emission on time-scales from years to as short as two hours has been detected. Multiwavelength observations have also revealed evidence that the VHE gamma-ray and hard X-ray fluxes may be correlated. Here we present results of observations made with the Whipple Collaboration's 10 m Atmospheric Cerenkov Imaging Telescope during 1999 and discuss them in the context of observations made on Markarian 501 during the period from 1996-1998

Unique Structure and Dynamics of the EphA5 Ligand Binding Domain Mediate Its Binding Specificity as Revealed by X-ray Crystallography, NMR and MD Simulations

10.1371/journal.pone.0074040PLoS ONE89-POLN

Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine

Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50 of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs

HelexKids:a word frequency database for Greek and Cypriot primary school children

In this article, we introduce HelexKids, an online written-word database for Greek-speaking children in primary education (Grades 1 to 6). The database is organized on a grade-by-grade basis, and on a cumulative basis by combining Grade 1 with Grades 2 to 6. It provides values for Zipf, frequency per million, dispersion, estimated word frequency per million, standard word frequency, contextual diversity, orthographic Levenshtein distance, and lemma frequency. These values are derived from 116 textbooks used in primary education in Greece and Cyprus, producing a total of 68,692 different word types. HelexKids was developed to assist researchers in studying language development, educators in selecting age-appropriate items for teaching, as well as writers and authors of educational books for Greek/Cypriot children. The database is open access and can be searched online at www.helexkids.org

Modeling allosteric signal propagation using protein structure networks

Allosteric communication in proteins can be induced by the binding of effective ligands, mutations or covalent modifications that regulate a site distant from the perturbed region. To understand allosteric regulation, it is important to identify the remote sites that are affected by the perturbation-induced signals and how these allosteric perturbations are transmitted within the protein structure. In this study, by constructing a protein structure network and modeling signal transmission with a Markov random walk, we developed a method to estimate the signal propagation and the resulting effects. In our model, the global perturbation effects from a particular signal initiation site were estimated by calculating the expected visiting time (EVT), which describes the signal-induced effects caused by signal transmission through all possible routes. We hypothesized that the residues with high EVT values play important roles in allosteric signaling. We applied our model to two protein structures as examples, and verified the validity of our model using various types of experimental data. We also found that the hot spots in protein binding interfaces have significantly high EVT values, which suggests that they play roles in mediating signal communication between protein domains

High susceptibility of c-KIT+CD34+ precursors to prolonged doxorubicin exposure interferes with Langerhans cell differentiation in a human cell line model

As neoadjuvant and adjuvant chemotherapy schedules often consist of multiple treatment cycles over relatively long periods of time, it is important to know what effects protracted drug administration can have on the immune system. Here, we studied the long-term effects of doxorubicin on the capacity of dendritic cell (DC) precursors to differentiate into a particular DC subset, the Langerhans cells (LC). In order to achieve high telomerase activity as detected in hematological stem cells, precursor cells from the acute-myeloid leukemia (AML)-derived cell line MUTZ3 were stably transduced with human telomerase reverse transcriptase (hTERT) to facilitate their growth potential, while preventing growth, and drug-induced senescence, and preserving their unique capacity for cytokine-dependent DC and LC differentiation. The hTERT-MUTZ3 cells were selected with increasing concentrations of the anthracyclin doxorubicin. After 1–2 months of selection with 30–90 nM doxorubicin, the cells completely lost their capacity to differentiate into LC. This inhibition turned out to be reversible, as the cells slowly regained their capacity to differentiate after a 3- to 4-month drug-free period and with this became capable again of priming allogeneic T cells. Of note, the loss and gain of this capacity to differentiate coincided with the loss and gain of a subpopulation within the CD34+ proliferative compartment with surface expression of the stem cell factor receptor (SCF-R/CD117/c-Kit). These data are in favor of cytostatic drug-free intervals before applying autologous DC-based vaccination protocols, as specific DC precursors may need time to recover from protracted chemotherapy treatment and re-emerge among the circulating CD34+ hematopoietic stem and precursor cells

Characterizing Hospital Workers' Willingness to Respond to a Radiological Event

Terrorist use of a radiological dispersal device (RDD, or "dirty bomb"), which combines a conventional explosive device with radiological materials, is among the National Planning Scenarios of the United States government. Understanding employee willingness to respond is critical for planning experts. Previous research has demonstrated that perception of threat and efficacy is key in the assessing willingness to respond to a RDD event.An anonymous online survey was used to evaluate the willingness of hospital employees to respond to a RDD event. Agreement with a series of belief statements was assessed, following a methodology validated in previous work. The survey was available online to all 18,612 employees of the Johns Hopkins Hospital from January to March 2009.Surveys were completed by 3426 employees (18.4%), whose demographic distribution was similar to overall hospital staff. 39% of hospital workers were not willing to respond to a RDD scenario if asked but not required to do so. Only 11% more were willing if required. Workers who were hesitant to agree to work additional hours when required were 20 times less likely to report during a RDD emergency. Respondents who perceived their peers as likely to report to work in a RDD emergency were 17 times more likely to respond during a RDD event if asked. Only 27.9% of the hospital employees with a perception of low efficacy declared willingness to respond to a severe RDD event. Perception of threat had little impact on willingness to respond among hospital workers.Radiological scenarios such as RDDs are among the most dreaded emergency events yet studied. Several attitudinal indicators can help to identify hospital employees unlikely to respond. These risk-perception modifiers must then be addressed through training to enable effective hospital response to a RDD event

Treatment of Infected Hip Arthroplasty

The clinical outcomes of a consecutive series of deep total joint infections treated with a prosthesis retaining protocol were reviewed. The treatment of deep periprosthetic joint infections is challenging. In recent years, two-stage exchange arthroplasty has emerged as the gold standard for successful elimination of infection. With success rates averaging 82% to 96%, this treatment method has both the highest and most consistent rate of infection eradication. Another alternative in the treatment of the deep periprosthetic infection is the single-stage exchange arthroplasty. Successful eradication of infection after single-stage exchange arthroplasty has been reported to average from 60% to 83% after total hip infections. While both the single and two-stage exchange arthroplasty are viable treatment options, they are associated with negative factors such as they are time consuming, expensive, and may entail a 6- to 12-week period with a minimally functioning extremity after prosthesis removal. This paper reports the general principles of management, the treatment of acute infection occurring in the postoperative period or later, and the treatment of chronic infection by exchange arthroplasty or resection arthroplasty

Mammography stages of change in middle-aged women with schizophrenia: An exploratory analysis

BACKGROUND: Health care providers and educators who seek to create health promotion programs and individualized comprehensive care plans for women with schizophrenia are hindered by the lack of data to guide their efforts. PURPOSE: This study tested the hypothesis that women with schizophrenia adhere to mammography screening guidelines at the same rate as other same-age women. The study also investigated the validity of the Health Belief (HB) and Stages of Change (SOC) models for breast cancer screening among women with schizophrenia. METHODS: Socio-demographic and clinical variables, as well as knowledge, attitudes, and barriers were assessed as a function of stage of change related to breast cancer screening in 46 women with schizophrenia. RESULTS: Women with schizophrenia were statistically less likely to be adherent to the screening recommendations than those without schizophrenia. Some support was found for the validity of the HB and SOC models for breast cancer screening in women with schizophrenia. Women in the Precontemplation stage had significantly higher negative attitude scores compared to Contemplation and Action/Maintenance stages (59.7, 45.7, and 43.2, respectively), and there was a trend for more barriers in the Precontemplation group (4.6, 2.6, 2.7 respectively). CONCLUSION: Given the small sample size, further research on the rates of breast cancer screening in women with schizophrenia is warranted. Nonetheless, these data suggest that providers who care for women with schizophrenia may need to make take additional measures to ensure that this population receives appropriate screening so as to not put them at greater risk for a late-stage diagnosis of breast cancer. Furthermore, these pilot data suggest that HB and SOC theory-based interventions may be valid for increasing mammography rates in women with schizophrenia