Reversible phosphorylation and dephosphorylation of key proteins on tyrosine residues are important parts of intracellular signaling triggered by hormones and other agents. Recent knock-out studies ...in mice have identified PTP1B as a potential target for the treatment of diabetes and obesity. As a consequence, a number of academic and industrial groups are aggressively pursuing the development of selective PTP1B inhibitors. In addition, other protein−tyrosine phosphatases (PTPs) appear to be critically involved in major diseases such as cancer and autoimmunity. Given the diversity of PTPs and their potential as drug targets in different diseases, we have taken a broad approach to develop active site-directed selective inhibitors of specific members of this family of enzymes. Using a high throughput screening, we have previously identified 2-(oxalylamino)benzoic acid 3a as a relatively weak but classical competitive inhibitor of several PTPs. On the basis of our early studies, indicating that 3a might be used as a starting point for the synthesis of selective PTP inhibitors, we now present our efforts in expansion of this concept and provide here a number of new chemical scaffolds for the development of inhibitors of different members of the PTP family. Although the core structure of these inhibitors is charged, good oral bioavailability has been observed in rat for some compounds. Furthermore, we have observed enhancement of 2-deoxy-glucose accumulation in C2C12 cells with prodrug analogues.
Various stakeholders in science have put research integrity high on their agenda. Among them, research funders are prominently placed to foster research integrity by requiring that the organizations ...and individual researchers they support make an explicit commitment to research integrity. Moreover, funders need to adopt appropriate research integrity practices themselves. To facilitate this, we recommend that funders develop and implement a Research Integrity Promotion Plan (RIPP). This Consensus View offers a range of examples of how funders are already promoting research integrity, distills 6 core topics that funders should cover in a RIPP, and provides guidelines on how to develop and implement a RIPP. We believe that the 6 core topics we put forward will guide funders towards strengthening research integrity policy in their organization and guide the researchers and research organizations they fund.
Objective: To identify psychopathological predictors for suicide in a population of major depressed Diagnostic Statistical Manual‐III (DSM‐III) in‐patients.
Method: A total of 210 previous ...participants in multicentre antidepressant drug trials, carried out in a randomized double‐blind design, were followed prospectively through a maximum of 10 years. Patients with a drug or alcohol abuse were excluded. The association between suicide and the pretreatment psychopathological profile was analysed using survival statistics.
Results: The suicide rate for non‐melancholic depressed patients was significantly higher than for melancholic depressed patients. Comorbid personality disorder was independently associated with an increased suicide rate relative hazard 3.41(CI: 1.15–10.10).
Conclusion: The study indicates that the non‐melancholic aspect of depression, and especially comorbid personality disorder, is associated with an increased suicidal vulnerability.
Dual-phase xenon detectors, as currently used in direct detection dark matter experiments, have observed elevated rates of background electron events in the low energy region. While this background ...negatively impacts detector performance in various ways, its origins have only been partially studied. In this paper we report a systematic investigation of the electron pathologies observed in the LUX dark matter experiment. Here, we characterize different electron populations based on their emission intensities and their correlations with preceding energy depositions in the detector. By studying the background under different experimental conditions, we identified the leading emission mechanisms, including photoionization and the photoelectric effect induced by the xenon luminescence, delayed emission of electrons trapped under the liquid surface, capture and release of drifting electrons by impurities, and grid electron emission. We discuss how these backgrounds can be mitigated in LUX and future xenon-based dark matter experiments.
We report two cases of intra-abdominal desmoplastic small round cell tumor with characteristic clinical, histological, immunohistochemical, and ultrastructural features. Fusion of the EWS gene on ...chromosome 22 and the WT1 gene on chromosome 11, resulting from the chromosomal translocation t(11;22)(p13;q12), was detected by reverse transcriptase polymerase chain reaction (RT-PCR) in both cases. This translocation has been previously reported in this type of tumor using either cytogenetic or molecular biological techniques. Tumor tissue from both cases revealed no chimeric fusion transcripts characteristic of the Ewing sarcoma family of peripheral primitive neuroectodermal tumors or of alveolar rhabdomyosarcoma, two tumors in the differential diagnosis of intra-abdominal desmoplastic small round cell tumor. This report demonstrates the utility of molecular studies as an adjunct in the diagnosis of this rare and aggressive tumor.
Behavioural responses of sexually-immature goldfish and common carp, two very closely related species of fish, were tested in a two-choice maze to determine if they use speciesspecific pheromonal ...attractants. Responses of these species to each other's washings and five other fish species were tested in a maze. We hypothesized that goldfish and common carp, which are known to hybridize, might be using relatively simple mixtures of common bodily metabolites to discern species identity and would, therefore, be attracted to each other but not distantly related species. However, we discovered that both of these species were only attracted to conspecific odours. Conspecific attraction was not influenced by immediate previous experience or accompanied by changes in feeding activity, suggesting it is pheromonally mediated. We hypothesize that carp and their relatives recognize each other using relatively complex mixtures of multiple classes of body metabolites. The pheromonal attractant used by common carp is of special interest because it could be used to attract and remove this species from North American waters where it is an invasive nuisance.
Chemical warfare agents (CWAs) have been disposed of in various fashions over the past decades. Significant amounts (∼11,000
tonnes) have been dumped in the Baltic Sea east of the island Bornholm ...following the disarmament of Germany after World War II, causing concerns over potential environmental risks. Absence of risk based on assumptions of extremely low solubility of CWAs cannot alone dismiss these concerns. Existing and modelled fate and effects data were used in the analysis to assess the fish community risk level. The most realistic and also conservative assessment result is the scenario describing 70
m water depth for the most realistic dump-site area with a focus on chronic toxicity, at 0–20
cm above the sediment, yielding a total mixture toxic unit (TU) of 0.62. Triphenylarsine is the CWA with the highest realistic risk profile at 0.2
TU for the fish community followed by Adamsite (0.17), Clark I (0.086) and Yperite (0.083) TU. Adamsite is more persistent and constitutes a potential risk for a longer period than triphenylarsine. The seawater volume potentially at risk is <4
m above sediment and <58
km down current of dump sites. Further risk assessment of dumped CWAs in the Baltic Sea is warranted.
Background: The vast majority of information on chiropractic and chiropractic patients originates from English-speaking countries. Lately, however, reports describing chiropractic patients and ...practice in other European countries have emerged.
Objective: To describe basic characteristics of Danish chiropractic patients.
Design: Survey questionnaire. All chiropractic clinics in Denmark were asked to collect information on new patients during 1 randomly assigned week in 1999.
Setting: Private chiropractic practice and a nonprofit research institution.
Outcome measures: Age and sex, location and duration of chief complaint, pain intensity, limitation of activities of daily living from chief complaint, and mode of referral.
Results: Eighty-eight percent of all chiropractic clinics in Denmark participated in the study. Out of 2020 patients from the participating clinics, 1897 (94%) filled out a self-administered questionnaire. The mean age of participants was 42 years, and slightly more women than men returned the questionnaire. By far the most frequent area of complaint was pain related to the lower back (50%) followed by pain related to the neck (15%). The majority of patients had complaints in the subacute or chronic category (duration 1-6 months). Patients with sciatica had significantly higher pain scores and limitation in activities of daily living (ADL) than any other group, whereas patients with neck pain tended to score lower. Patients in the subacute category had the highest pain scores and limitation in ADL. For complaints lasting more than 6 months, limitation in ADL remained constant at a low level. Twenty-three percent of all patients were referred to the chiropractor, most frequently by a general medical practitioner. More than half of all patients had previously been treated for the same or similar problems, most frequently by a chiropractor. Fifty-one percent had also received chiropractic care for other types of problems.
Conclusions: Most Danish chiropractic patients complain of pain related to the low back or neck of between 1 and 6 months' duration. This study confirms that chiropractic is fairly well integrated in the Danish primary health care system. There are differences between the chiropractic patient population in Denmark compared with that of Sweden and Holland.
