204 research outputs found
2-Isopropoxyethanol – Determination of 2-isopropoxyethanol in workplace air using gas chromatography (GC-FID)
This analytical method is a validated measurement procedure for the determination of 2-isopropoxyethanol [109-59-1] in workplace air in a concentration range of one tenth up to twice the currently valid occupational exposure limit value (OELV) in Germany of 44 mg/m3. For sampling a defined volume of air is drawn through a sorbent tube (for thermal desorption) filled with Chromosorb 106. The flow rate is set to 5 ml/min and sampling is performed over 2 hours (which corresponds to a sampling volume of 600 ml). The samples to which cyclooctane is added as internal standard are thermally desorbed. The quantitative determination is based on a calibration function, whereby the 2-isopropoxyethanol concentration of the calibration standard is plotted against the intensities, calculated over the internal cyclooctane standard. The limit of quantification is 4.48 mg/m3 based on an air sample volume of 600 ml. The mean recovery is 92% and the expanded uncertainty for the validation range of 4.62 to 83.08 mg/m3 is 28.4
1,3-Dioxolane – Determination of 1,3-dioxolane in workplace air using gas chromatography (GC-FID)
This analytical method is a validated measurement procedure for the determination of 1,3-dioxolane [646-06-0] in workplace air in a concentration range of one tenth up to twice the currently valid Occupational Exposure Limit Value (OELV) in Germany of 150 mg/m3. For sampling, a defined volume of air is drawn through a sorbent tube (for thermal desorption) filled with Chromosorb 106. The flow rate is set to 5 ml/min and sampling is performed over 2 hours (which corresponds to a sampling volume of 600 ml). The samples to which cyclooctane is added as internal standard are thermally desorbed. The quantitative determination is based on a calibration function, whereby the 1,3-dioxolane concentration of the calibration standard is plotted against the intensities, calculated over the internal cyclooctane standard. The limit of quantification is 12.9 mg/m3 based on an air sample volume of 600 ml. The mean recovery is 97% and the expanded uncertainty for the validation range of 16.3 to 293 mg/m3 is 11.5 to 12.1%
Charge photogeneration in few-layer MoS2
The two-dimensional semiconductor MoS2 in its mono- and few-layer form is
expected to have a significant exciton binding energy of several 100 meV,
leading to the consensus that excitons are the primary photoexcited species.
Nevertheless, even single layers show a strong photovoltaic effect and work as
the active material in high sensitivity photodetectors, thus indicating
efficient charge carrier photogeneration (CPG). Here we use continuous wave
photomodulation spectroscopy to identify the optical signature of long-lived
charge carriers and femtosecond pump-probe spectroscopy to follow the CPG
dynamics. We find that intitial photoexcitation yields a branching between
excitons and charge carriers, followed by excitation energy dependent hot
exciton dissociation as an additional CPG mechanism. Based on these findings,
we make simple suggestions for the design of more efficient MoS2 photovoltaic
and photodetector devices
NFAT-mediated defects in erythropoiesis cause anemia in Il2-/- mice.
The role of NFAT family transcription factors in erythropoiesis is so far unknown, although their involvement has been suggested previously. We have shown recently that Il2-/- mice develop severe anemia due to defects in KLF1 activity during BM erythropoiesis. Although, KLF1 activity is indispensable for erythropoiesis, the molecular details of Klf1 expression have not yet been elucidated. Here we show that an enhanced NFATc1 activity induced by increased integrin-cAMP signaling plays a critical role in the dysregulation of Klf1 expression and thereby cause anemia in Il2-/- mice. Interestingly, enhanced NFATc1 activity augmented apoptosis of immature erythrocytes in Il2-/- mice. On the other hand, ablation of NFATc1 activity enhanced differentiation of Ter119+ cells in BM. Restoring IL-2 signaling in Il2-/- mice reversed the increase in cAMP-NFAT signaling and facilitated normal erythropoiesis. Altogether, our study identified an NFAT-mediated negative signaling axis, manipulation of which could facilitate erythropoiesis and prevent anemia development
Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy
BACKGROUND: The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis.
One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the
appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the
spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and
aneuploidy. Therefore, MPS1 inhibition represents an attractive strategy to target cancers.
METHODS: To evaluate CCT271850 cellular potency, two specific antibodies that recognise the activation sites of MPS1 were used
and its antiproliferative activity was determined in 91 human cancer cell lines. DLD1 cells with induced GFP-MPS1 and HCT116
cells were used in in vivo studies to directly measure MPS1 inhibition and efficacy of CCT271850 treatment.
RESULTS: CCT271850 selectively and potently inhibits MPS1 kinase activity in biochemical and cellular assays and in in vivo models.
Mechanistically, tumour cells treated with CCT271850 acquire aberrant numbers of chromosomes and the majority of cells divide
their chromosomes without proper alignment because of abrogation of the mitotic checkpoint, leading to cell death. We
demonstrated a moderate level of efficacy of CCT271850 as a single agent in a human colorectal carcinoma xenograft model.
CONCLUSIONS: CCT271850 is a potent, selective and orally bioavailable MPS1 kinase inhibitor. On the basis of in vivo
pharmacodynamic vs efficacy relationships, we predict that more than 80% inhibition of MPS1 activity for at least 24 h is required to
achieve tumour stasis or regression by CCT271850
Rapid Discovery of Pyrido[3,4- d ]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach
Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft mode
Amygdala and dlPFC abnormalities, with aberrant connectivity and habituation in response to emotional stimuli in females with BPD
Background: Little is known about the frontolimbic abnormalities thought to underlie borderline personality disorder (BPD). We endeavoured to study regional responses, as well as their connectivity and habituation during emotion processing. Methods: 14 BPD patients and 14 normal female controls (NC) controlled for menstrual phase underwent emotion-induction during an fMRI task using standardised images in a block design. We then performed psychophysiological interaction (PPI) analysis to investigate functional connectivity. Results: BPD patients reported more disgust in questionnaires compared to controls. Relative to NC, they showed reduced left amygdala and increased dorsolateral prefrontal cortex (dlPFC) activation to all emotions collapsed versus neutral. Habituation of ventral striatal activity to repeated emotional stimuli was observed in controls but not in BPD. Finally, in the context of disgust (but not other emotions) versus neutral, BPD patients displayed enhanced left amygdala coupling with the dlPFC and ventral striatum. Limitations: Strict inclusion criteria reduced the sample size. Conclusions: In summary, BPD showed abnormal patterns of activation, habituation and connectivity in regions linked to emotion regulation. Amygdala deactivation may be mediated by abnormal top-down regulatory control from the dorsolateral prefrontal cortex. Aberrant emotion processing may play a unique role in the pathophysiology of BPD
Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis
BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London
Role of RNA helicases in HIV-1 replication
Viruses are replication competent genomes which are relatively gene-poor. Even the largest viruses (i.e. Herpesviruses) encode only slightly >200 open reading frames (ORFs). However, because viruses replicate obligatorily inside cells, and considering that evolution may be driven by a principle of economy of scale, it is reasonable to surmise that many viruses have evolved the ability to co-opt cell-encoded proteins to provide needed surrogate functions. An in silico survey of viral sequence databases reveals that most positive-strand and double-stranded RNA viruses have ORFs for RNA helicases. On the other hand, the genomes of retroviruses are devoid of virally-encoded helicase. Here, we review in brief the notion that the human immunodeficiency virus (HIV-1) has adopted the ability to use one or more cellular RNA helicases for its replicative life cycle
The spatial scale of competition from recruits on an older cohort in Atlantic salmon
Competitive effects of younger cohorts on older ones are frequently assumed to be negligible in species where older, larger individuals dominate in pairwise behavioural interactions. Here, we provide field estimates of such competition by recruits on an older age class in Atlantic salmon (Salmo salar), a species where observational studies have documented strong body size advantages which should favour older individuals in direct interactions. By creating realistic levels of spatial variation in the density of underyearling (YOY) recruits over a 1-km stretch of a stream, and obtaining accurate measurements of individual growth rates of overyearlings (parr) from capture–mark–recapture data on a fine spatial scale, we demonstrate that high YOY density can substantially decrease parr growth. Models integrating multiple spatial scales indicated that parr were influenced by YOY density within 16 m. The preferred model suggested parr daily mass increase to be reduced by 39% when increasing YOY density from 0.0 to 1.0 m−2, which is well within the range of naturally occurring densities. Reduced juvenile growth rates will in general be expected to reduce juvenile survival (via increased length of exposure to freshwater mortality) and increase generation times (via increased age at seaward migrations). Thus, increased recruitment can significantly affect the performance of older cohorts, with important implications for population dynamics. Our results highlight that, even for the wide range of organisms that rely on defendable resources, the direction of competition among age classes cannot be assumed a priori or be inferred from behavioural observations alone
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