Velocity map imaging spectroscopy of C<inf>2</inf>H^-and C<inf>2</inf>D^-: A benchmark study of vibronic coupling interactions

High-resolution velocity-map imaged photoelectron spectra of the ethynyl anions C2H- and C2D- are measured at photon wavelengths between 355 and 266 nm to investigate the complex interactions between the closely lying X 2ς+ and A 2Π electronic states. An indicative kinetic energy resolution of 0.4%, together with the full angular dependence of the fast electrons, provides a detailed description of the vibronically coupled structure. It is demonstrated that a modest quadratic vibronic coupling model, parameterized by the quasidiabatic ansatz, is sufficient to accurately recreate all the observed vibronic interactions. Simulated spectra are shown to be in excellent agreement with the experimental data, verifying the proposed model and providing a framework that may be used to accurately simulate spectra of larger C2nH monohydride carbon chains. New spectral assignments are supported by experimental electron anisotropy measurements and Dyson orbital calculations

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

Coping style and quality of life in patients with epilepsy: a cross-sectional study

Having epilepsy has a large impact on one's well-being, but often seizure frequency and severity do not explain self-reported quality of life. We hypothesized that one's personal coping style is more important. In this study, 105 patients attending the outpatient neurological clinic at the University Medical Centre in Utrecht, the Netherlands, with a diagnosis of partial epilepsy, aged 17–80 years, completed questionnaires. Demographic information, disease characteristics, health-related quality of life (HRQoL), and coping styles were obtained by postal-validated HRQoL questionnaires: the EQ5D and RAND-36 and the Utrecht Coping List. A passive coping style explained 45% of the variance in the mental component of HRQoL and was more important than ‘objective’ seizure-related measures. Confounders such as employment, gender, and side-effects of treatment explained another 6%. Passive coping style also influenced the physical component of the HRQoL, but here seizure-related factors predominated. Overall, epilepsy patients showed a more avoiding coping style, and female patients a less active coping style and more reassuring thoughts, compared to the Dutch population. The personal coping style of patients appears to be more important than seizure-related measures in predicting mental aspects of quality of life. Coping style characteristics rather than disease characteristics should guide clinical decision-making in patients with epilepsy. Further studies should investigate the effect on HRQoL of behavioral interventions to improve coping

A Knockout of the Tsg101 Gene Leads to Decreased Expression of ErbB Receptor Tyrosine Kinases and Induction of Autophagy Prior to Cell Death

The Tumor Susceptibility Gene 101 (Tsg101) encodes a multi-domain protein that mediates a variety of molecular and biological processes including the trafficking and lysosomal degradation of cell surface receptors. Conventional and conditional knockout models have demonstrated an essential requirement of this gene for cell cycle progression and cell viability, but the consequences of a complete ablation of Tsg101 on intracellular processes have not been examined to date. In this study, we employed mouse embryonic fibroblasts that carry two Tsg101 conditional knockout alleles to investigate the expression of ErbB receptor tyrosine kinases as well as stress-induced intracellular processes that are known to be associated with a defect in growth and cell survival. The conditional deletion of the Tsg101 gene in this well-controlled experimental model resulted in a significant reduction in the steady-state levels of the EGFR and ErbB2 but a stress-induced elevation in the phosphorylation of mitogen activated protein (MAP) kinases independent of growth factor stimulation. As part of an integrated stress response, Tsg101-deficient cells exhibited extensive remodeling of actin filaments and greatly enlarged lysosomes that were enriched with the autophagy-related protein LC3. The increase in the transcriptional activation and expression of LC3 and its association with Lamp1-positive lysosomes in a PI3K-dependent manner suggest that Tsg101 knockout cells utilize autophagy as a survival mechanism prior to their ultimate death. Collectively, this study shows that a knockout of the Tsg101 gene causes complex intracellular changes associated with stress response and cell death. These multifaceted alterations need to be recognized as they have an impact on defining particular functions for Tsg101 in processes such as signal transduction and lysosomal/endosomal trafficking

Hopefulness predicts resilience after hereditary colorectal cancer genetic testing: a prospective outcome trajectories study

<p>Abstract</p> <p>Background -</p> <p>Genetic testing for hereditary colorectal cancer (HCRC) had significant psychological consequences for test recipients. This prospective longitudinal study investigated the factors that predict psychological resilience in adults undergoing genetic testing for HCRC.</p> <p>Methods -</p> <p>A longitudinal study was carried out from April 2003 to August 2006 on Hong Kong Chinese HCRC family members who were recruited and offered genetic testing by the Hereditary Gastrointestinal Cancer Registry to determine psychological outcomes after genetic testing. Self-completed questionnaires were administered immediately before (pre-disclosure baseline) and 2 weeks, 4 months and 1 year after result disclosure. Using validated psychological inventories, the cognitive style of hope was measured at baseline, and the psychological distress of depression and anxiety was measured at all time points.</p> <p>Results -</p> <p>Of the 76 participating subjects, 71 individuals (43 men and 28 women; mean age 38.9 ± 9.2 years) from nine FAP and 24 HNPCC families completed the study, including 39 mutated gene carriers. Four patterns of outcome trajectories were created using established norms for the specified outcome measures of depression and anxiety. These included chronic dysfunction (13% and 8.7%), recovery (0% and 4.3%), delayed dysfunction (13% and 15.9%) and resilience (76.8% and 66.7%). Two logistic regression analyses were conducted using hope at baseline to predict resilience, with depression and anxiety employed as outcome indicators. Because of the small number of participants, the chronic dysfunction and delayed dysfunction groups were combined into a non-resilient group for comparison with the resilient group in all subsequent analysis. Because of low frequencies, participants exhibiting a recovery trajectory (n = 3 for anxiety and n = 0 for depression) were excluded from further analysis. Both regression equations were significant. Baseline hope was a significant predictor of a resilience outcome trajectory for depression (<it>B </it>= -0.24, <it>p </it>< 0.01 for depression); and anxiety (<it>B </it>= -0.11, <it>p </it>= 0.05 for anxiety).</p> <p>Conclusions -</p> <p>The current findings suggest that hopefulness may predict resilience after HCRC genetic testing in Hong Kong Chinese. Interventions to increase the level of hope may be beneficial to the psychological adjustment of CRC genetic testing recipients.</p

Biological effects of naturally occurring and man-made fibres: in vitro cytotoxicity and mutagenesis in mammalian cells

Cytotoxicity and mutagenicity of tremolite, erionite and the man-made ceramic (RCF-1) fibre were studied using the human– hamster hybrid A L cells. Results from these fibres were compared with those of UICC Rhodesian chrysotile fibres. The A L cell mutation assay, based on the S1 gene marker located on human chromosome 11, the only human chromosome contained in the hybrid cell, has been shown to be more sensitive than conventional assays in detecting deletion mutations. Tremolite, erionite and RCF-1 fibres were significantly less cytotoxic to A L cells than chrysotile. Mutagenesis studies at the HPRT locus revealed no significant mutant yield with any of these fibres. In contrast, both erionite and tremolite induced dose-dependent S1− mutations in fibre-exposed cells, with the former inducing a significantly higher mutant yield than the latter fibre type. On the other hand, RCF-1 fibres were largely non-mutagenic. At equitoxic doses (cell survival at ∼ 0.7), erionite was found to be the most potent mutagen among the three fibres tested and at a level comparable to that of chrysotile fibres. These results indicate that RCF-1 fibres are non-genotoxic under the conditions used in the studies and suggest that the high mesothelioma incidence previously observed in hamster may either be a result of selective sensitivity of hamster pleura to fibre-induced chronic irritation or as a result of prolonged fibre treatment. Furthermore, the relatively high mutagenic potential for erionite is consistent with its documented carcinogenicity. © 1999 Cancer Research Campaig

Influences on uptake of reproductive health services in Nsangi community of Uganda and their implications for cervical cancer screening

<p>Abstract</p> <p>Background</p> <p>Cervical cancer is the most common female cancer in Uganda. Over 80% of women diagnosed or referred with cervical cancer in Mulago national referral and teaching hospital have advanced disease. Plans are underway for systematic screening programmes based on visual inspection, as Pap smear screening is not feasible for this low resource country. Effectiveness of population screening programmes requires high uptake and for cervical cancer, minimal loss to follow up. Uganda has poor indicators of reproductive health (RH) services uptake; 10% postnatal care attendance, 23% contraceptive prevalence, and 38% skilled attendance at delivery. For antenatal attendance, attendance to one visit is 90%, but less than 50% for completion of care, i.e. three or more visits.</p> <p>Methods</p> <p>We conducted a qualitative study using eight focus group discussions with a total of 82 participants (16 men, 46 women and 20 health workers). We aimed to better understand factors that influence usage of available reproductive health care services and how they would relate to cervical cancer screening, as well as identify feasible interventions to improve cervical cancer screening uptake.</p> <p>Results</p> <p>Barriers identified after framework analysis included ignorance about cervical cancer, cultural constructs/beliefs about the illness, economic factors, domestic gender power relations, alternative authoritative sources of reproductive health knowledge, and unfriendly health care services. We discuss how these findings may inform future planned screening programmes in the Ugandan context.</p> <p>Conclusion</p> <p>Knowledge about cervical cancer among Ugandan women is very low. For an effective cervical cancer-screening programme, awareness about cervical cancer needs to be increased. Health planners need to note the power of the various authoritative sources of reproductive health knowledge such as paternal aunts (<it>Sengas</it>) and involve them in the awareness campaign. Cultural and economic issues dictate the perceived reluctance by men to participate in women's reproductive health issues; men in this community are, however, potential willing partners if appropriately informed. Health planners should address the loss of confidence in current health care units, as well as consider use of other cervical cancer screening delivery systems such as mobile clinics/camps.</p

Transcriptomic and metabolomic profiling of Zymomonas mobilis during aerobic and anaerobic fermentations

<p>Abstract</p> <p>Background</p> <p><it>Zymomonas mobilis </it>ZM4 (ZM4) produces near theoretical yields of ethanol with high specific productivity and recombinant strains are able to ferment both C-5 and C-6 sugars. <it>Z. mobilis </it>performs best under anaerobic conditions, but is an aerotolerant organism. However, the genetic and physiological basis of ZM4's response to various stresses is understood poorly.</p> <p>Results</p> <p>In this study, transcriptomic and metabolomic profiles for ZM4 aerobic and anaerobic fermentations were elucidated by microarray analysis and by high-performance liquid chromatography (HPLC), gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) analyses. In the absence of oxygen, ZM4 consumed glucose more rapidly, had a higher growth rate, and ethanol was the major end-product. Greater amounts of other end-products such as acetate, lactate, and acetoin were detected under aerobic conditions and at 26 h there was only 1.7% of the amount of ethanol present aerobically as there was anaerobically. In the early exponential growth phase, significant differences in gene expression were not observed between aerobic and anaerobic conditions via microarray analysis. HPLC and GC analyses revealed minor differences in extracellular metabolite profiles at the corresponding early exponential phase time point.</p> <p>Differences in extracellular metabolite profiles between conditions became greater as the fermentations progressed. GC-MS analysis of stationary phase intracellular metabolites indicated that ZM4 contained lower levels of amino acids such as alanine, valine and lysine, and other metabolites like lactate, ribitol, and 4-hydroxybutanoate under anaerobic conditions relative to aerobic conditions. Stationary phase microarray analysis revealed that 166 genes were significantly differentially expressed by more than two-fold. Transcripts for Entner-Doudoroff (ED) pathway genes (<it>glk, zwf, pgl, pgk, and eno</it>) and gene <it>pdc</it>, encoding a key enzyme leading to ethanol production, were at least 30-fold more abundant under anaerobic conditions in the stationary phase based on quantitative-PCR results. We also identified differentially expressed ZM4 genes predicted by The Institute for Genomic Research (TIGR) that were not predicted in the primary annotation.</p> <p>Conclusion</p> <p>High oxygen concentrations present during <it>Z. mobilis </it>fermentations negatively influence fermentation performance. The maximum specific growth rates were not dramatically different between aerobic and anaerobic conditions, yet oxygen did affect the physiology of the cells leading to the buildup of metabolic byproducts that ultimately led to greater differences in transcriptomic profiles in stationary phase.</p

Altered Error Processing following Vascular Thalamic Damage: Evidence from an Antisaccade Task

Event-related potentials (ERP) research has identified a negative deflection within about 100 to 150 ms after an erroneous response – the error-related negativity (ERN) - as a correlate of awareness-independent error processing. The short latency suggests an internal error monitoring system acting rapidly based on central information such as an efference copy signal. Studies on monkeys and humans have identified the thalamus as an important relay station for efference copy signals of ongoing saccades. The present study investigated error processing on an antisaccade task with ERPs in six patients with focal vascular damage to the thalamus and 28 control subjects. ERN amplitudes were significantly reduced in the patients, with the strongest ERN attenuation being observed in two patients with right mediodorsal and ventrolateral and bilateral ventrolateral damage, respectively. Although the number of errors was significantly higher in the thalamic lesion patients, the degree of ERN attenuation did not correlate with the error rate in the patients. The present data underline the role of the thalamus for the online monitoring of saccadic eye movements, albeit not providing unequivocal evidence in favour of an exclusive role of a particular thalamic site being involved in performance monitoring. By relaying saccade-related efference copy signals, the thalamus appears to enable fast error processing. Furthermore early error processing based on internal information may contribute to error awareness which was reduced in the patients

Left ventricular mechanical dysfunction in diet-induced obese mice is exacerbated during inotropic stress: a cine DENSE cardiovascular magnetic resonance study

BACKGROUND: Obesity is a risk factor for cardiovascular disease. There is evidence of impaired left ventricular (LV) function associated with obesity, which may relate to cardiovascular mortality, but some studies have reported no dysfunction. Ventricular function data are generally acquired under resting conditions, which could mask subtle differences and potentially contribute to these contradictory findings. Furthermore, abnormal ventricular mechanics (strains, strain rates, and torsion) may manifest prior to global changes in cardiac function (i.e., ejection fraction) and may therefore represent more sensitive markers of cardiovascular disease. This study evaluated LV mechanics under both resting and stress conditions with the hypothesis that the LV mechanical dysfunction associated with obesity is exacerbated with stress and manifested at earlier stages of disease compared to baseline. METHODS: C57BL/6J mice were randomized to a high-fat or control diet (60 %, 10 % kcal from fat, respectively) for varying time intervals (n = 7 – 10 subjects per group per time point, 100 total; 4 – 55 weeks on diet). LV mechanics were quantified under baseline (resting) and/or stress conditions (40 μg/kg/min continuous infusion of dobutamine) using cine displacement encoding with stimulated echoes (DENSE) with 7.4 ms temporal resolution on a 7 T Bruker ClinScan. Peak strain, systolic strain rates, and torsion were quantified. A linear mixed model was used with Benjamini-Hochberg adjustments for multiple comparisons. RESULTS: Reductions in LV peak longitudinal strain at baseline were first observed in the obese group after 42 weeks, with no differences in systolic strain rates or torsion. Conversely, reductions in longitudinal strain and circumferential and radial strain rates were seen under inotropic stress conditions after only 22 weeks on diet. Furthermore, stress cardiovascular magnetic resonance (CMR) evaluation revealed supranormal values of LV radial strain and torsion in the obese group early on diet, followed by later deficits. CONCLUSIONS: Differences in left ventricular mechanics in obese mice are exacerbated under stress conditions. Stress CMR demonstrated a broader array of mechanical dysfunction and revealed these differences at earlier time points. Thus, it may be important to evaluate cardiac function in the setting of obesity under stress conditions to fully elucidate the presence of ventricular dysfunction. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12968-015-0180-7) contains supplementary material, which is available to authorized users