Preconditioning and triggering of offshore slope failures and turbidity currents revealed by most detailed monitoring yet at a fjord-head delta

Rivers and turbidity currents are the two most important sediment transport processes by volume on Earth. Various hypotheses have been proposed for triggering of turbidity currents offshore from river mouths, including direct plunging of river discharge, delta mouth bar flushing or slope failure caused by low tides and gas expansion, earthquakes and rapid sedimentation. During 2011, 106 turbidity currents were monitored at Squamish Delta, British Columbia. This enables statistical analysis of timing, frequency and triggers. The largest peaks in river discharge did not create hyperpycnal flows. Instead, delayed delta-lip failures occurred 8–11 h after flood peaks, due to cumulative delta top sedimentation and tidally-induced pore pressure changes. Elevated river discharge is thus a significant control on the timing and rate of turbidity currents but not directly due to plunging river water. Elevated river discharge and focusing of river discharge at low tides cause increased sediment transport across the delta-lip, which is the most significant of all controls on flow timing in this setting

Structure of amyloid-β (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface.

Amyloid-β (Aβ) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer's disease (AD) pathogenesis. Here we present the 1.1 Å resolution MicroED structure of an Aβ 20-34 fibril with and without the disease-associated PTM, L-isoaspartate, at position 23 (L-isoAsp23). Both wild-type and L-isoAsp23 protofilaments adopt β-helix-like folds with tightly packed cores, resembling the cores of full-length fibrillar Aβ structures, and both self-associate through two distinct interfaces. One of these is a unique Aβ interface strengthened by the isoaspartyl modification. Powder diffraction patterns suggest a similar structure may be adopted by protofilaments of an analogous segment containing the heritable Iowa mutation, Asp23Asn. Consistent with its early onset phenotype in patients, Asp23Asn accelerates aggregation of Aβ 20-34, as does the L-isoAsp23 modification. These structures suggest that the enhanced amyloidogenicity of the modified Aβ segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD

The measurement of response shift in patients with advanced prostate cancer and their partners

BACKGROUND: There is increasing evidence to support the phenomenon of response shift (RS) in quality of life (QoL) studies, with many current QoL measures failing to allow for this. If significant response shift occurs amongst prostate cancer patients, it will be necessary to allow for this in the design of future clinical research and to reassess the conclusions of previous studies that have not allowed for this source of bias. This study therefore aimed to assess the presence of RS and psychosocial morbidity in patients with advanced prostate cancer and their partners. METHODS: 55 consecutive advanced prostate cancer patients and their partners completed the Prostate Cancer Patient & Partner questionnaire (PPP), shortly after diagnosis and again at 3 months and 6 months. At the follow-up visits, both patients and partners also completed a then-test in order to assess RS. RESULTS: Partners consistently showed greater psychological morbidity than patients in relation to the prostate cancer. This was most marked on the General Cancer Distress (GCD) subscale (p < 0.001, paired t-test), and regarding worries about treatment (p = 0.01). Significant RS was identified in partners and patients by the use of the then-test technique, particularly on the GCD subscale, the concerns about treatment and the concerns about urinary symptoms items. CONCLUSION: These results suggest the presence of RS in patients with advanced prostate cancer and their partners, with higher levels of psychosocial morbidity noted amongst partners. This is the first study to identify RS in partners and calls into question the interpretation of all studies assessing changes in QoL that fail to allow for this phenomenon

The assessment of cognition in visually impaired older adults

Background: visual and cognitive impairments are common in later life. Yet there are very few cognitive screening tests for the visually impaired. Objective: to screen for cognitive impairment in the visually impaired. Methods: case-control study including 150 elderly participants with visual impairment (n=74) and a control group without visual impairment (n=76) using vision-independent cognitive tests and cognitive screening tests (MMSE and clock drawing tests (CDT)) which are in part vision dependent. Results: the scoring of the two groups did not differ in the vision-independent cognitive tests. Visually impaired patients performed poorer than controls in the vision-dependent items of the MMSE (T=7.3; df: 148; P<0.001) and in CDT (T=3.1; df: 145; P=0.003). No group difference was found when vision-independent items were added to MMSE and CDT. The test score gain by the use of vision-independent items correlated with the severity of visual impairment (P<0.002). Conclusion: visually impaired patients benefit from cognitive tests, which do not rely on vision. The more visually impaired the greater the benefi

Effect of vitamin K2 on postural sway in older people who fall:a randomized controlled trial

OBJECTIVES: Vitamin K is thought to be involved in both bone health and maintenance of neuromuscular function. We tested the effect of vitamin K2 supplementation on postural sway, falls, healthcare costs, and indices of physical function in older people at risk of falls.DESIGN: Parallel-group double-blind randomized placebo-controlled trial.SETTING: Fourteen primary care practices in Scotland, UK.PARTICIPANTS: A total of 95 community-dwelling participants aged 65 and older with at least two falls, or one injurious fall, in the previous year.INTERVENTION: Once/day placebo, 200 μg or 400 μg of oral vitamin K2 for 1 year.MEASUREMENTS: The primary outcome was anteroposterior sway measured using sway plates at 12 months, adjusted for baseline. Secondary outcomes included the Short Physical Performance Battery, Berg Balance Scale, Timed Up &amp; Go Test, quality of life, health and social care costs, falls, and adverse events.RESULTS: Mean participant age was 75 (standard deviation [SD] = 7) years. Overall, 58 of 95 (61%) were female; 77 of 95 (81%) attended the 12-month visit. No significant effect of either vitamin K2 dose was seen on the primary outcome of anteroposterior sway (200 μg vs placebo: -.19 cm [95% confidence interval [CI] -.68 to .30; P = .44]; 400 μg vs placebo: .17 cm [95% CI -.33 to .66; P = .50]; or 400 μg vs 200 μg: .36 cm [95% CI -.11 to .83; P = .14]). Adjusted falls rates were similar in each group. No significant treatment effects were seen for other measures of sway or secondary outcomes. Costs were higher in both vitamin K2 arms than in the placebo arm.CONCLUSION: Oral vitamin K2 supplementation did not improve postural sway or physical function in older people at risk of falls.</p

Comparison of long and short axis quantification of left ventricular volume parameters by cardiovascular magnetic resonance, with ex-vivo validation

<p>Abstract</p> <p>Background</p> <p>The purpose of the study was to compare the accuracy and evaluation time of quantifying left ventricular (LV), left atrial (LA) volume and LV mass using short axis (SAX) and long axis (LAX) methods when using cardiovascular magnetic resonance (CMR).</p> <p>Materials and methods</p> <p>We studied 12 explanted canine hearts and 46 patients referred for CMR (29 male, age 47 ± 18 years) in a clinical 1.5 T CMR system, using standard cine sequences. In standard short axis stacks of various slice thickness values in dogs and 8 mm slice thickness (gap 2 mm) in patients, we measured LV volumes using reference slices in a perpendicular, long axis orientation using certified software. Volumes and mass were also measured in six radial long axis (LAX) views.</p> <p>LV parameters were also assessed for intra- and inter-observer variability. In 24 patients, we also analyzed reproducibility and evaluation time of two very experienced (> 10 years of CMR reading) readers for SAX and LAX.</p> <p>Results</p> <p>In the explanted dog hearts, there was excellent agreement between ex vivo data and LV mass and volume data as measured by all methods for both, LAX (r²= 0.98) and SAX (r²= 0.88 to 0.98). LA volumes, however, were underestimated by 13% using the LAX views. In patients, there was a good correlation between all three assessed methods (r²≥ 0.95 for all). In experienced clinical readers, left-ventricular volumes and ejection fraction as measured in LAX views showed a better inter-observer reproducibility and a 27% shorter evaluation time.</p> <p>Conclusion</p> <p>When compared to an ex vivo standard, both, short axis and long axis techniques are highly accurate for the quantification of left ventricular volumes and mass. In clinical settings, however, the long axis approach may be more reproducible and more time-efficient. Therefore, the rotational long axis approach is a viable alternative for the clinical assessment of cardiac volumes, function and mass.</p

DNA-binding by Haemophilus influenzae and Escherichia coli YbaB, members of a widely-distributed bacterial protein family

BACKGROUND: Genes orthologous to the ybaB loci of Escherichia coli and Haemophilus influenzae are widely distributed among eubacteria. Several years ago, the three-dimensional structures of the YbaB orthologs of both E. coli and H. influenzae were determined, revealing a novel tweezer -like structure. However, a function for YbaB had remained elusive, with an early study of the H. influenzae ortholog failing to detect DNA-binding activity. Our group recently determined that the Borrelia burgdorferi YbaB ortholog, EbfC, is a DNA-binding protein. To reconcile those results, we assessed the abilities of both the H. influenzae and E. coli YbaB proteins to bind DNA to which B. burgdorferi EbfC can bind. RESULTS: Both the H. influenzae and the E. coli YbaB proteins bound to tested DNAs. DNA-binding was not well competed with poly-dI-dC, indicating some sequence preferences for those two proteins. Analyses of binding characteristics determined that both YbaB orthologs bind as homodimers. Different DNA sequence preferences were observed between H. influenzae YbaB, E. coli YbaB and B. burgdorferi EbfC, consistent with amino acid differences in the putative DNA-binding domains of these proteins. CONCLUSION: Three distinct members of the YbaB/EbfC bacterial protein family have now been demonstrated to bind DNA. Members of this protein family are encoded by a broad range of bacteria, including many pathogenic species, and results of our studies suggest that all such proteins have DNA-binding activities. The functions of YbaB/EbfC family members in each bacterial species are as-yet unknown, but given the ubiquity of these DNA-binding proteins among Eubacteria, further investigations are warranted

Mapping pneumonia research: a systematic analysis of UK investments and published outputs 1997–2013

BackgroundThe burden of pneumonia continues to be substantial, particularly among the poorest in global society. We describe here the trends for UK pneumonia R&amp;D investment and published outputs, and correlate with 2013 global mortality.MethodsData related to awards to UK institutions for pneumonia research from 1997 to 2013 were systematically sourced and categorised by disease area and type of science. Investment was compared to mortality figures in 2010 and 2013 for pneumonia, tuberculosis and influenza. Investment was also compared to publication data.ResultsOf all infectious disease research between 2011 and 2013 (£917.0 million), £28.8 million (3.1%) was for pneumonia. This was an absolute and proportionate increase from previous time periods. Translational pneumonia research (33.3%) received increased funding compared with 1997–2010 where funding was almost entirely preclinical (87.5%, here 30.9%), but high-burden areas such as paediatrics, elderly care and antimicrobial resistance received little investment. Annual investment remains volatile; publication temporal trends show a consistent increase. When comparing investment to global burden with a novel ‘investment by mortality observed’ metric, tuberculosis (£48.36) and influenza (£484.21) receive relatively more funding than pneumonia (£43.08), despite investment for pneumonia greatly increasing in 2013 compared to 2010 (£7.39). Limitations include a lack of private sector data and the need for careful interpretation of the comparisons with burden, plus categorisation is subjective.ConclusionsThere has been a welcome increase for pneumonia funding awarded to UK institutions in 2011–2013 compared with 1997–2010, along with increases for more translational research. Published outputs relating to pneumonia rose steadily from 1997 to 2013. Investment relative to mortality for pneumonia has increased, but it remains low compared to other respiratory infections and clear inequities remain. Analyses that measure investments in pneumonia can provide an insight into funding trends and research gaps.Research in contextPneumonia continues to be a high-burden illness around the globe. This paper shows that although research funding is increasing in the UK (between 1997 and 2013), it remains poorly funded compared to other important respiratory infectious diseases such as tuberculosis and influenza. Publications about pneumonia have been steadily increasing over time, indicating continuing academic and clinical interest in the topic. Though global mortality of pneumonia is declining, it should still be an area of high priority for funders, policymakers and researchers

PIP3-dependent macropinocytosis is incompatible with chemotaxis

In eukaryotic chemotaxis, the mechanisms connecting external signals to the motile apparatus remain unclear. The role of the lipid phosphatidylinositol 3,4,5-trisphosphate (PIP3) has been particularly controversial. PIP3 has many cellular roles, notably in growth control and macropinocytosis as well as cell motility. Here we show that PIP3 is not only unnecessary for Dictyostelium discoideum to migrate toward folate, but actively inhibits chemotaxis. We find that macropinosomes, but not pseudopods, in growing cells are dependent on PIP3. PIP3 patches in these cells show no directional bias, and overall only PIP3-free pseudopods orient up-gradient. The pseudopod driver suppressor of cAR mutations (SCAR)/WASP and verprolin homologue (WAVE) is not recruited to the center of PIP3 patches, just the edges, where it causes macropinosome formation. Wild-type cells, unlike the widely used axenic mutants, show little macropinocytosis and few large PIP3 patches, but migrate more efficiently toward folate. Tellingly, folate chemotaxis in axenic cells is rescued by knocking out phosphatidylinositide 3-kinases (PI 3-kinases). Thus PIP3 promotes macropinocytosis and interferes with pseudopod orientation during chemotaxis of growing cells