Social encounter networks: characterizing Great Britain

A major goal of infectious disease epidemiology is to understand and predict the spread of infections within human populations, with the intention of better informing decisions regarding control and intervention. However, the development of fully mechanistic models of transmission requires a quantitative understanding of social interactions and collective properties of social networks. We performed a cross-sectional study of the social contacts on given days for more than 5000 respondents in England, Scotland and Wales, through postal and online survey methods. The survey was designed to elicit detailed and previously unreported measures of the immediate social network of participants relevant to infection spread. Here, we describe individual-level contact patterns, focusing on the range of heterogeneity observed and discuss the correlations between contact patterns and other socio-demographic factors. We find that the distribution of the number of contacts approximates a power-law distribution, but postulate that total contact time (which has a shorter-tailed distribution) is more epidemiologically relevant. We observe that children, public-sector and healthcare workers have the highest number of total contact hours and are therefore most likely to catch and transmit infectious disease. Our study also quantifies the transitive connections made between an individual''s contacts (or clustering); this is a key structural characteristic of social networks with important implications for disease transmission and control efficacy. Respondents'' networks exhibit high levels of clustering, which varies across social settings and increases with duration, frequency of contact and distance from home. Finally, we discuss the implications of these findings for the transmission and control of pathogens spread through close contact.     

Dissecting a complex chemical stress: chemogenomic profiling of plant hydrolysates

The efficient production of biofuels from cellulosic feedstocks will require the efficient fermentation of the sugars in hydrolyzed plant material. Unfortunately, plant hydrolysates also contain many compounds that inhibit microbial growth and fermentation. We used DNA‐barcoded mutant libraries to identify genes that are important for hydrolysate tolerance in both Zymomonas mobilis (44 genes) and Saccharomyces cerevisiae (99 genes). Overexpression of a Z. mobilis tolerance gene of unknown function (ZMO1875) improved its specific ethanol productivity 2.4‐fold in the presence of miscanthus hydrolysate. However, a mixture of 37 hydrolysate‐derived inhibitors was not sufficient to explain the fitness profile of plant hydrolysate. To deconstruct the fitness profile of hydrolysate, we profiled the 37 inhibitors against a library of Z. mobilis mutants and we modeled fitness in hydrolysate as a mixture of fitness in its components. By examining outliers in this model, we identified methylglyoxal as a previously unknown component of hydrolysate. Our work provides a general strategy to dissect how microbes respond to a complex chemical stress and should enable further engineering of hydrolysate tolerance.     

Activating and Relaxing Music Entrains the Speed of Beat Synchronized Walking

Inspired by a theory of embodied music cognition, we investigate whether music can entrain the speed of beat synchronized walking. If human walking is in synchrony with the beat and all musical stimuli have the same duration and the same tempo, then differences in walking speed can only be the result of music-induced differences in stride length, thus reflecting the vigor or physical strength of the movement. Participants walked in an open field in synchrony with the beat of 52 different musical stimuli all having a tempo of 130 beats per minute and a meter of 4 beats. The walking speed was measured as the walked distance during a time interval of 30 seconds. The results reveal that some music is ‘activating’ in the sense that it increases the speed, and some music is ‘relaxing’ in the sense that it decreases the speed, compared to the spontaneous walked speed in response to metronome stimuli. Participants are consistent in their observation of qualitative differences between the relaxing and activating musical stimuli. Using regression analysis, it was possible to set up a predictive model using only four sonic features that explain 60% of the variance. The sonic features capture variation in loudness and pitch patterns at periods of three, four and six beats, suggesting that expressive patterns in music are responsible for the effect. The mechanism may be attributed to an attentional shift, a subliminal audio-motor entrainment mechanism, or an arousal effect, but further study is needed to figure this out. Overall, the study supports the hypothesis that recurrent patterns of fluctuation affecting the binary meter strength of the music may entrain the vigor of the movement. The study opens up new perspectives for understanding the relationship between entrainment and expressiveness, with the possibility to develop applications that can be used in domains such as sports and physical rehabilitation.     

Distinct molecular features of colorectal cancer in Ghana

Objectives: While colorectal cancer (CRC) is common, its incidence significantly varies around the globe. The incidence of CRC in West Africa is relatively low, but it has a distinctive clinical pattern and its molecular characteristics have not been studied. This study is one of the first attempts to analyze molecular, genetic, and pathological characteristics of colorectal cancer in Ghana. Methods: DNA was extracted from microdissected tumor and adjacent normal tissue of 90 paraffin blocks of CRC cases (1997–2007) collected at the University of Ghana. Microsatellite instability (MSI) was determined using fragment analysis of ten microsatellite markers. We analyzed expression of mismatch repair (MMR) proteins by immunohistochemistry and sequenced exons 2 and 3 of KRAS and exon 15 of BRAF. Results: MSI analysis showed 41% (29/70) MSI-High, 20% (14/70) MSI-Low, and 39% (27/70) microsatellite-stable (MSS) tumors. Sequencing of KRAS exons 2 and 3 identified activating mutations in 32% (24/75) of tumors, and sequencing of BRAF exon 15, the location of the common activating mutation (V600), did not show mutations at codons 599 and 600 in 88 tumors. Conclusions: Our study found a high frequency of MSI-High colorectal tumors (41%) in Ghana. While the frequency of KRAS mutations is comparable with other populations, absence of BRAF mutations is intriguing and would require further analysis of the molecular epidemiology of CRC in West Africa.     

Microparticle-Induced Coagulation Relates to Coronary Artery Atherosclerosis in Severe Aortic Valve Stenosis

Background

Circulating microparticles (MPs) derived from endothelial cells and blood cells bear procoagulant activity and promote thrombin generation. Thrombin exerts proinflammatory effects mediating the progression of atherosclerosis. Aortic valve stenosis may represent an atherosclerosis-like process involving both the aortic valve and the vascular system. The aim of this study was to investigate whether MP-induced thrombin generation is related to coronary atherosclerosis and aortic valve calcification.

Methods

In a cross-sectional study of 55 patients with severe aortic valve stenosis, we assessed the coronary calcification score (CAC) as indicator of total coronary atherosclerosis burden, and aortic valve calcification (AVC) by computed tomography. Thrombin-antithrombin complex (TATc) levels were measured as a marker for thrombin formation. Circulating MPs were characterized by flow cytometry according to the expression of established surface antigens and by measuring MP-induced thrombin generation.

Results

Patients with CAC score below the median were classified as patients with low CAC, patients with CAC Score above the median as high CAC. In patients with high CAC compared to patients with low CAC we detected higher levels of TATc, platelet-derived MPs (PMPs), endothelial-derived MPs (EMPs) and MP-induced thrombin generation. Increased level of PMPs and MP-induced thrombin generation were independent predictors for the severity of CAC. In contrast, AVC Score did not differ between patients with high and low CAC and did neither correlate with MPs levels nor with MP-induced thrombin generation.

Conclusion

In patients with severe aortic valve stenosis MP-induced thrombin generation was independently associated with the severity of CAC but not AVC indicating different pathomechanisms involved in coronary artery and aortic valve calcification.     

Deprescribing in Frail Older People: A Randomised Controlled Trial

Objectives

Deprescribing has been proposed as a way to reduce polypharmacy in frail older people. We aimed to reduce the number of medicines consumed by people living in residential aged care facilities (RACF). Secondary objectives were to explore the effect of deprescribing on survival, falls, fractures, hospital admissions, cognitive, physical, and bowel function, quality of life, and sleep.

Methods

Ninety-five people aged over 65 years living in four RACF in rural mid-west Western Australia were randomised in an open study. The intervention group (n = 47) received a deprescribing intervention, the planned cessation of non-beneficial medicines. The control group (n = 48) received usual care. Participants were monitored for twelve months from randomisation. Primary outcome was change in the mean number of unique regular medicines. All outcomes were assessed at baseline, six, and twelve months.

Results

Study participants had a mean age of 84.3±6.9 years and 52% were female. Intervention group participants consumed 9.6±5.0 and control group participants consumed 9.5±3.6 unique regular medicines at baseline. Of the 348 medicines targeted for deprescribing (7.4±3.8 per person, 78% of regular medicines), 207 medicines (4.4±3.4 per person, 59% of targeted medicines) were successfully discontinued. The mean change in number of regular medicines at 12 months was -1.9±4.1 in intervention group participants and +0.1±3.5 in control group participants (estimated difference 2.0±0.9, 95%CI 0.08, 3.8, p = 0.04). Twelve intervention participants and 19 control participants died within 12 months of randomisation (26% versus 40% mortality, p = 0.16, HR 0.60, 95%CI 0.30 to 1.22) There were no significant differences between groups in other secondary outcomes. The main limitations of this study were the open design and small participant numbers.

Conclusions

Deprescribing reduced the number of regular medicines consumed by frail older people living in residential care with no significant adverse effects on survival or other clinical outcomes.

Trial Registration

Australian New Zealand Clinical Trials Registry ACTRN12611000370909     

Genetic and Quantitative Trait Locus Analysis for Bio-Oil Compounds after Fast Pyrolysis in Maize Cobs

Fast pyrolysis has been identified as one of the biorenewable conversion platforms that could be a part of an alternative energy future, but it has not yet received the same attention as cellulosic ethanol in the analysis of genetic inheritance within potential feedstocks such as maize. Ten bio-oil compounds were measured via pyrolysis/gas chromatography-mass spectrometry (Py/GC-MS) in maize cobs. 184 recombinant inbred lines (RILs) of the intermated B73 x Mo17 (IBM) Syn4 population were analyzed in two environments, using 1339 markers, for quantitative trait locus (QTL) mapping. QTL mapping was performed using composite interval mapping with significance thresholds established by 1000 permutations at α = 0.05. 50 QTL were found in total across those ten traits with R² values ranging from 1.7 to 5.8%, indicating a complex quantitative inheritance of these traits.     

An approach to overcoming regeneration recalcitrance in genetic transformation of lupins and other legumes

For pulse legume research to fully capitalise on developments in plant molecular genetics, a high throughput genetic transformation methodology is required. In Western Australia the dominant grain legume is Lupinus angustifolius L. (narrow leafed lupin; NLL). Standard transformation methodology utilising Agrobacterium tumefaciens on wounded NLL seedling shoot apices, in combination with two different herbicide selections (phosphinothricin and glyphosate) is time consuming, inefficient, and produces chimeric shoots that often fail to yield transgenic progeny. Investigation of hygromycin as an alternative selection in combination with expression of green fluorescent protein indicated that transformation of NLL apical cells was not the rate limiting step to achieve transgenic shoot materials. In this research it was identified that despite ready transformation, apical cells were not competent to regenerate. However a deep and broad wounding procedure to expose underlying axillary shoot and vascular cells to Agrobacterium, in combination with delayed selection proved successful, increasing initial explants transformation efficiency up to 75?% and generating axillary shoots with significant transgenic content. Based on knowledge gained from studies of plant chimeras, further subculture of these initial axillary shoots will result in development of low chimeric transgenic materials with heritable content. Furthermore, the method was also tested successfully on other Lupinus species, faba bea and field pea. These results demonstrate that development of a high yielding transformation methodology for pulse legume crops is achievable.     

A specific inhibitor of lactate dehydrogenase overcame the resistance toward gemcitabine in hypoxic mesothelioma cells,and modulated the expression of the human equilibrative transporter-1

ABSTRACT

Malignant pleural mesothelioma (MPM) is a very hypoxic malignancy, and hypoxia has been associated with resistance towards gemcitabine. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis. Therefore we investigated the combination of a new LDH-A inhibitor (NHI-1) with gemcitabine in MPM cell lines. Under hypoxia (O₂ tension of 1%) the cell growth inhibitory effects of gemcitabine, were reduced, as demonstrated by a 5- to 10-fold increase in IC₅₀s. However, the simultaneous addition of NHI-1 was synergistic (combination index < 1). Flow cytometry demonstrated that hypoxia caused a G1 arrest, whereas the combination of NHI-1 significantly increased gemcitabine-induced cell death. Finally, the mRNA expression levels of the human equilibrative transporter-1 (hENT1) were significantly down-regulated under hypoxia, but treatment with NHI-1 was associated with a recovery of hENT1 expression. In conclusion, our data show that hypoxia increased MPM resistance to gemcitabine. However, cell death induction and modulation of the key transporter in gemcitabine uptake may contribute to the synergistic interaction of gemcitabine with the LDH-A inhibitor NHI-1 and support further studies for the rational development of this combination.